Publications by authors named "Sathisha Upparahalli Venkateshaiah"

29 Publications

  • Page 1 of 1

Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy.

Life Sci Alliance 2021 Aug 28;4(8). Epub 2021 Jun 28.

Department of Medicine, Tulane Eosinophilic Disorders Centre, Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA, USA

Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.202000979DOI Listing
August 2021

Chronic inflammation promotes epithelial-mesenchymal transition-mediated malignant phenotypes and lung injury in experimentally-induced pancreatitis.

Life Sci 2021 Aug 25;278:119640. Epub 2021 May 25.

Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA. Electronic address:

Patients with chronic pancreatitis have an increased risk of pancreatic malignancy, but the mechanisms underlying this relationship are poorly understood. We developed a mouse model of chronic pancreatitis by treatment with a combination of cerulein and azoxymethane. In our model, we show that cerulein and azoxymethane treated mice develop pathological malignant phenotype and associated lung inflammation. We observed chronic pancreatitis-associated induction of proinflammatory cytokines such as interleukin-6, interleukin-15, and granulocyte-macrophage colony-stimulating factor, along with accumulation of macrophages and eosinophilic inflammation. We also observed eosinophils degranulation, pancreatic stellate cell activation-mediated epithelial-to-mesenchymal transition-associated proteins that display a pancreatic malignant phenotype including acinar-to-ductal metaplasia and acinar cell atrophy. We observed highly induced interleukin-15 that has been earlier reported to have a protective role against fibrosis and malignancy; therefore, further evaluated its role in our mouse model of chronic pancreatitis. We observed that introduction of recombinant interleukin-15 has indeed improve chronic pancreatitis-associated epithelial-to-mesenchymal transition-mediated development of a malignant phenotype in the mouse model of chronic pancreatitis. In conclusion, we present evidence that rIL-15 overexpression improves eosinophilic inflammation-induced epithelial-to-mesenchymal transition-mediated progression of pancreatic remodeling associated malignant phenotype and acute lung injury by inducing NKT cells and IFN-γ mediated innate immunity in experimental pancreatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2021.119640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245354PMC
August 2021

Blood mRNA levels of T cells and IgE receptors are novel non-invasive biomarkers for eosinophilic esophagitis (EoE).

Clin Immunol 2021 06 1;227:108752. Epub 2021 May 1.

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA. Electronic address:

Eosinophilic esophagitis (EoE) is often misdiagnosed as GERD; therefore, the goal of the current study is to establish a non-invasive diagnostic and monitoring biomarker that differentiated GERD from EoE. Reports indicates that IL-15 responsive iNKT cells and tissue specific IgE have a critical in EoE pathogenesis, not in GERD. Therefore, we tested the hypothesis that the panel of IL-15-responsive T cell and IgE receptors may be novel non-invasive biomarkers for EoE. Accordingly, the receptors of IL-15 responsive T cells (Vα24, Jα18, γδT, αβT) and IgE (FcεRI & FcεRII) were examined. The data indicates that blood mRNA levels of Vα24, Jα18, γδ T, αβ T and FcεRI are significantly reduced in EoE compared to the GERD patients and normal individuals. The ROC curve analysis indicated FcεRII, Jα18 and δ TCR are the positive predictors that discriminate EoE from GERD. Thus, these molecules will be a novel non-invasive diagnostic biomarker for EoE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2021.108752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215583PMC
June 2021

Eosinophils in the pathogenesis of pancreatic disorders.

Semin Immunopathol 2021 Jun 30;43(3):411-422. Epub 2021 Mar 30.

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA.

Eosinophils comprise approximately 1-4% of total blood leukocytes that reside in the intestine, bone marrow, mammary gland, and adipose tissues to maintain innate immunity in healthy individuals. Eosinophils have four toxic granules known as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), and upon degranulation, these granules promote pathogenesis of inflammatory diseases like allergy, asthma, dermatitis, and gastrointestinal disorders. Additionally, the role of eosinophils is underscored in exocrine disorders including pancreatitis. Chronic pancreatitis (CP) is an inflammatory disorder that occurs due to the alcohol consumption, blockage of the pancreatic duct, and trypsinogen mutation. Eosinophil levels are detected in higher numbers in both CP and pancreatic cancer patients compared with healthy individuals. The mechanistic understanding of chronic inflammation-induced pancreatic malignancy has not yet been reached and requires further exploration. This review provides a comprehensive summary of the epidemiology, pathophysiology, evaluation, and management of eosinophil-associated pancreatic disorders and further summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of eosinophilic pancreatitis (EP) and pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00281-021-00853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249347PMC
June 2021

Tacrolimus (FK506) treatment protects allergen-, IL-5- and IL-13-induced mucosal eosinophilia.

