Publications by authors named "Axel Lorentz"

37 Publications

Probiotic Potential of Lactobacillus Species in Allergic Rhinitis.

Int Arch Allergy Immunol 2021 Apr 21:1-12. Epub 2021 Apr 21.

Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Since conventional allergy medication for asthma or allergic rhinitis (AR) can cause side effects which limit the patients' quality of life, it is of interest to find other forms of therapy. In particular, probiotic bacteria, such as Lactobacillus species, have shown anti-allergic effects in various mouse and human studies. For instance, administration of some Lactobacillus species resulted in nasal and ocular symptom relief and improvement of quality of life in children and adults suffering from rhinitis. Different changes in cytokine profiles, such as elevated Th1 and decreased Th2 cytokines, reduced allergy-related immunoglobulins and cell immigration have been found in both human and murine studies. Positive effects on patients like less activity limitations or fewer rhinitis episodes and longer periods free from asthma or rhinitis were also described following oral administration of Lactobacillus bacteria. However, it is still unclear how this type of lactic acid bacteria leads to changes in the immune system and thus inhibits the development of allergies or relieves their symptoms. This review gives an overview of current studies and draws conclusions concerning the usage of probiotic Lactobacillus strains in AR.
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http://dx.doi.org/10.1159/000515352DOI Listing
April 2021

Dietary restrictions modulate the gut microbiota: Implications for health and disease.

Nutr Res 2021 May 21;89:10-22. Epub 2021 Mar 21.

Institute of Nutritional Medicine, University of Hohenheim, D-70593 Stuttgart, Germany. Electronic address:

The health benefits of carefully restricting the energy intake in a strategic manner whilst avoiding malnutrition are widely discussed. In the recent years, the great impact of the gut microbiota on its host has been clarified more and more. Since the gut microbiota produces a number of metabolites and molecules that can affect host metabolism, modulating it with dietary restriction can influence the health and the progression of disease of its host on various levels. This review comprises 15 studies investigating the effect of different variants of fasting and caloric restriction on the gastrointestinal microbiome and its metabolites. The data suggest that changing the gut microbiota composition by dietary restriction has the potential to positively influence the progression of several diseases such as obesity, diabetes, neurological diseases or inflammatory bowel disease. Finally, the relevance of the findings for clinical practice is evaluated and approaches for future research are proposed.
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http://dx.doi.org/10.1016/j.nutres.2021.03.001DOI Listing
May 2021

Role of the microbiota in circadian rhythms of the host.

Chronobiol Int 2020 03 12;37(3):301-310. Epub 2020 Feb 12.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Life for meta-organisms is based on a strong relationship between gut bacteria and body cells. This review summarizes to what extent the microbiota can influence host circadian rhythms via a literature review on the topic. The results show that microbiota can influence the host's circadian gene expression through direct interactions via immunoreceptors and microbiota-derived metabolites, especially in peripheral tissues. Noteworthy metabolites that are only attributable to the microbiota are short-chain fatty acids and unconjugated bile acids. The microbiota also serves as a mediator for the interplay between the host's diet and circadian rhythmicity. This work furthermore displays that the microbiota is subject to diurnal variations in terms of structure and function and that the host and the host's diet influence these fluctuations. As most of these results originate in mouse models, we hope this work stimulates further research in human derived tissue to verify these conclusions.
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http://dx.doi.org/10.1080/07420528.2020.1726374DOI Listing
March 2020

Mast Cells in Irritable Bowel Syndrome: A Systematic Review.

J Gastrointestin Liver Dis 2019 Dec 9;28(4):463-472. Epub 2019 Dec 9.

Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Background And Aims: As mast cells (MC) serve as a link between mucosal immune activity and the nervous system, it is likely they also play a role in the pathogenesis of irritable bowel syndrome (IBS). This connection might be an important factor in the development of IBS-related symptoms.

Method: This overview comprises 36 case-control studies published from 2000 to 2018 that investigated MC in bowel biopsies of IBS patients and controls. The studies were selected from PubMed, EMBASE, Central, SemanticScholar by an electronic search, performed using RISMed R package.

Results: Significantly increased mucosal MC counts/or density in IBS patients compared to controls was observed in 30 studies. Five studies reported no differences and only one of the studies found a decreased amount of MC in an IBS patient. Furthermore, 15 studies made a statement regarding the correlation between the amount of MC and IBS associated symptoms. A significant positive correlation between MC count and IBS-associated symptoms was found in six investigations. A negative correlation was not reported.

Conclusion: The results support the idea that MC are involved in IBS pathophysiology as key players in the interplay between psychological factors and the frequency and severity of IBS symptoms.
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http://dx.doi.org/10.15403/jgld-229DOI Listing
December 2019

The Circadian Clock Drives Mast Cell Functions in Allergic Reactions.

Front Immunol 2018 6;9:1526. Epub 2018 Jul 6.

