Publications by authors named "Marcelo De Franco"

37 Publications

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.

J Immunol Res 2019 31;2019:5298792. Epub 2019 Mar 31.

Laboratory of Immunogenetics, Instituto Butantan, São Paulo, Brazil.

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-, IL-1, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.
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http://dx.doi.org/10.1155/2019/5298792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462334PMC
August 2019

Early Peritoneal CC Chemokine Production Correlates with Divergent Inflammatory Phenotypes and Susceptibility to Experimental Arthritis in Mice.

J Immunol Res 2019 26;2019:2641098. Epub 2019 Feb 26.

Immunogenetics Laboratory, Butantan Institute, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil.

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.
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http://dx.doi.org/10.1155/2019/2641098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413398PMC
July 2019

miRNA Expression and Interaction with Genes Involved in Susceptibility to Pristane-Induced Arthritis.

J Immunol Res 2018 16;2018:1928405. Epub 2018 Dec 16.

Laboratório de Imunogenética, Instituto Butantan, São Paulo 05503000, Brazil.

Pristane-induced arthritis (PIA) in mice is an experimental model that resembles human rheumatoid arthritis, a chronic autoimmune disease that affects joints and is characterized by synovial inflammation and articular cartilage and bone destruction. AIRmax and AIRmin mouse lines differ in their susceptibility to PIA, and linkage analysis in this model mapped arthritis severity QTLs in chromosomes 5 and 8. miRNAs are a class of small RNA molecules that have been extensively studied in the development of arthritis. We analyzed miRNA and gene expression profiles in peritoneal cells of AIRmax and AIRmin lines, in order to evaluate the genetic architecture in this model. Susceptible AIRmax mice showed higher gene (2025 vs 1043) and miRNA (240 vs 59) modulation than resistant AIRmin mice at the onset of disease symptoms. miR-132-3p/212-3p, miR-106-5p, miR-27b-3p, and miR-25-3p were among the miRNAs with the highest expression in susceptible animals, showing a negative correlation with the expression of predicted target genes (, , and ). Our study showed that global gene and miRNA expression profiles in peritoneal cells of susceptible AIRmax and resistant AIRmin lines during pristane-induced arthritis are distinct, evidencing interesting targets for further validation.
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http://dx.doi.org/10.1155/2018/1928405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311868PMC
April 2019

Phagocytosis of Leptospira by leukocytes from mice with different susceptibility to leptospirosis and possible role of chemokines.

BMC Microbiol 2019 01 7;19(1). Epub 2019 Jan 7.

Laboratório de Bacteriologia, Instituto Butantan, São Paulo, Brazil.

Background: Leptospirosis is a widespread zoonosis caused by pathogenic prokaryotic microbes of the genus Leptospira. Although there are several reports in the literature, host-pathogen interaction is still poorly understood. The role of chemokine expression is important on the chemotaxis, activation and regulation of immune cells. Recent studies have shown that their expression profiles play an important role on the severity of leptospirosis outcome. We evaluated the phagocytosis of Leptospira by spleens cells from C3H/HeJ, C3H/HePas and BALB/c mouse strains, respectively susceptible, intermediate and resistant to leptospirosis, and by RAW 264.7 macrophages. Besides, we evaluated the effects of CCL2 treatment on the phagocytosis. The cells were incubated with or without CCL2 chemokine, and infected with virulent L. interrogans sv Copenhageni. Cells and culture supernatants were collected for subsequent analysis.

Results: The number of leptospires was higher in BALB/c cells, CCL2 pre-treated or only infected groups, when compared to C3H/HeJ and C3H/HePas cells. Indeed, CCL2 activation did not interfere in the phagocytosis of Leptospira. Expression of chemokines CXCL5 and CCL8 levels were significantly inhibited in infected BALB/c cells when compared to the non-infected control.