Immunology 2021 Jun 28;163(2):220-235. Epub 2021 Feb 28.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-β, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-β-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114213PMC
June 2021

Experimental Modeling of Eosinophil-Associated Diseases.

Methods Mol Biol 2021 ;2241:275-291

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA.

Eosinophils are an important subtype of leukocytes derived from bone marrow multipotent hematopoietic stem cells and represent about 1% of leukocytes in circulating blood. In homeostatic conditions, eosinophils reside in the intestine to maintain the balance of immune responses by communicating with gut microbes without causing inflammation. However, under the stressed or diseased condition, eosinophils degranulate, releasing their granule-derived cytotoxic proteins that are involved in inflammatory responses. Various eosinophil-associated inflammatory diseases are eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC), together called EGID, asthma, hypereosinophilic syndrome, and eosinophilic pneumonia (EP). Eosinophil degranulation results in the release of their four toxic proteins [major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN)] which promote disease pathogenesis. Pancreatitis is the inflammatory disease of the pancreas that arises due to blockage of the pancreatic duct, trypsinogen mutation, alcohol consumption, and repeated occurrence of pancreatitis leading to chronic pancreatitis (CP); subsequently some CP patients may also develop pancreatic cancer. The presence of eosinophils is now shown in various case reports with acute, recurrent acute, and chronic pancreatitis and pancreatic cancer indicating the role of eosinophils in the pathogenesis of various pancreatic inflammatory disorders. However, the details of eosinophil accumulation during pancreatic diseases are not well explored and need further attention. Overall, the chapter provides the current understanding of reported eosinophils associated with inflammatory diseases like EGID diseases, asthma, and pancreatic disorders, i.e., acute, chronic pancreatitis, and pancreatic cancer. This knowledge will be helpful for future studies to develop novel treatment options for the eosinophils associated diseases. Therefore, more efforts are needed to perform preclinical and clinical studies in this field for the successful development of eosinophil-targeting treatments for a variety of eosinophil-associated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1095-4_21DOI Listing
March 2021

IL-15 immunotherapy is a viable strategy for COVID-19.

Cytokine Growth Factor Rev 2020 08 6;54:24-31. Epub 2020 Jun 6.

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA, 70112, USA. Electronic address:

Coronavirus disease 2019 (COVID-19) is a pulmonary inflammatory disease induced by a newly recognized coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was detected for the first time in the city of Wuhan in China and spread all over the world at the beginning of 2020. Several millions of people have been infected with SARS-CoV-2, and almost 382,867 human deaths worldwide have been reported so far. Notably, there has been no specific, clinically approved vaccine or anti-viral treatment strategy for COVID-19. Herein, we review COVID-19, the viral replication, and its effect on promoting pulmonary fibro-inflammation via immune cell-mediated cytokine storms in humans. Several clinical trials are currently ongoing for anti-viral drugs, vaccines, and neutralizing antibodies against COVID-19. Viral clearance is the result of effective innate and adaptive immune responses. The pivotal role of interleukin (IL)-15 in viral clearance involves maintaining the balance of induced inflammatory cytokines and the homeostatic responses of natural killer and CD8 T cells. This review presents supporting evidence of the impact of IL-15 immunotherapy on COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cytogfr.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537239PMC
August 2020

Significance of Interleukin (IL)-15 in IgE associated eosinophilic Esophagitis (EoE).

Int J Basic Clin Immunol 2019 Dec 12;2:1-12. Epub 2019 Sep 12.

Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Background And Aim: IgE-mediated immune responses contribute to the pathogenesis of eosinophilic esophagitis (EoE). Interleukin (IL)-4 is a well-established cytokine involved in B cell activation, immunoglobulin (Ig) E production and isotype class switching. Earlier reports indicated that IL-15, B cells and IgE are induced in EoE pathogenesis. Therefore, we hypothesized that induced IL-15 and IgE may have a significant correlation in promoting EoE pathogenesis.

Methods: Accordingly, we performed ELISA, qPCR, flowcytometric and immunostaining analyses to examine IgE, B cells, eosinophils and mast cells in the esophagus of IL-15 overexpressed mice following EoE induction.