Institute for Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Allergic diseases are known to vary in the severity of their symptoms throughout the day/night cycle. This rhythmicity is also observed in mast cell function and responsiveness. Mast cells are key effector cells of allergic reactions and release cytokines, chemokines, and important inflammatory mediators such as histamine, which have been shown to display diurnal variation. Recent research clarified that mast cells are controlled by their internal clock-which is regulated by a specific set of clock genes-as well as external factors such as light sensed by the suprachiasmatic nuclei, hormonal status, or diet. Here, we give an overview of the connections between circadian clock, mast cells, and allergic disease. Further work aimed at studying the role of chronotherapy/chronomedicine should take into account this rhythmic nature of not only mast cells but also the immune responses generated by mast cell signaling.
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http://dx.doi.org/10.3389/fimmu.2018.01526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043637PMC
July 2018

Nobiletin acts anti-inflammatory on murine IL-10 colitis and human intestinal fibroblasts.

Eur J Nutr 2019 Jun 10;58(4):1391-1401. Epub 2018 Mar 10.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany.

Purpose: Inflammatory bowel disease (IBD) shows increasing prevalence over the last years. We propose that anti-inflammatory plant substances could be used as additional or alternative agents with good compliance in prevention and/or therapy of IBD and its complication intestinal fibrosis. We could recently show that the citrus flavonoid nobiletin acts anti-inflammatory on activation of intestinal mast cells. Here, we analysed the effects of nobiletin on inflammation and fibrosis in IL-10 colitis.

Methods: IL-10 and wild-type (WT) mice were orally treated with/without vehicle or nobiletin. Clinical symptoms of colitis and disease activity index (DAI) were assessed, and colon tissue was analysed for tissue damage, cellular infiltration, bowel wall thickness, mast cell number and degranulation, as well as collagen deposition as marker for fibrosis. Human intestinal fibroblasts (hiFB) were treated with nobiletin and the expression of collagen and pro-inflammatory cytokines was measured.

Results: Nobiletin treatment of IL-10 mice resulted in a reduction of clinical colitis symptoms and a longer survival time. In addition, histological scores of colitis were reduced compared to control groups. Mast cell number and degranulation was lower in nobiletin treated IL-10 mice, and correlated positively with DAI. As well, fibrotic marker of collagen deposition was reduced by nobiletin. In hiFB, the expression of collagen as well as of pro-inflammatory cytokines IL-6, TNF and CCL2 was down-regulated by nobiletin treatment.

Conclusions: Nobiletin decreases inflammatory symptoms and markers in murine colitis as well as fibrotic collagen deposition and expression. Thus, nobiletin could be a potential new agent in therapy of chronic colitis.
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http://dx.doi.org/10.1007/s00394-018-1661-xDOI Listing
June 2019

Basophil testing with CD63 in pollen-sensitized patients is independent of the circadian clock.

J Allergy Clin Immunol 2018 05 9;141(5):1906-1908. Epub 2018 Jan 9.

Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.10.048DOI Listing
May 2018

Cinnamon reduces inflammatory response in intestinal fibroblasts in vitro and in colitis in vivo leading to decreased fibrosis.

Mol Nutr Food Res 2017 09 12;61(9). Epub 2017 May 12.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Scope: Intestinal fibrosis, a complication of inflammatory bowel disease, is currently being addressed by surgery alone, with no adequate alternative therapy available for patients. We propose that anti-inflammatory plant substances like cinnamon extract (CE) or its main compound cinnamaldeyde (CA) could aid in therapy. We recently found CE reducing inflammation in murine colitis. Here, we analyzed effects of CE on fibrosis in IL-10 colitis.

Methods And Results: IL-10 and wild-type (WT) mice were orally treated with/without vehicle or CE. Colonic tissue was analyzed for collagen deposition and expression of matrix metalloproteinases (MMPs). Influence of CE or CA on expression and release of cytokines, and phosphorylation of IκB in LPS-activated fibroblasts was assessed. Fibrosis score and mRNA expression of MMPs were down-regulated in colonic tissue of CE-treated IL-10 mice. Fibroblasts treated with CE or CA showed reduced expression and release of IL-6, KC/C-X-C motif ligand (CXCL) 8, and C-C motif ligand (CCL) 2 in response to LPS-treatment. CE and CA appear to act via reducing phosphorylation of IκB.

Conclusions: Cinnamon decreases fibrotic symptoms and markers in murine colitis, and expression of inflammatory and fibrotic markers in hiFB. Thus, CE and CA could be potential anti-fibrotic agents in chronic colitis.
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http://dx.doi.org/10.1002/mnfr.201601085DOI Listing
September 2017

Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF.

Respir Res 2017 03 15;18(1):48. Epub 2017 Mar 15.

Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.