Conclusions: Higher ability to phagocytosis and early modulation of some chemokines correlated with the resistance to leptospirosis disease. Exposure to CCL2 did not interfere on phagocytosis of Leptospira in our experimental conditions, but acted in the modulation of chemokines expression during Leptospira infection.
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http://dx.doi.org/10.1186/s12866-018-1371-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323685PMC
January 2019

Alveolar bone healing in mice genetically selected in the maximum (AIRmax) or minimum (AIRmin) inflammatory reaction.

Cytokine 2019 02 22;114:47-60. Epub 2018 Dec 22.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil. Electronic address:

The exact role of inflammatory immune response in bone healing process is still unclear, but the success of the alveolar bone healing process seems to be associated with a moderate and transitory inflammatory response, while insufficient or exacerbated responses seems to have a detrimental influence in the healing outcome. In this context, we performed a comparative analysis of mice strains genetically selected for maximum (AIRmax) or minimum (AIRmin) acute inflammatory response to address the influence of inflammation genes in alveolar bone healing outcome. Experimental groups comprised 8-week-old male or female AIRmax and AIRmin submitted to extraction of upper right incisor, and evaluated at 0, 3, 7, 14 and 21 days after upper incision extraction by micro-computed tomography (μCT), histomorphometry, birefringence, immunohistochemistry and molecular (PCRArray) analysis. Overall, the results demonstrate a similar successful bone healing outcome at the endpoint was evidenced in both AIRmin and AIRmax strains. The histormophometric analysis reveal a slight but significant decrease in blood clot and inflammatory cells density, as well a delay in the bone formation in AIRmax strain in the early times, associated with a decreased expression of BMP2, BMP4, BMP7, TGFb1, RUNX2, and ALP. The evaluation of inflammatory cells nature reveals increased GR1+ cells counts in AIRmax strain at 3d, associated with increased levels of neutrophil chemoattractants such as CXCL1 and CXCL2, and its receptor CXCR1, while F4/80+ cell prevails in AIRmin strain at 7d. Also, our results demonstrate a relative predominance of M2 macrophages in AIRmin strain, associated with an increased expression of ARG1, IL10, TGFb, while M1 macrophages prevail in AIRmax, which parallel with increased IL-1B, IL-6 and TNF expression. At late repair stage, AIRmax presents evidences of increased bone remodeling, characterized by increased density of blood vessels and osteoclasts in parallel with decreased bone matrix density, as well increased levels of MMPs, osteoclastogenic and osteocyte markers. In the view of contrasting inflammatory and healing phenotypes of AIRmin and AIRmax strains in other models, the unpredicted phenotype observed suggests the existence of specific QTLs (Quantitative trait loci) responsible for the regulation 'sterile' inflammation and bone healing events. Despite the similar endpoint healing, AIRmax strain delayed repair was associated with increased presence of neutrophils and M1 macrophages, supporting the association of M2 cells with faster bone healing. Further studies are required to clarify the elements responsible for the regulation of inflammatory events at bone healing sites, as well the determinants of bone healing outcome.
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http://dx.doi.org/10.1016/j.cyto.2018.11.027DOI Listing
February 2019

Mice Selected for Acute Inflammation Present Altered Immune Response during Pristane-Induced Arthritis Progression.

Biomed Res Int 2018 8;2018:1267038. Epub 2018 Oct 8.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Mouse lines selected for maximal (AIRmax) or minimal acute inflammatory reaction (AIRmin) were used to characterize the immune response and the influence of genetic background during pristane-induced arthritis (PIA). Susceptible AIRmax mice demonstrated exacerbated cellular profiles during PIA, with intense infiltration of lymphocytes, as well as monocytes/macrophages and neutrophils, producing higher levels of IL-1, IFN-, TNF-, IL-10, total IgG3, and chemokines. Resistant AIRmin mice controlled cell activation more efficiently than the AIRmax during arthritis progression. The weight alterations of the spleen and thymus in the course of PIA were observed. Our data suggest that selected AIRmax cellular and genetic immune mechanisms contribute to cartilage damage and arthritis severity, evidencing many targets for therapeutic actions.
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http://dx.doi.org/10.1155/2018/1267038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197000PMC
February 2019

Germline control of somatic Kras mutations in mouse lung tumors.