Results: Herein, we show that IL-15 overexpressed mice indeed have induced baseline IL-4, B cells, eosinophils, mast cells and IgE levels in the blood and esophagus. Further, we observed that IL-15 overexpressed mice show induction of IgE, and accumulation of degranulated eosinophils and mast cells in allergen-induced experimental EoE. Notably, despite induced blood IgE, esophageal eosinophilia is not induced in intestinal fatty acid binding protein IL-15 overexpressed gene (Fabpi-IL-15) mice. Fabpi-IL-15 transgenic mice showed IgE in the blood and intestine and intestinal eosinophilia, but no esophageal eosinophilia at baseline and comparable eosinophils in the esophagus of saline and allergen challenged Fabpi-IL-15 mice. Similarly, allergen challenged gene-deficient mice show reduced IgE and esophageal eosinophilia in allergen-induced experimental EoE.

Conclusions: Taken together, we for the first time provide direct evidence that tissue-specific IL-15 induced IgE mediated responses, not systemic IgE is critical in promoting EoE pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158884PMC
December 2019

Possible novel non-invasive biomarker for inflammation mediated pancreatic malignancy.

Int J Basic Clin Immunol 2020 25;3(1-4):1-8. Epub 2020 Dec 25.

Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Objectives: Pancreatic malignancy is a major public health problem worldwide and recent reports indicated that pancreatic cancer will be second most common cause of cancer-related deaths by the end of 2021. The cause of increasing death rate is due to the nonexistence of detection tools to early diagnose, poor prognosis, resistance to chemotherapy and also lack in understanding the mechanism of PDAC pathogenesis. Circulating tumor cells (CTCs) play a major role in metastatic step of intravasation and presence of these cells are strong prognostic marker for the progression of pancreatic malignancy in chronic pancreatitis (CP).

Goal: Identifying the novel CTCs in the chronic inflammation mediated experimental model for the progression of malignancy in CP.

Methods: We have performed flow cytometer and immunofluorescence analyses in the lymphoid and lung samples was performed o detect CTCs in the chronic inflammation induced mouse model CP.

Results: We report that induced SOX9 positive cells were observed in the blood, lymph node and spleen samples of cerulein with azoximethane (AOM) treated mouse model of CP compared to cerulein alone. Further, we provide evidence that early metastasis through the migration and homing of mega merged SOX9 and PDX ductal stem cells (CTCs) in the lungs of cerulein with AOM treated mice. These identified CTCs in experimentally induced malignant pancreatitis may serve as a novel finding to identify a non-invasive biomarker that needs to be examined in the blood of human pancreatic cancer.

Conclusions: Taken together, the presented data of identified mega merged SOX9 and PDX ductal stem cells (CTCs) may serve a non-invasive biomarker for the early detection of pancreatic malignancy and metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204699PMC
December 2020

Synergy of Interleukin (IL)-5 and IL-18 in eosinophil mediated pathogenesis of allergic diseases.

Cytokine Growth Factor Rev 2019 06 10;47:83-98. Epub 2019 May 10.

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States. Electronic address:

Eosinophils are circulating granulocytes that have pleiotropic effects in response to inflammatory signals in the body. In response to allergens or pathogens, exposure eosinophils are recruited in various organs that execute pathological immune responses. IL-5 plays a key role in the differentiation, development, and survival of eosinophils. Eosinophils are involved in a variety of allergic diseases including asthma, dermatitis and various gastrointestinal disorders (EGID). IL-5 signal transduction involves JAK-STAT-p38MAPK-NFκB activation and executes extracellular matrix remodeling, EMT transition and immune responses in allergic diseases. IL-18 is a classical cytokine also involved in immune responses and has a critical role in inflammasome pathway. We recently identified the IL-18 role in the generation, transformation, and maturation of (CD101CD274) pathogenic eosinophils. In, addition, several other cytokines like IL-2, IL-4, IL-13, IL-21, and IL-33 also contribute in advancing eosinophils associated immune responses in innate and adaptive immunity. This review discusses with a major focus (1) Eosinophils and its constituents, (2) Role of IL-5 and IL-18 in eosinophils development, transformation, maturation, signal transduction of IL-5 and IL-18, (3) The role of eosinophils in allergic disorders and (4) The role of several other associated cytokines in promoting eosinophils mediated allergic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cytogfr.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781864PMC
June 2019

Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders.