Mast cells are accumulated in advanced chronic obstructive pulmonary disease (COPD), and interleukin (IL)-17 signaling plays a role in disease progression. The expression, localization and functional relevance of IL-17 receptor (R)A and IL-17RC was explored in COPD by immunodetection, and functional assays.IL-17RA and IL-17RC was increased in very severe COPD, and expressed by mast cells. Increased secretion of the pro-angiogenic basic fibroblast growth factor and vascular endothelial growth factor was observed in vitro-maintained mast cells stimulated with IL-17A. Expression of these mediators was confirmed in end-stage COPD. Thus, accumulation of mast cells in COPD may contribute to vascular remodeling.
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http://dx.doi.org/10.1186/s12931-017-0534-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353957PMC
March 2017

Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells.

Eur J Nutr 2017 Jun 28;56(4):1609-1620. Epub 2016 Mar 28.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany.

Purpose: Allergic diseases with mast cells (MC) as main effector cells show an increased prevalence. MC also play an essential role in other inflammatory conditions. Therapeutical use of anti-inflammatory nutraceuticals directly targeting MC activation could be of interest for afflicted patients. Nobiletin and tangeretin are citrus peel polymethoxyflavones, a group of citrus flavonoids, possessing anticancer, antimetastatic, and anti-inflammatory activities. Here, we analyzed the effects of nobiletin/tangeretin on LPS- and IgE-mediated stimulation of human intestinal mast cells (hiMC).

Methods: MC isolated from human intestinal tissue were treated with different concentrations of nobiletin or tangeretin prior to stimulation via LPS/sCD14 or IgE-dependently. Degranulation, pro-inflammatory cytokine expression and phosphorylation of ERK1/2 were examined.

Results: Expression of CXCL8, CCL3, CCL4 and IL-1β in response to LPS-mediated stimulation was inhibited by nobiletin/tangeretin. hiMC activated IgE-dependently showed a reduced release of β-hexosaminidase and cysteinyl LTC in response to nobiletin, but not in response to tangeretin. Expression of CXCL8, CCL2, CCL3, CCL4 and TNF in IgE-dependently activated hiMC was decreased in a dose-dependent manner following treatment with nobiletin/tangeretin. IL-1β expression was only reduced by tangeretin. Compared to treatment with NF-κB inhibitor BMS345541 or MEK-inhibitor PD98059, nobiletin and tangeretin showed similar effects on mediator production. Phosphorylation of ERK1/2 upon IgE-mediated antigen stimulation was significantly suppressed by nobiletin and tangeretin.

Conclusions: Nobiletin and, to a lesser extent, tangeretin could be considered as anti-inflammatory nutraceuticals by reducing release and production of proinflammatory mediators in MC.
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http://dx.doi.org/10.1007/s00394-016-1207-zDOI Listing
June 2017

Cinnamon extract reduces symptoms, inflammatory mediators and mast cell markers in murine IL-10(-/-) colitis.

J Nutr Biochem 2016 Apr 11;30:85-92. Epub 2015 Dec 11.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593 Stuttgart, Germany. Electronic address:

Inflammatory bowel disease (IBD) shows an increasing prevalence and harm in western countries. Conventional therapies are associated with bad compliance and adverse side effects. Natural substances like cinnamon extract (CE) could be an additional therapy. We found recently that CE acts anti-inflammatory on mast cells - discussed of being relevant in IBD. Here, we analysed the effects of CE on murine IL-10(-/-) colitis as model for IBD. Mice were treated 12 weeks with or without CE in drinking water. Clinical scores and disease activity index were assessed. Colonic tissue samples were analysed for infiltration, tissue damage, bowel wall thickness, expression of pro-inflammatory mediators, mast cell proteases, tight junction proteins, and NF-κB signaling. Following treatment with CE, symptoms of murine colitis as well as increased infiltration of immune cells, tissue damage and bowel wall thickness in colon tissue of IL-10(-/-) mice were diminished significantly. MIP-2, TNF, IFNγ, CCL2, CCL3, CCL4 and IL-1β as well as MC-CPA, MCP-1 and MCP-4 were strongly upregulated in IL-10(-/-) mice compared to WT, but noteworthy not in CE group. Expression of tight junction proteins was not influenced by CE. Phosphorylation of IκB was slightly down-regulated in CE treated IL-10(-/-) mice compared to IL-10(-/-) controls. In summary, CE decreases inflammatory symptoms and expression of inflammatory markers in murine IL-10(-/-) colitis. CE has no influence on tight junction proteins, but seems acting via reducing pro-inflammatory mediators and recruitment of neutrophil granulocytes probably by inhibiting NF-κB signaling.
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http://dx.doi.org/10.1016/j.jnutbio.2015.11.015DOI Listing
April 2016

Diurnal variation of CD63 expression on activated blood basophils: a pilot study.

Ann Allergy Asthma Immunol 2016 Jan 28;116(1):77-8. Epub 2015 Oct 28.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2015.10.004DOI Listing
January 2016

Cinnamaldehyde is the main mediator of cinnamon extract in mast cell inhibition.