Mol Carcinog 2018 06 25;57(6):745-751. Epub 2018 Mar 25.

Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Somatic KRAS mutations are common in human lung adenocarcinomas and are associated with worse prognosis. In mice, Kras is frequently mutated in both spontaneous and experimentally induced lung tumors, although the pattern of mutation varies among strains, suggesting that such mutations are not random events. We tested if the occurrence of Kras mutations is under genetic control in two mouse intercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotide changes differed between the intercrosses. Whole genome analysis with SNPs in (A/J x C57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19 and 2 particular codon 61 variants (CTA and CGA). In (AIRmax × AIRmin) F2 mice, there was a significant linkage between SNPs located on distal chromosome 6 (around 135 Mbp) and the frequency of codon 61 mutation. These results reveal the presence of two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency in different mouse intercrosses. These findings indicate that somatic mutation frequency and type are not simple random events, but are under genetic control.
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http://dx.doi.org/10.1002/mc.22796DOI Listing
June 2018

Slc11a1 (Nramp-1) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice.

Inflamm Res 2017 Nov 1;66(11):969-980. Epub 2017 Jul 1.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503000, Brazil.

Objective And Design: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA.

Treatment: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days.

Results: AIRmax mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of HO, NO, IL-1β, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development.

Conclusion: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines.
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http://dx.doi.org/10.1007/s00011-017-1077-8DOI Listing
November 2017

Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses.

Inflamm Res 2016 Apr 28;65(4):313-23. Epub 2016 Jan 28.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503900, Brazil.

Objective And Design: AIRmax and AIRmin mice differ in their local acute inflammatory reactions to polyacrylamide beads (Biogel). These lines were developed to identify genes that affect the intensity of the acute inflammatory response (AIR) and to investigate the cellular and molecular mechanisms of acute inflammation. Although these lines are well established, differences in their responses to chronic inflammatory Biogel exposure have not yet been described. We investigated whether the selective process that modified the acute inflammatory responses in these animals also affected the development of their chronic inflammatory responses.

Results: Inflammatory exudate cell infiltration was more intense in AIRmax than AIRmin mice at both 48 h and 30 days. Genes involved in signal transduction and immune/inflammatory responses were differentially expressed in the treated skin of AIRmax and AIRmin mice, and divergent expression of some acute inflammatory response genes was detected up to 30 days post-Biogel. However, distinct expression of several pro and anti-inflammatory response genes in both periods was observed.

Conclusion: These results indicate that the selective process for acute inflammation affected the development of chronic inflammatory responses to Biogel, suggesting common genetic control.
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http://dx.doi.org/10.1007/s00011-016-0918-1DOI Listing
April 2016

7,12-Dimethylbenz(a)anthracene-induced genotoxicity on bone marrow cells from mice phenotypically selected for low acute inflammatory response.

DNA Repair (Amst) 2016 Jan 2;37:43-52. Epub 2015 Dec 2.

Immunogenetics Laboratory, Butantan Institute, São Paulo, Brazil. Electronic address:

Exposure to polycyclic aromatic hydrocarbon (PAH) environmental contaminants has been associated with the development of mutations and cancer. 7,12-Dimethylbenz(a)anthracene ( DMBA), a genotoxic agent, reacts with DNA directly, inducing p53-dependent cytotoxicity resulting in cell death by apoptosis or giving rise to cancer. DMBA metabolism largely depends on activation of the aryl hydrocarbon receptor (AhR). Mice phenotypically selected for high (AIRmax) or low (AIRmin) acute inflammatory response present a complete segregation of Ahr alleles endowed with low (Ahr(d)) or high (Ahr(b1)) affinity to PAHs, respectively. To evaluate the role of AhR genetic polymorphism on the bone marrow susceptibility to DMBA, AIRmax and AIRmin mice were treated with a single intraperitoneal injection of DMBA (50mg/kg b.w.) in olive oil. Bone marrow cells (BMCs) were phenotyped by both flow cytometry and cytoslide preparations. Despite a significant decrease in total cell count in BM from AIRmin mice, there was an increase of blast cells and immature neutrophils at 1 and 50 days after DMBA treatment, probably due to a cell-cycle blockade at the G1/S transition leading to immature stage cell production. A panel of proteins related to cell cycle regulation was evaluated in immature BM cells (Lin(-)) by Western Blot, and DNA damage and repair were measured using an alkaline version of the Comet assay. In Lin(-) cells isolated from AIRmin mice, high levels were found in both p53 and p21 protein contents in contrast with the low levels of CDK4 and Ciclin D1. Evaluation of DNA repair in DMBA-treated BMCs, indicated long-lasting genotoxicity and cytotoxicity in BMC from AIRmin mice and a blockade of cell cycle progression. On the other hand, AIRmax mice have a high capacity of DNA damage repair and protection. These mechanisms can be associated with the differential susceptibility to the toxic and carcinogenic effects of DMBA observed in these mice.
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http://dx.doi.org/10.1016/j.dnarep.2015.11.006DOI Listing
January 2016

Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model.

Adv Wound Care (New Rochelle) 2014 Sep;3(9):582-591

Laboratory of Immunogenetics, Butantan Institute , Secretary of Health, Government of the State of São Paulo, São Paulo, Brazil .

Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms involved in the initiation of wound repair processes. The pleiotropic effects of the QTL are important in the identification of the genes responsible for tissue repair processes, especially when combined with global gene expression research. Microarray analysis complements the biological information obtained in QTL mapping, making this tool essential for gene identification. This approach will allow the investigation of future targets for therapeutic wound healing treatments.
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http://dx.doi.org/10.1089/wound.2013.0494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152789PMC
September 2014

Trypanosoma cruzi infection in genetically selected mouse lines: genetic linkage with quantitative trait locus controlling antibody response.

Mediators Inflamm 2014 13;2014:952857. Epub 2014 Aug 13.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, 05503-900 São Paulo, SP, Brazil.

Trypanosoma cruzi infection was studied in mouse lines selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reaction and for high (HIII) or low (LIII) antibody (Ab) responses to complex antigens. Resistance was associated with gender (females) and strain-the high responder lines AIRmax and HIII were resistant. The higher resistance of HIII as compared to LIII mice extended to higher infective doses and was correlated with enhanced production of IFN-γ and nitric oxide production by peritoneal and lymph node cells, in HIII males and females. We also analyzed the involvement of previously mapped Ab and T. cruzi response QTL with the survival of Selection III mice to T. cruzi infections in a segregating backcross [F1(HIII×LIII) ×LIII] population. An Ab production QTL marker mapping to mouse chromosome 1 (34.8 cM) significantly cosegregated with survival after acute T. cruzi infections, indicating that this region also harbors genes whose alleles modulate resistance to acute T. cruzi infection.
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http://dx.doi.org/10.1155/2014/952857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146349PMC
May 2015

The Butantan Institute: history and future perspectives.

PLoS Negl Trop Dis 2014 Jul 3;8(7):e2862. Epub 2014 Jul 3.

Instituto Butantan, São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1371/journal.pntd.0002862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080994PMC
July 2014

Mycobacterium leprae Hsp65 administration reduces the lifespan of aged high antibody producer mice.

Immun Ageing 2014 Mar 26;11(1). Epub 2014 Mar 26.

Departamento de Microbiologia, Imunologia e Parasitologia, UNIFESP, Rua Botucatu 862, 04023-062 São Paulo, Brasil.