Immunology 2019 06 21;157(2):110-121. Epub 2019 Mar 21.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101 CD274 tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526631PMC
June 2019

Attenuation of Allergen-, IL-13-, and TGF-α-induced Lung Fibrosis after the Treatment of rIL-15 in Mice.

Am J Respir Cell Mol Biol 2019 07;61(1):97-109

1 Section of Pulmonary Medicine, Department of Medicine, Tulane Eosinophilic Disorder Center, New Orleans, Louisiana; and.

Endogenous IL-15 deficiency promotes lung fibrosis; therefore, we examined the effect of induced IL-15 in restricting the progression of lung fibrosis. Our objective in this work was to establish a novel therapeutic molecule for pulmonary fibrosis. Western blot, qPCR, and ELISA were performed on the lung tissues of IL-15-deficient mice, and recombinant IL-15 (rIL-15)-treated CC10-IL-13 and CC10-TGF-α mice, and allergen-challenged CC10-IL-15 mice were examined to establish the antifibrotic effect of IL-15 in lung fibrosis. We show that endogenous IL-15 deficiency induces baseline profibrotic cytokine and collagen accumulation in the lung, and pharmacological delivery of rIL-15 downregulates antigen-induced lung collagen, the profibrotic cytokines IL-13 and TGF-β1, and α-SMA and FSP1 cells in mice. To confirm that overexpression of IL-15 diminishes pulmonary fibrosis, we generated CC10-rtTA-tetO7-IL-15 transgenic mice and challenged them with antigen. antigen-challenged, doxycycline (DOX)-treated CC10-IL-15 transgenic mice exhibited decreased collagen accumulation, profibrotic cytokine (IL-13 and TGF-β1) expression, and α-SMA and FSP1 cells compared with IL-15-overexpressing mice not treated with DOX. Additionally, to establish that the antifibrotic effect of IL-15 is not limited to allergen-induced fibrosis, we showed that rIL-15 or IL-15 agonist treatment restricted pulmonary fibrosis even in CC10-IL-13 and CC10-TGF-α mice. Mechanistically, we show that T-helper cell type 17 suppressor IL-15-responsive RORγ T regulatory cells are induced in DOX-treated, allergen-challenged IL-15-overexpressing mice, which may be a novel pathway for restricting progression of pulmonary fibrosis. Taken together, our data establishes antifibrotic activity of IL-15 that might be a novel therapeutic molecule to combat the development of pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2018-0254OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604217PMC
July 2019

Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells.

J Mucosal Immunol Res 2018 2;2(1). Epub 2018 Jul 2.

Department of Medicine, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, USA.

A significant amount of correlational evidence has linked increased levels of IL-18 with allergic diseases in both human and animal models, and, as mast cells are major mediators of allergies, we hypothesized that IL-18 may have a role in mast cell biology. Rationale for our hypothesis is based on the evidence that IL-3 deficient mice are not devoid of mast cells, even though IL-3 is a major differentiation and growth factor for mast cells. Accordingly, we cultured IL-18 responsive bone marrow CD34+ cells under a variety of conditions and cytokine combinations to examine mast cell differentiation and maturation using flow cytometry, quantitative PCR,and immunostaining techniques. Additionally, mast cell transformation and maturation were also analysed using endogenous IL-18 gene-deficient or Fabpi-IL-18 overexpressed mice. Our data indicate that both IL-3 and IL-18 exposed CD34+ bone marrow precursors differentiate and mature into mast cells. Further, we observed that IL-18 differentiates mast cells independent of IL-3, as pharmacologic blockade of IL-3 does not prevent IL-18-driven mast cell differentiation. Further, we found that endogenous IL-18 deficiency restricts maturation of IL-3 generated mast cells and IL-18 derived mast cells require IL-3 for their survival. Additionally, we observed IL-18 intestinal overexpression promotes tissue mast cell proliferation and mucosal mast cell development. Taken together, we provide the evidence that IL-18 has an important contributory role in mast cell differentiation, maturation and development of mucosal mast cells. Therefore, IL-18 may represent a future pharmacologic target for treating mast cell-mediated allergic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248340PMC
July 2018

A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils.

J Allergy Clin Immunol 2018 07 2;142(1):301-305. Epub 2018 Mar 2.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center (TEDC), Tulane University School of Medicine, New Orleans, La. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035772PMC
July 2018

Chronic Pancreatitis Associated Acute Respiratory Failure.