Eur J Nutr 2015 Dec 11;54(8):1297-309. Epub 2014 Dec 11.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany.

Purpose: In terms of their involvement in allergic and inflammatory conditions, mast cells (MC) can be promising targets for medical agents in therapy. Because of their good compliance and effectiveness, phytochemicals are of great interest as new therapeutic tools in form of nutraceuticals. We found recently that cinnamon extract (CE) inhibits mast cell activation. Here, we analysed the effects of a major compound of CE, cinnamaldehyde (CA), on mast cell activation.

Methods: Release of prestored and de novo synthesised mediators as well as expression of pro-inflammatory cytokines and mast cell-specific proteases were analysed in RBL-2H3 cells or in human mast cells isolated from intestinal tissue (hiMC) treated with CA prior to stimulation by FcεRI crosslinking or IONO/PMA. The results were compared with the corresponding effects of CE.

Results: Following treatment with CA, release of β-hexosaminidase in IgE-dependent or IgE-independent activated RBL-2H3 cells was down-regulated in a dose-dependent manner to about 10%. In hiMC, release of β-hexosaminidase was also significantly reduced, and release of LTC4 and CXCL8 was almost completely inhibited by CA. Moreover, IgE-mediated expression of CXCL8, CCL2, CCL3 and CCL4 in hiMC was significantly down-regulated by CA. With the exception of the expression of the mast cell proteases tryptase and chymase, the inhibitory effects of CA were very similar to the effects shown for CE treatment. The reducing effect of CA on mast cell mediators-seen for long- and for short-term incubations-could be related to particular signalling pathways as CA caused a down-regulation in ERK as well as PLCγ1 phosphorylation.

Conclusions: CA decreases release and expression of pro-inflammatory mast cell mediators. This inhibitory action is similar to the effects observed for CE indicating CA as the main active compound in CE leading to its anti-allergic properties.
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http://dx.doi.org/10.1007/s00394-014-0810-0DOI Listing
December 2015

IgE-dependent activation of human mast cells and fMLP-mediated activation of human eosinophils is controlled by the circadian clock.

Mol Immunol 2015 Mar 15;64(1):76-81. Epub 2014 Nov 15.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany. Electronic address:

Symptoms of allergic attacks frequently exhibit diurnal variations. Accordingly, we could recently demonstrate that mast cells and eosinophils - known as major effector cells of allergic diseases - showed an intact circadian clock. Here, we analyzed the role of the circadian clock in the functionality of mast cells and eosinophils. Human intestinal mast cells (hiMC) were isolated from intestinal mucosa; human eosinophils were isolated from peripheral blood. HiMC and eosinophils were synchronized by dexamethasone before stimulation every 4h around the circadian cycle by FcɛRI crosslinking or fMLP, respectively. Signaling molecule activation was examined using Western blot, mRNA expression by real-time RT-PCR, and mediator release by multiplex analysis. CXCL8 and CCL2 were expressed and released in a circadian manner by both hiMC and eosinophils in response to activation. Moreover, phosphorylation of ERK1/2, known to be involved in activation of hiMC and eosinophils, showed circadian rhythms in both cell types. Interestingly, all clock genes hPer1, hPer2, hCry1, hBmal1, and hClock were expressed in a similar circadian pattern in activated and unstimulated cells indicating that the local clock controls hiMC and eosinophils and subsequently allergic reactions but not vice versa.
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http://dx.doi.org/10.1016/j.molimm.2014.10.026DOI Listing
March 2015

Isolation and characterization of human intestinal mast cells.

Methods Mol Biol 2015 ;1220:163-77

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70599, Stuttgart, Germany,

Mast cells are granulated immune cells typically located at barrier sites of the body, such as the skin and the mucosa of the respiratory, urogenital, and gastrointestinal tract. They are well known for their capacity to participate in the orchestration of inflammatory and immune responses by releasing a broad array of mediators as a consequence of IgE-dependent and IgE-independent activation. Mast cells derive from myeloid progenitors, but in contrast to other myeloid cells, they leave the bone marrow in an immature state; therefore, mast cells are not visible in the blood under normal conditions. For full maturation, the tissue environment is necessary. Thus, mature mast cells can be only isolated from tissue such as skin or mucosal sites, which makes mast cell isolation complicated. This chapter describes methods to isolate, purify, and culture mast cells from the human intestinal mucosa. Human mucosal mast cells can be used to characterize their mediators and to study the mechanisms of human mast cell activation, signal transduction, and exocytosis in response to specific stimuli.
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http://dx.doi.org/10.1007/978-1-4939-1568-2_11DOI Listing
June 2015

Interferon-γ regulates growth and controls Fcγ receptor expression and activation in human intestinal mast cells.

BMC Immunol 2014 Jul 5;15:27. Epub 2014 Jul 5.

Department of Internal Medicine III, University Hospital Aachen, RWTH University, Aachen, Germany.