Background: Aging process may result in immune modifications that lead to disruption of innate and acquired immunity mechanisms that may induce chronic-degenerative events. The heat shock proteins (Hsp), phylogeneticaly conserved among organisms, present as main function the ability of folding and refolding proteins, but they also are associated with chronic-degenerative disorders. Here were evaluated the role of M. leprae native Hsp65 (WT) and its point-mutated (K409A) on survival and anti-DNA and anti-Hsp65 antibody production of aged genetically selected mice for high (HIII) and low (LIII) antibody production; data from 120- and 270-days old mice (named "adult" or "aged", respectively) were compared.

Results: WT Hsp65 administration induces reduction in the mean survival time of adult and aged female HIII mice, this effect being stronger in aged individuals. Surprisingly, the native protein administration increased the survival of aged female LIII when compared to K409A and control groups. No survival differences were observed in aged male mice after Hsp65 proteins inoculation. We observed increase in IgG1 anti-Hsp65 in WT and K409A aged HIII female mice groups and no marked changes in the anti-DNA (adult and aged HIII) and anti-Hsp65 IgG1 or IgG2a isotypes production in adult HIII female and aged male mice. LIII male mice presented increased anti-DNA and anti-Hsp65 IgG2a isotype production after WT or K409A injection, and LIII female groups showed no alterations.

Conclusions: The results revealed that the WT Hsp65 interferes with survival of aged HIII female mice without involvement of a remarkable IgG1 and IgG2a anti-DNA and anti-Hsp65 antibodies production. The deleterious effects of Hsp65 on survival time in aged HIII female mice could be linked to a gender-effect and are in agreement with those previously reported in lupus-prone mice.
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http://dx.doi.org/10.1186/1742-4933-11-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986931PMC
March 2014

7,12-Dimethylbenz(a)anthracene-induced myelotoxicity differs in mice selected for high or low acute inflammatory response: relationship with aryl hydrocarbon receptor polymorphism.

Int J Toxicol 2014 Mar-Apr;33(2):130-42. Epub 2014 Feb 20.

Laboratório de Imunogenética, Instituto Butantan, Av Dr Vital Brazil, 1500, CEP 05503-900, São Paulo, SP, Brazil. Email:

Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.
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http://dx.doi.org/10.1177/1091581814522837DOI Listing
November 2014

Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.

PLoS One 2014 5;9(2):e88302. Epub 2014 Feb 5.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmax (SS) mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmax(SS) mice susceptibility to PIA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914970PMC
September 2014

Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

BMC Genomics 2013 Oct 22;14:724. Epub 2013 Oct 22.

Laboratory of Immunogenetics, Instituto Butantan, Avenida Dr, Vital Brazil, 1500, 05503-900 São Paulo, Brazil.

Background: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age.

Results: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas.

Conclusions: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.
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http://dx.doi.org/10.1186/1471-2164-14-724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046818PMC
October 2013

Ovariectomized OVA-sensitized mice display increased frequency of CD4(+)Foxp3(+) T regulatory cells in the periphery.

PLoS One 2013 17;8(6):e65674. Epub 2013 Jun 17.

Programa de Pós-graduação em Biofotônica Aplicada às Ciências da Saúde, Universidade Nove de Julho - UNINOVE, São Paulo, SP, Brazil.