MOJ Immunol 2017 8;5(2). Epub 2017 Feb 8.

Department of Medicine and Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, USA.

Pancreatitis is a condition characterized by parenchymal inflammation of the pancreas, which is often associated with lung injury due to low level of oxygen and the condition is termed as acute pancreatitis-associated lung injury (APALI). Clinical reports indicated that ~ 20% to 50% of patients from low oxygen levels in blood with acute respiratory distress syndrome (ARDS). ARDS is a severe form of acute lung injury (ALI), a pulmonary disease with impaired airflow making patients difficult to breathe. ALI is frequently observed in patients with severe acute pancreatitis. Approximately one third of severe pancreatitis patients develop acute lung injury and acute respiratory distress syndrome that account for 60% of all deaths within the first week. The major causes of ALI and ARDS are sepsis, trauma, aspiration, multiple blood transfusion, and most importantly acute pancreatitis. The molecular mechanisms of ALI and ARDS are still not well explored, but available reports indicate the involvement of several pro-inflammatory mediators including cytokines (TNF-α, IL-1β, IL-6) and chemokines [like interleukin-8 (IL-8) and macrophage inhibitory factor (MIF)], as well as macrophage polarization regulating the migration and pulmonary infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the pulmonary parenchyma. Acute lung injury and acute respiratory distress syndrome in acute pancreatitis remains an unsolved issue and needs more research and resources to develop effective treatments and therapies. However, recent efforts have tested several molecules in an experimental model and showed promising results as a treatment option. The current review summarized the mechanism that is operational in pancreatitis-associated acute respiratory failure and respiratory distress syndrome in patients and current treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15406/moji.2017.05.00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793936PMC
February 2017

Intestinal overexpression of interleukin (IL)-15 promotes tissue eosinophilia and goblet cell hyperplasia.

Immunol Cell Biol 2018 03 29;96(3):273-283. Epub 2017 Dec 29.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.

Interleukin (IL)-15 overexpression in eosinophilic gastrointestinal disorders is reported, but IL-15's role in promoting eosinophilic gastroenteritis is largely unknown. Therefore, we generated enterocyte-overexpressed IL-15 transgenic mice using Fabpi promoter. The Fabpi-IL-15 (iIL-15) transgenic mice showed induced IL-15 levels in the jejunum with a marked increase in jejunum eosinophils. However, no induction of eosinophilia in the blood or any other gastrointestinal segment was observed. Eosinophilia in the jejunum villus was substantially higher in iIL-15 mice compared to wild-type mice. In addition, goblet cell hyperplasia was also observed in the jejunum of iIL-15 mice. Furthermore, a significant correlation between induced IL-15 transcript and the IL-18 transcripts was observed. Therefore, to further understand the role of IL-18 in IL-15 mice associated gastrointestinal disorders, we generated iIL-15/IL-18Rα mice. Using these mice, we found that IL-18 has an important role in promoting IL-15-induced eosinophilia. As intestinal IL-15 overexpression is reported in food intolerance, we examined OVA intolerance in iIL-15 mice. The OVA-sensitized and challenged iIL-15 mice experienced weight loss, diarrhea and eosinophilia in the jejunum. Taken together, our findings demonstrate that intestinal IL-15 overexpression induces IL-18-dependent eosinophilia and immunoglobulins in the intestine that promotes food allergic responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866184PMC
March 2018

Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE).

Cell Mol Gastroenterol Hepatol 2018 22;5(1):99-100.e7. Epub 2017 Sep 22.

Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, Louisiana.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736881PMC
September 2017

Food-Induced Acute Pancreatitis.

Dig Dis Sci 2017 12 30;62(12):3287-3297. Epub 2017 Oct 30.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.

Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-017-4817-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718054PMC
December 2017

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases.

Cytokine Growth Factor Rev 2017 Dec 23;38:37-48. Epub 2017 Sep 23.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address:

Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cytogfr.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705463PMC
December 2017

Role of eosinophils in the initiation and progression of pancreatitis pathogenesis.

Am J Physiol Gastrointest Liver Physiol 2018 02 21;314(2):G211-G222. Epub 2017 Sep 21.

Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana.