Background: Development and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4. The effects of the Th1-type cytokine IFN-γ on human MCs is less clear.

Results: Here, we analyzed the effects of IFN-γ on tissue-derived, mature human MCs. We found that INF-γ decreases proliferation, without affecting apoptosis in human intestinal MCs cultured in the presence of optimal concentrations of stem cell factor (SCF) or SCF and IL-4. However, in the absence of growth factors or at suboptimal concentrations of SCF, INF-γ promotes survival through inhibition of MC apoptosis. Interestingly, we found that INF-γ has no effect on FcϵRI expression and FcϵRI-mediated release of histamine and leukotriene (LT)C4, while it has profound effects on FcγR expression and activation. We show that intestinal MCs express FcγRI, FcγRIIa, and FcγRIIc, whereas FcγRIIb expression was found in only 40% of the isolates and FcγRIII was never detectable. INF-γ strongly increases FcγRI and decreases FcγRIIa expression. INF-γ-naïve MCs produce LTC4 but fail to degranulate upon crosslinking of surface-bound monomeric IgG. In contrast, INF-γ-treated MCs rapidly release granule-stored histamine in addition to de novo-synthesized LTC4.

Conclusion: In summary, we identify INF-γ as an important regulator of tissue-resident human MCs. IFN-γ displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing FcγRI expression and activation. These results emphasize the involvement of mucosal MCs in Th1-mediated disorders.
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http://dx.doi.org/10.1186/1471-2172-15-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227132PMC
July 2014

Soluble CD14 is essential for lipopolysaccharide-dependent activation of human intestinal mast cells from macroscopically normal as well as Crohn's disease tissue.

Immunology 2014 Oct;143(2):174-83

Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Mast cells are now considered sentinels in immunity. Given their location underneath the gastrointestinal barrier, mast cells are entrusted with the task of tolerating commensal microorganisms and eliminating potential pathogens in the gut microbiota. The aim of our study was to analyse the responsiveness of mast cells isolated from macroscopically normal and Crohn's disease-affected intestine to lipopolysaccharide (LPS). To determine the LPS-mediated signalling, human intestinal mast cells were treated with LPS alone or in combination with soluble CD14 due to their lack of surface CD14 expression. LPS alone failed to stimulate cytokine expression in human intestinal mast cells from both macroscopically normal and Crohn's disease tissue. Upon administration of LPS and soluble CD14, there was a dose- and time-dependent induction of cytokine and chemokine expression. Moreover, CXCL8 and interleukin-1β protein expression was induced in response to activation with LPS plus soluble CD14. Expression of cytokines and chemokines was at similar levels in mast cells from macroscopically normal and Crohn's disease-affected intestine after LPS/soluble CD14 treatment. In conclusion, human intestinal mast cells appear to tolerate LPS per se. The LPS-mediated activation in mast cells may be provoked by soluble CD14 distributed by other LPS-triggered cells at the gastrointestinal barrier.
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http://dx.doi.org/10.1111/imm.12299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172134PMC
October 2014

Immunomodulation of mast cells by nutrients.

Mol Immunol 2015 Jan 11;63(1):25-31. Epub 2014 Feb 11.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, D-70593 Stuttgart, Germany. Electronic address:

In the past decades an increasing prevalence of allergic disorders was observed in industrialized countries. Thus, it is necessary to develop adequate therapeutic and preventive strategies. Many of the conservative strategies possess diverse harmful side effects. Therefore agents with fewer side effects and a better compliance among afflicted patients would be of interest. Especially substances with natural origin acting immunomodulatory on mast cells - the key effector cells of allergic diseases - could be used. Among them there are components of the daily diet such as distinct fatty acids and amino acids as well as a range of secondary plant substances such as carotenoids, flavonoids and spices. These nutritional substances could be applied as nutraceuticals in the therapy of mast cell associated diseases. Many of these substances show inhibitory influences on the release of prestored mast cell mediators such as histamine or de novo expression of mast cell mediators such as cytokines and eicosanoids which are involved in the pathogenesis of mast cell associated inflammatory conditions like allergic reactions.
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http://dx.doi.org/10.1016/j.molimm.2013.12.005DOI Listing
January 2015

Obesity - a promoter of allergy?

Int Arch Allergy Immunol 2013 6;162(3):205-13. Epub 2013 Sep 6.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

The prevalence of both obesity and allergy has been increasing throughout the world, leading to the hypothesis that the two are linked to one another. This overview summarizes the results of 34 studies from 2002 to 2012 that investigated a possible contributing effect of increasing body mass on the development and prevalence of various atopic diseases. Obesity was found to clearly affect bronchial asthma. However, the correlation was stronger in the nonatopic asthma phenotype. Obesity was found to be associated with the development of atopic dermatitis in children only. No clear association was found between obesity and the prevalence of allergic rhinitis or allergic conjunctivitis or increased sensitization to food allergens. This review sums up our study results and discusses a possible role of obesity in the promotion of allergy and asthma.
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http://dx.doi.org/10.1159/000353972DOI Listing
December 2013

The circadian clock is functional in eosinophils and mast cells.