It is well established that female sex hormones have a pivotal role in inflammation. For instance, our group has previously reported that estradiol has proinflammatory actions during allergic lung response in animal models. Based on these findings, we have decided to further investigate whether T regulatory cells are affected by female sex hormones absence after ovariectomy. We evaluated by flow cytometry the frequencies of CD4(+)Foxp3(+) T regulatory cells (Tregs) in central and peripheral lymphoid organs, such as the thymus, spleen and lymph nodes. Moreover, we have also used the murine model of allergic lung inflammation a to evaluate how female sex hormones would affect the immune response in vivo. To address that, ovariectomized or sham operated female Balb/c mice were sensitized or not with ovalbumin 7 and 14 days later and subsequently challenged twice by aerosolized ovalbumin on day 21. Besides the frequency of CD4(+)Foxp3(+) T regulatory cells, we also measured the cytokines IL-4, IL-5, IL-10, IL-13 and IL-17 in the bronchoalveolar lavage from lungs of ovalbumine challenged groups. Our results demonstrate that the absence of female sex hormones after ovariectomy is able to increase the frequency of Tregs in the periphery. As we did not observe differences in the thymus-derived natural occurring Tregs, our data may indicate expansion or conversion of peripheral adaptive Tregs. In accordance with Treg suppressive activity, ovariectomized and ovalbumine-sensitized and challenged animals had significantly reduced lung inflammation. This was observed after cytokine analysis of lung explants showing significant reduction of pro-inflammatory cytokines, such as IL-4, IL-5, IL-13 and IL-17, associated to increased amount of IL-10. In summary, our data clearly demonstrates that OVA sensitization 7 days after ovariectomy culminates in reduced lung inflammation, which may be directly correlated with the expansion of Tregs in the periphery and further higher IL-10 secretion in the lungs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065674PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684611PMC
March 2014

Role of m2 muscarinic receptor in the airway response to methacholine of mice selected for minimal or maximal acute inflammatory response.

Biomed Res Int 2013 18;2013:805627. Epub 2013 Apr 18.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, Brazil.

Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation.
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http://dx.doi.org/10.1155/2013/805627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652127PMC
December 2013

Induction of TNF-alfa and CXCL-2 mRNAs in different organs of mice infected with pathogenic Leptospira.

Microb Pathog 2012 Apr 8;52(4):206-16. Epub 2012 Feb 8.

Centro de Biotecnologia, Instituto Butantan, São Paulo, SP, Brazil.

The role of innate immune response in protection against leptospirosis is poorly understood. We examined the expression of the chemokine CXCL2/MIP-2 and the cytokine TNF-α in experimental resistant and susceptible mice models, C3H/HeJ, C3H/HePas and BALB/c strains, using a virulent strain of Leptospira interrogans serovar Copenhageni. Animals were infected intraperitoneally with 10(7) cells and the development of the disease was followed. Mortality of C3H/HeJ mice was observed whereas C3H/HePas presented jaundice and BALB/c mice remained asymptomatic. The infection was confirmed by the presence of leptospiral DNA in the organs of the animals, demonstrated by PCR. Sections of the organs were analyzed, after H&E stain. The relative expression of mRNA of chemokine CXCL2/MIP-2 and cytokine TNF-α was measured in lung, kidney and liver of the mice by qPCR. The concentrations of these proteins were measured in extracts of tissues and in serum of the animals, by ELISA. Increasing levels of transcripts and protein CXCL2/MIP-2 were detected since the first day of infection. The highest expression was observed at third day of infection in kidney, liver and lung of BALB/c mice. In C3H/HeJ the expression of CXCL2/MIP-2 was delayed, showing highest protein concentration in lung and kidney at the 5th day. Increasing in TNF-α transcripts were detected after infection, in kidney and liver of animals from the three mice strains. The expression of TNF-α protein in C3H/HeJ was also delayed, being detected in kidney and lung. Our data demonstrated that Leptospira infection stimulates early expression of CXCL2/MIP-2 and TNF-α in the resistant strain of mice. Histological analysis suggests that the expression of those molecules may be related to the influx of distinct immune cells and plays a role in the naturally acquired protective immunity.
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http://dx.doi.org/10.1016/j.micpath.2012.01.002DOI Listing
April 2012

Distinct early inflammatory events during ear tissue regeneration in mice selected for high inflammation bearing Slc11a1 R and S alleles.

Inflammation 2011 Oct;34(5):303-13

Laboratório de Imunogenética, Instituto Butantan, São Paulo, SP, Brasil.