Eosinophilic pancreatitis (EP) is reported in humans; however, the etiology and role of eosinophils in EP pathogenesis are poorly understood and not well explored. Therefore, it is interesting to examine the role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Accordingly, we performed anti-major basic protein immunostaining, chloroacetate esterase, and Masson's trichrome analyses to detect eosinophils, mast cells, and collagen in the tissue sections of mouse and human pancreas. Induced eosinophils accumulation and degranulation were observed in the tissue sections of human pancreatitis, compared with no eosinophils in the normal pancreatic tissue sections. Similarly, we observed induced tissue eosinophilia along with mast cells and acinar cells atrophy in cerulein-induced mouse model of chronic pancreatitis. Additionally, qPCR and ELISA analyses detected induced transcript and protein levels of proinflammatory and profibrotic cytokines, chemokines like IL 5, IL-18, eotaxin-1, eotaxin-2, TGF-β1, collagen-1, collagen-3, fibronectin, and α-SMA in experimental pancreatitis. Mechanistically, we show that eosinophil-deficient GATA1 and endogenous IL-5-deficient mice were protected from the induction of proinflammatory and profibrotic cytokines, chemokines, tissue eosinophilia, and mast cells in a cerulein-induced murine model of pancreatitis. These human and experimental data indicate that eosinophil accumulation and degranulation may have a critical role in promoting pancreatitis pathogenesis including fibrosis. Taken together, eosinophil tissue accumulation needs appropriate attention to understand and restrict the progression of pancreatitis pathogenesis in humans. NEW & NOTEWORTHY The present study for the first time shows that eosinophils accumulate in the pancreas and promote disease pathogenesis, including fibrosis in earlier reported cerulein-induced experimental models of pancreatitis. Importantly, we show that GATA-1 and IL-5 deficiency protects mice form the induction of eosinophil active chemokines, and profibrotic cytokines, including accumulation of tissue collagen in an experimental model of pancreatitis. Additionally, we state that cerulein-induced chronic pancreatitis is independent of blood eosinophilia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpgi.00210.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866419PMC
February 2018

Regulatory effects of IL-15 on allergen-induced airway obstruction.

J Allergy Clin Immunol 2018 03 9;141(3):906-917.e6. Epub 2017 Jun 9.

Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, La. Electronic address:

Background: Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis.

Objective: We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine.

Methods: Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA.

Results: We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ- and IL-10-producing regulatory CD4CD25 forkhead box p3 (Foxp3) T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model.

Conclusion: We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2017.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723242PMC
March 2018

Pathogenic mechanisms of pancreatitis.

World J Gastrointest Pharmacol Ther 2017 Feb;8(1):10-25

Murli Manohar, Alok Kumar Verma, Sathisha Upparahalli Venkateshaiah, Nathan L Sanders, Anil Mishra, Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, United States.

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, ., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4292/wjgpt.v8.i1.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292603PMC
February 2017

Significance of Eosinophils in Promoting Pancreatic malignancy.

J Gastroenterol Pancreatol Liver Disord 2017 2;5(1). Epub 2017 Oct 2.

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, USA.

Background: Several reports indicate that eosinophils are induced in chronic pancreatitis including patients with pancreatic malignancy. However, significance of eosinophilic pancreatitis (EP) is poorly understood and unexplored.

Aim: Accumulation and degranulation of eosinophils promote pancreatic fibrosis and malignancy.

Method: Human pancreatic tissue biopsy samples including chronic pancreatitis (n=3), malignant (n=4), non-malignant (n=3), and normal (n=3) were used for H&E, anti-MBP staining, anti-tryptase staining, anti-IgE staining and Mason's trichrome staining.

Results: We show induced eosinophils and degranulated eosinophils indicated by the presence of anti-MBP stained extracellular granules in the malignant pancreatic (pancreatic cancer) and non-malignant human pancreatic tissues. A comparable number of eosinophils were observed in non-malignant and malignant pancreatic tissue sections, but the sections differed in degranulated eosinophils and the presence of extracellular granules. Additionally, induced mast cells and tissue-specific IgE positive cells were also detected in the tissue sections of malignant pancreatitis patients compared to non-malignant human pancreatic patients. Tissue-specific IgE induction is critical for the degranulation of eosinophils and mast cells that may lead to increased accumulation of collagen in malignant compared to non-malignant human pancreatic tissue samples. We show a large number of anti-tryptase stained extracellular granules in the tissue sections of malignant pancreatic cancer patients. Both IgE and eosinophil major basic proteins (MBP) are reported for the activation and degranulation of mast cells in tissues.