Immunology 2013 Dec;140(4):465-74

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Allergic diseases are frequently exacerbated between midnight and early morning, suggesting a role for the biological clock. Mast cells (MC) and eosinophils are the main effector cells of allergic diseases and some MC-specific or eosinophil-specific markers, such as tryptase or eosinophil cationic protein, exhibit circadian variation. Here, we analysed whether the circadian clock is functional in mouse and human eosinophils and MC. Mouse jejunal MC and polymorphonuclear cells from peripheral blood (PMNC) were isolated around the circadian cycle. Human eosinophils were purified from peripheral blood of non-allergic and allergic subjects. Human MC were purified from intestinal tissue. We found a rhythmic expression of the clock genes mPer1, mPer2, mClock and mBmal1 and eosinophil-specific genes mEcp, mEpo and mMbp in murine PMNC. We also found circadian variations for hPer1, hPer2, hBmal1, hClock, hEdn and hEcp mRNA and eosinophil cationic protein (ECP) in human eosinophils of both healthy and allergic people. Clock genes mPer1, mPer2, mClock and mBmal1 and MC-specific genes mMcpt-5, mMcpt-7, mc-kit and mFcεRI α-chain and protein levels of mMCPT5 and mc-Kit showed robust oscillation in mouse jejunum. Human intestinal MC expressed hPer1, hPer2 and hBmal1 as well as hTryptase and hFcεRI α-chain, in a circadian manner. We found that pre-stored histamine and de novo synthesized cysteinyl leukotrienes, were released in a circadian manner by MC following IgE-mediated activation. In summary, the biological clock controls MC and eosinophils leading to circadian expression and release of their mediators and, hence it might be involved in the pathophysiology of allergy.
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http://dx.doi.org/10.1111/imm.12157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839650PMC
December 2013

Relationship between allergy and cancer: an overview.

Int Arch Allergy Immunol 2012 20;159(3):216-25. Epub 2012 Jun 20.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Allergic diseases and malignancies cause a lot of morbidity, mortality and high costs for healthcare systems. An inverse association between allergy and cancer has been suspected for a long time, but even despite extensive research no general relationship has been determined. This review comprises 32 epidemiological studies published between 1960 and 2011 and draws conclusions regarding relationships between specific types of cancer and allergic diseases. On the one hand, inflammatory reactions in the course of allergy can support carcinogenesis but are limited to specific areas, whereas on the other hand systemic effects in terms of enhanced immunosurveillance can prevent cancer.
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http://dx.doi.org/10.1159/000338994DOI Listing
December 2012

The SNARE Machinery in Mast Cell Secretion.

Front Immunol 2012 5;3:143. Epub 2012 Jun 5.

Department of Nutritional Medicine, University of Hohenheim Stuttgart, Germany.

Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.
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http://dx.doi.org/10.3389/fimmu.2012.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367400PMC
August 2012

Combined arginine and glutamine decrease release of de novo synthesized leukotrienes and expression of proinflammatory cytokines in activated human intestinal mast cells.

Eur J Nutr 2013 Mar 20;52(2):505-12. Epub 2012 Apr 20.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Purpose: Glutamine and arginine modulate inflammatory responses of epithelial cells and monocytes. Here, we studied the response of human mast cells to pharmacological doses of arginine and glutamine.

Methods: Mast cells isolated from intestinal tissue were incubated with physiological doses of arginine (0.1 mmol/L) and glutamine (0.6 mmol/L) or with pharmacological doses of arginine (2 mmol/L) and glutamine (10 mmol/L) for 18 h. Following stimulation by IgE receptor crosslinking mast cell mediators were measured by enzymatic assay, ELISA, multiplex bead immunoassay, or real-time RT-PCR, and activation of intracellular signaling molecules was determined using proteome profiler array or immunoblotting.

Results: We found that the combined challenge of mast cells with pharmacological doses of arginine and glutamine caused a decrease in induced release of de novo synthesized leukotriene C(4) but not of pre-stored β-hexosaminidase. Moreover, we found reduced expression of chemokines monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein-1β (CCL4), IL-8 (CXCL8), and TNF in response to high doses of both amino acids. The anti-inflammatory effects of arginine and glutamine were associated with decreased activation levels of signaling molecules known to be involved in mast cell cytokine expression such as MAPK family members extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, and the protein kinase B (Akt).

Conclusion: Arginine and glutamine attenuate IgE-dependent human mast cell activation by decreasing lipid mediator release and expression of proinflammatory cytokines.
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http://dx.doi.org/10.1007/s00394-012-0353-1DOI Listing
March 2013

Central role of IL-6 and MMP-1 for cross talk between human intestinal mast cells and human intestinal fibroblasts.