High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmax(SS) mice showed faster ear tissue regeneration than AIRmax(RR) mice, suggesting that the S allele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmax(RR) and AIRmax(SS) mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema in AIRmax(SS) mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmax(RR), while 735 genes were found to be up- and 1616 down-regulated in AIRmax(SS) mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmax(SS) displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmax(SS) mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration.
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http://dx.doi.org/10.1007/s10753-010-9235-yDOI Listing
October 2011

Genetic control of IL-1 beta production and inflammatory response by the mouse Irm1 locus.

J Immunol 2010 Aug 7;185(3):1616-21. Epub 2010 Jul 7.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Genome-wide linkage analysis using single nucleotide polymorphism arrays was carried out in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin). The AIR phenotype was determined by quantifying the number of infiltrating cells in the 24-h exudate induced by Biogel P-100 s.c. injection and by ex vivo IL-1beta production by leukocytes stimulated with LPS and ATP. We mapped the major inflammatory response modulator 1 locus on chromosome 7, at the 1-logarithm of odds (LOD) confidence interval from 116.75 to 139.75 Mb, linked to the number of infiltrating cells (LOD = 3.61) through the production of IL-1beta (LOD = 9.35). Of several interesting candidate genes mapping to the inflammatory response modulator 1 locus, 28 of these were differentially expressed in the bone marrow of AIRmax and AIRmin mice. These findings represent a step toward the identification of the genes underlying this complex phenotype.
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http://dx.doi.org/10.4049/jimmunol.1000358DOI Listing
August 2010

Transcriptome of normal lung distinguishes mouse lines with different susceptibility to inflammation and to lung tumorigenesis.

Cancer Lett 2010 Aug 1;294(2):187-94. Epub 2010 Mar 1.

Laboratory of Imunogenetics, Instituto Butantan, Avenida Dr. Vital Brazil, 1500, 05503-900, São Paulo, Brazil.

AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of approximately 24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treated AIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as "leukocyte transendothelial migration", "cell adhesion" and "tight junctions" were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.
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http://dx.doi.org/10.1016/j.canlet.2010.01.038DOI Listing
August 2010

Influence of calcium hydroxide addition to AH Plus sealer on its biocompatibility.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010 Jan;109(1):e50-4

Discipline of Plastic Surgery, Federal University of São Paulo, UNIFESP, São Paulo, Brazil.

Objective: The objective of this study was to determine whether the addition of 5% calcium hydroxide to AH Plus sealer improves its biocompatibility in subcutaneous connective tissue of rats.

Study Design: Thirty female rats distributed into 3 groups of 10 animals each received subcutaneous dorsal implants of silicone tubes filled with AH Plus (Group 1), AH Plus containing 5% (wt/wt) calcium hydroxide (Group 2), or no material (Group 3: control). The animals were killed after 14 days and the subcutaneous tissue containing the tubes was removed and processed for histological analysis. Biocompatibility was assessed by evaluating the inflammatory response to the implants qualitatively and quantitatively. Data were analyzed statistically by the Wilcoxon and Kruskal-Wallis tests (alpha = 0.05).

Results: The area adjacent to the implant was characterized by nonspecific chronic inflammation and was qualitatively similar in the 3 groups. Animals implanted with AH Plus/calcium hydroxide showed significantly less intense inflammatory response when compared with the animals implanted with AH Plus alone.

Conclusion: The addition of calcium hydroxide to AH Plus root canal sealer improved its histopathological behavior within 14 days of analysis, producing less severe inflammatory response and less cytotoxicity when implanted in the subcutaneous tissue of rats.
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http://dx.doi.org/10.1016/j.tripleo.2009.08.026DOI Listing
January 2010

Gene expression profiles of bone marrow cells from mice phenotype-selected for maximal or minimal acute inflammations: searching for genes in acute inflammation modifier loci.