Conclusion: Taken together, our investigation concludes that eosinophils and mast cells accumulation and degranulation are critical in promoting pancreatitis pathogenesis that may lead to the development of pancreatic fibrosis and malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945222PMC
http://dx.doi.org/10.15226/2374-815X/5/1/001109DOI Listing
October 2017

Possible Noninvasive Biomarker of Eosinophilic Esophagitis: Clinical and Experimental Evidence.

Case Rep Gastroenterol 2016 Sep-Dec;10(3):685-692. Epub 2016 Nov 14.

Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, New Orleans, LA, USA.

Eosinophilic esophagitis (EoE) diagnosis and follow-up response to therapy is based on repeated endoscopies and histological examination for eosinophils/HPF. The procedure is invasive and risky in particular for the pediatric population. Presently, there is no highly sensitive and specific noninvasive blood test available to monitor the disease pathogenesis. Reports indicate the expression of PDL1 (CD274) on the eosinophils in allergic patients. Herein, we report that CD274-expressing and -nonexpressing eosinophils were detected in both examined pediatric and adult EoE patients. We show that CD274 expression on blood eosinophils and blood mRNA expression levels increase in the blood of EoE patients and decrease following treatment. These observations are consistent with the esophageal eosinophilia of before and after treatment in both examined patients. These two clinical and experimental analysis reports provide the possibility that the CD274 mRNA and CD274-expressing esinophil levels may be novel possible noninvasive biomarkers for EoE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000452654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126594PMC
November 2016

Elements Involved In Promoting Eosinophilic Gastrointestinal Disorders.

J Genet Syndr Gene Ther 2015 Aug 7;6(2). Epub 2015 Aug 7.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, 1430 Tulane Avenue, New Orleans, LA 70112.

Eosinophilic gastrointestinal disorders (EGID) are food allergen-induced allergic gastrointestinal disorders, characterized by accumulation of highly induced eosinophils in different segments of gastrointestinal tract along with eosinophil microabssess and extracellular eosinophilic granules in the epithelial layer. EGID are both IgE- and cell-mediated group of diseases that include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC). Despite the increased incidences and considerable progress made in understanding EGID pathogenesis. The mechanism is still not well understood. It has been shown that IL-4, IL-5, IL-13, IL-15, IL-18, eotaxin-1, eotaxin-2 and eotaxin-3 play a critical role in EGID pathogenesis. Currently, the only criterion for diagnosing EoE, EGE and EC are repetitive endoscopic and histopathological evaluation of biopsies along with other clinical characteristics/manifestations. Antigen elimination and corticosteroid therapies are the most effective therapies currently in practice for the treatment of EGID. The cytokines (anti-IL-5 and anti-IL-13) therapy trials were not very successful in case of EoE. Most recently, a clinical trial using anti-IL-13 reported only 60% reduced esophageal eosinophilia without achieving primary endpoint. This clinical finding is not surprising and is in accordance with our earlier report indicating that IL-13 is not critical in the initiation of EoE. Notably, EGID still has no reliable noninvasive diagnostic biomarkers. Hence, there is a great necessity to identify novel noninvasive diagnostic biomarkers that can easily diagnose EGID and provide an effective therapy. Now, the attention is required to target cell types like iNKT cells that produce eosinophil active cytokines and is found induced in the pathogenesis of both experimental and human EoE. iNKT cell neutralization is shown to protect allergen-induced EoE in experimental model. In this review, we have discussed the key elements that are critical in the disease initiation, progression, pathogenesis and important for future diagnostic and therapeutic interventions for EGID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/2157-7412.1000265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102338PMC
August 2015

Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease.

Am J Hematol 2013 Jun 28;88(6):463-71. Epub 2013 Mar 28.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. Am. J. Hematol. 88:463-471, 2013. © 2013 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.23433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971999PMC
June 2013

NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity.