Immunobiology 2012 Sep 4;217(9):912-9. Epub 2012 Jan 4.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Mast cells (MC) are key effector cells in allergic reactions but also involved in host defence, tissue remodeling, angiogenesis, and fibrogenesis. Here, we show that human intestinal fibroblasts (FB) suppress apoptosis in human intestinal MC dependent on IL-6. Intestinal FB produced IL-6 upon direct stimulation by intestinal MC in co-culture or by MC mediators such as TNF-α, IL-1β, tryptase or histamine. MC incubated with IL-6 survived for up to 3 weeks similar to MC co-cultured with FB and MC survival could be blocked by neutralizing anti-IL-6 Abs. Moreover, FB stimulated by MC mediators upregulated their expression of matrix metalloproteinase-1 (MMP-1), a key fibrolytic enzyme. Noteworthy, FB co-cultured with MC or treated with MMP-1 lost confluence and showed increased numbers of apoptotic cells. Our data indicate an intimate cross talk between mucosal MC and FB resulting in MC survival and induction of a fibrolytic rather than a profibrotic state in FB.
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http://dx.doi.org/10.1016/j.imbio.2012.01.003DOI Listing
September 2012

Human intestinal mast cells are a potent source of multiple chemokines.

Cytokine 2012 May 1;58(2):178-85. Epub 2012 Feb 1.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70599 Stuttgart, Germany.

Mast cells are key effector cells of immediate type allergic reactions. Upon activation they release a broad array of pre-stored and de novo synthesized mediators including immunoregulatory cytokines and chemokines. Here, we analyzed the chemokine profile expressed by mature human mast cells. Human mast cells were isolated from intestinal tissue and cultured with stem cell factor (SCF) in the presence or absence of IL-4 for 10d. Cells were stimulated by cross-linking of the high affinity IgE receptor (FcεRI) and/or by SCF. Chemokine and chemokine receptor mRNA expression was determined by real-time RT-PCR and chemokine release was measured by multiplex bead immunoassay. Out of 43 chemokines and 19 chemokine receptors human intestinal mast cells express 27 chemokines and nine chemokine receptors. Twelve chemokines (CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL18, CCL20, CXCL2, CXCL3, CXCL8, and XCL1) were more than four-fold up-regulated in response to FcεRI cross-linking. Combination of pre-culture with IL-4 and/or stimulation with SCF in addition to FcεRI cross-linking further increased the antigen-dependent expression of mRNA for most chemokines. In contrast, the expression of CCL20, CXCL2, and CXCL3 was strongly inhibited by IL-4 treatment. In conclusion, human intestinal mast cells express a broad spectrum of different chemokines underlining their important role as immunoregulatory cells. Furthermore, combined treatment with IL-4 and SCF increases the antigen-mediated expression and release of multiple chemokines, but IL-4 priming inhibits the expression of CCL20, CXCL2, and CXCL3.
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http://dx.doi.org/10.1016/j.cyto.2012.01.001DOI Listing
May 2012

SNAP-23 and syntaxin-3 are required for chemokine release by mature human mast cells.

Mol Immunol 2011 Oct 6;49(1-2):353-8. Epub 2011 Oct 6.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, D-70593 Stuttgart, Germany.

Mast cells play a key role in allergic and non-allergic disease by releasing a broad array of mediators. Soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNAREs) are necessary for membrane fusion events during mast cell exocytosis. We have shown recently that the SNAREs SNAP-23, syntaxin (STX)-4, vesicle associated membrane protein (VAMP)-7, and VAMP-8 are required for release of pre-stored histamine by mast cells. Here we analyze the involvement of different SNARE isoforms in exocytosis of de novo synthesized chemokines in mast cells isolated from human intestine. Following IgE receptor cross-linking, mast cells released substantial amounts of the chemokines CXCL8, CCL2, CCL3, and CCL4. Measurement of SNARE mRNA expression revealed only a moderate up-regulation of mRNA for STX-4 after stimulation for 1.5h. Inhibition of SNAP-23 or STX-3 abolished IgE mediated release of the chemokines CXCL8, CCL2, CCL3, and CCL4. In contrast, blocking of STX-2, or VAMP-3 did not affect the chemokine release. Inhibition of STX-4 or VAMP-8 resulted in a reduced release of CXCL8, but not of CCL2, CCL3, or CCL4. Inhibition of STX-6 attenuated the release of CXCL8 and CCL2, inhibition of VAMP-7 that of CCL3. In summary, STX-3 and SNAP-23 are crucial for the release of all chemokines in mature human mast cells whereas other SNAREs affect only release of selected chemokines.
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http://dx.doi.org/10.1016/j.molimm.2011.09.011DOI Listing
October 2011

Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells.

Mol Immunol 2011 Jan 23;48(4):546-52. Epub 2010 Nov 23.

Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593 Stuttgart, Germany.

Challenge of human mast cells with both stem cell factor (SCF) and IL-4 enhances antigen-dependent mediator release raising the assumption of intracellular crosstalk between the IL-4, SCF, and FcɛRI signaling pathways. Here, we analyzed the intracellular crosstalk of IL-4-, SCF-, and IgE-dependent activation pathways in mucosal mast cells isolated from human intestine. The release of β-hexosaminidase, leukotriene C(4), and IL-8, but not IL-6, was strongly enhanced in response to sequential challenge of mast cells with IL-4, SCF and FcɛRI cross-linking compared to stimulation by FcɛRI cross-linking alone. Previous studies revealed that MAPK and other serine/threonine kinases are involved in mast cell activation processes. Here we found that activation of mast cells by FcɛRI cross-linking alone results in phosphorylation of ERK and p38, but not of Akt. Stimulation with SCF alone also induced phosphorylation of ERK and p38, and additionally of Akt. IL-4 priming enhanced activation of ERK, but blocked activation of p38. Activation of p38 was required for IL-6 production explaining the inhibitory effect of IL-4 on IL-6 expression in human mast cells. Moreover, IL-4 priming that anteceded FcɛRI cross-linking induced activation of Akt. The combined challenge of mast cells with IL-4, SCF and FcɛRI cross-linking substantially up-regulated activation of Akt, whereas blocking of Akt inhibited the pronounced production and release of IL-8 in response to the three mast cell agonists. In summary, our data demonstrate that ERK, p38, and especially Akt play an important role in cross-linking IL-4 priming, SCF signaling, and IgE-dependent activation of mature human mast cells.
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http://dx.doi.org/10.1016/j.molimm.2010.10.010DOI Listing
January 2011

Corecognition of pathogens: an important trigger for mast cell response?

Authors:
Axel Lorentz

Int Arch Allergy Immunol 2011 21;154(3):183-4. Epub 2010 Sep 21.

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http://dx.doi.org/10.1159/000321104DOI Listing
April 2011

Long-term restricted feeding alters circadian expression and reduces the level of inflammatory and disease markers.

J Cell Mol Med 2011 Dec;15(12):2745-59

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.

The circadian clock in peripheral tissues can be entrained by restricted feeding (RF), a regimen that restricts the duration of food availability with no calorie restriction (CR). However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR. We measured circadian expression of clock genes, disease marker genes, metabolic factors and inflammatory and allergy markers in mouse serum, liver, jejunum and white adipose tissue (WAT) after long-term RF of 4 months. We found that circadian rhythmicity is more robust and is phase advanced in most of the genes and proteins tested under RF. In addition, average daily levels of some disease and inflammatory markers were reduced under RF, including liver Il-6 mRNA, tumour necrosis factor (TNF)-α and nuclear factor κB (NF-κB) protein; jejunum Arginase, Afp, Gadd45β, Il-1α and Il-1β mRNA, and interleukin (IL)-6 and TNF-α protein and WAT Il-6, Il-1β, Tnfα and Nfκb mRNA. In contrast, the anti-inflammatory cytokine Il-10 mRNA increased in the liver and jejunum. Our results suggest that RF may share some benefits with those of CR. As RF is a less harsh regimen to follow than CR, the data suggest it could be proposed for individuals seeking to improve their health.
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http://dx.doi.org/10.1111/j.1582-4934.2010.01160.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373423PMC
December 2011

Selective activation of human intestinal mast cells by Escherichia coli hemolysin.

J Immunol 2008 Jul;181(2):1438-45

Department of Nutritional Medicine and Immunology, University of Hohenheim, Stuttgart, Germany.

Mast cells (MCs) are recognized to play an important role in bacterial host defense in the murine system. In this study, we studied the interaction of human MCs, isolated from the intestine and purified to homogeneity, with different Escherichia coli and Shigella flexneri strains. We show that alpha-hemolysin (Hly)-producing E. coli strains induce the release of histamine, leukotrienes, and proinflammatory cytokines in intestinal MCs. In contrast, MCs were virtually unresponsive to S. flexneri and several Hly-negative E. coli strains, including the isogenic Hly-deficient mutants of Hly(+) strains. Hly(+) E. coli but not Hly(-) E. coli caused an increase in intracellular Ca(2+) levels. Blocking of extracellular Ca(2+) and of the calmodulin/calcineurin pathway by cyclosporin A inhibited the response to Hly(+) E. coli. Furthermore, inhibition of MAPKs p38 and ERK reduces activation of MCs by Hly(+) E. coli. In addition, using an ex vivo system, we directly record the histamine release by MCs located in the lamina propria after infection with Hly(+) E. coli. Our data indicate that human intestinal mast cells interact with selected Gram-negative bacteria, establish E. coli Hly as a factor regulating MC effector functions, and argue further for a role of human MCs in innate immunity.
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http://dx.doi.org/10.4049/jimmunol.181.2.1438DOI Listing
July 2008