Exp Hematol 2013 Jun 19;41(6):547-557.e2. Epub 2013 Feb 19.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is not only essential for cellular metabolism; it also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide. Coculture of primary MM cells with osteoclasts induced PBEF1 upregulation in both cell types. PBEF1 expression was higher in experimental myelomatous bones than in nonmyelomatous bone and higher in MM patients' plasma cells than in healthy donors' counterparts. APO866 is a specific PBEF1 inhibitor known to deplete cellular NAD(+). APO866 at low nanomolar concentrations inhibited growth of primary MM cells or MM cell lines cultured alone or cocultured with osteoclasts and induced apoptosis in these cells. PBEF1 activity and NAD(+) content were reduced in MM cells by APO866, resulting in lower activity of PARP-1 and SIRT-1. The inhibitory effect of APO866 on MM cell growth was abrogated by supplementation of extracellular NAD(+) or NAM. APO866 inhibited NF-κB activity in osteoclast precursors and suppressed osteoclast formation and activity. PBEF1 knockdown similarly inhibited MM cell growth and osteoclast formation. In the SCID-rab model, APO866 inhibited growth of primary MM and H929 cells and prevented bone disease. These findings indicate that MM cells and osteoclasts are highly sensitive to NAD(+) depletion and that PBEF1 inhibition represents a novel approach to target cellular metabolism and inhibit PARP-1 and bone disease in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exphem.2013.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648259PMC
June 2013

Galectin-3 in urine of cancer patients: stage and tissue specificity.

J Cancer Res Clin Oncol 2009 Mar 3;135(3):355-63. Epub 2008 Oct 3.

Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore, 570020, India.

Purpose: Galectin-3 has been implicated in advanced stage of cancer disease. In the current study we examined the possibility of urinary galectin-3 levels to stage cancer disease and to follow up therapy.

Experimental Design: Urine was collected from all types of cancer patients at different stages including patients undergoing radio/chemotherapy. Galectin-3 level was determined by anti-galectin-3 based ELISA and agglutination assays. Immunoblotting and purification on lactosyl affinity column further confirmed the presence of galectin-3.

Results: Cancer samples exhibited stage dependent expression of galectin-3 approx. ranging from 1.0 to 3.3, 4.4 to 5.4, 5.4 to 24.7, 13.1 to 31.9, 13.9 to 32.9 ng/mg C (creatinine) for stage I-V, respectively, at P approximately <0.05 level. Galectin-3 levels were decreased by approx. threefolds after 5th day of therapy.

Conclusions: Sample collection being simple and non-invasive, urinary galectin-3 may be used as a potential diagnostic tool for monitoring or follow up of the stage of cancer disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-008-0481-4DOI Listing
March 2009

Antioxidant activity of indigenous edible mushrooms.

J Agric Food Chem 2006 Dec;54(26):9764-72

Department of Fruit and Vegetable Technology and Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore 570 020, India.

The current study was undertaken to measure the antioxidant potential from water and methanolic extracts of fruiting bodies of 23 species of mushrooms naturally grown in different geographic locations of India. The antioxidant ability of each species was analyzed for the total antioxidative status, employing multimechanistic antioxidative assays such as inhibition of lipid peroxidation, determination of reducing power, and free radical scavenging ability, in addition to determination of total phenolics and identification of phenolic acids by HPLC analysis, because the phenolics are known to contribute largely to antioxidant potential. The antioxidant potential of these varieties of mushrooms was determined by summing the antioxidative activity (AOA) of each variety by varied antioxidant assays followed by determining the relative percent of AOA defined as the "antioxidant index" (AI). On the basis of the AI, the mushroom species were graded as very high, high, moderate, and low. Termitomyces heimii was identified as the best variety, which showed 100% AI with 37 mg of phenolics/g of sample, 418 units of reducing power ability (RPA)/g, and an IC50 of approximately 1.1 mg (dry weight)/mL, free radical scavenging activity (FRS) in the water extract followed by 11.2 mg of phenolics/g, 275 units of RPA/g, and an IC50 of approximately 2.7 mg (dry weight)/mL of FRS in the methanolic extract. Following T. heimii, Termitomyces mummiformis exhibited an AI of 86% within the "very high" group. Potent inhibitions of lipid peroxidation of approximately 100 and 69% was also observed in T. heimii and T. mummiformis, respectively. Water extracts ranged from 34 to 49% and methanolic extracts varied from 20 to 32% on dry weight of mushroom fruiting body. Total phenolic compounds were higher in the water extracts (2-37 mg/g) than in methanolic extract (0.7-11.2 mg/g). The AOA measured in the water extract was better than that from the methanolic extract. HPLC analysis of phenolic acids in the two mushroom species, namely, T. heimii and T. mummiformis, displaying maximum AOA potential indicated a preponderance of tannic acid, gallic acid, protocatacheuic acid, and gentisic acid. Studies thus provide the precise antioxidant status of 23 indigenous species of mushrooms, which can serve as a useful database for the selection of mushrooms for the function of preparation of mushroom-based nutraceutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jf0615707DOI Listing
December 2006
-->