Immunology 2009 Sep 18;128(1 Suppl):e562-71. Epub 2008 Dec 18.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Two mouse lines were phenotype-selected for maximum (AIRmax) or minimum (AIRmin) acute inflammation responses to polyacrylamide bead (Biogel) injection. These lines differ in terms of bone marrow granulopoiesis, neutrophil resistance to apoptosis, and inflammatory cytokine production during acute inflammation responses. We compared gene expression profiles in bone marrow cells (BMC) of AIRmax and AIRmin mice during acute inflammatory reactions. The BMC from femurs were recovered 24 hr after subcutaneous injections of Biogel. Global gene expression analysis was performed on CodeLink Bioarrays (36K genes) using RNA pools of BMC from both control and treated AIRmax and AIRmin mice. Differentially expressed genes were statistically established and the over-represented gene ontology biological process categories were identified. Upregulations of about 136 and 198 genes were observed in the BMC of Biogel-treated AIRmax and AIRmin mice, respectively, but 740 genes were found to be downregulated in AIRmin mice compared with 94 genes in AIRmax mice. The over-represented biological themes of the differently expressed genes among AIRmax and AIRmin mice represent inflammatory response, signal transduction, cell proliferation and immune cell chemotaxis. We were able to demonstrate a broad downmodulation of gene transcripts in BMC from AIRmin mice during acute inflammation, and significant differentially expressed genes colocalized with previously mapped regions for inflammation-related phenotypes in chromosomes 1, 3, 6 and 11.
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http://dx.doi.org/10.1111/j.1365-2567.2008.03032.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753958PMC
September 2009

Chemokines expression during Leptospira interrogans serovar Copenhageni infection in resistant BALB/c and susceptible C3H/HeJ mice.

Microb Pathog 2009 Aug 19;47(2):87-93. Epub 2009 May 19.

Centro de Biotecnologia-Instituto Butantan, São Paulo, SP, Brazil.

The role of innate immune responses in protection against leptospirosis remains unclear. We examined the expression of the chemokines CCL2/JE (MCP-1), CCL3/MIP-1 alpha (MIP-1 alpha) and CXCL1/KC (IL-8) regarding resistance and susceptibility to leptospirosis in experimental mice models BALB/c and C3H/HeJ, respectively. A virulent strain of Leptospira interrogans serovar Copenhageni was used in this study. Twenty-five animals of each mouse strain of C3H/HeJ and BALB/c, were infected intraperitoneally with 10(6) cells. Five un-infected animals of each strain were kept as control. Mortality of C3H/HeJ mouse was observed while BALB/c mice were asymptomatic. The presence of leptospire DNA in tissues of infected animals was demonstrated by PCR. Chemokines were measured in serum, spleen, liver, kidney and lung of both strains of animals using immunoenzymatic assay (ELISA). Elevations in the levels of chemokines MCP-1 and IL-8 occurred in all organs and sera of C3H/HeJ and BALB/c infected mice. The levels of MIP-1 alpha were lower when compared to MCP-1 and IL-8 in all analyzed organs, with a slight increase in liver and kidney. Our results indicate that the expression of inflammatory mediators can vary greatly, depending on the tissue and mouse strains. It is possible that the resistance to Leptospira can be partially correlated to the increase of MIP-1 alpha observed in BALB/c mice, while an increasing and a sustained expression of MCP-1 and IL-8 in the lungs of C3H/HeJ mice can be correlated to the severity and progression of leptospirosis.
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http://dx.doi.org/10.1016/j.micpath.2009.05.002DOI Listing
August 2009

Aryl hydrocarbon receptor polymorphism modulates DMBA-induced inflammation and carcinogenesis in phenotypically selected mice.

Int J Cancer 2009 Mar;124(6):1478-82

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12-dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1beta, Tnf, Il6, Tgfbeta1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr(b1)), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor (Ahr(d)), to DMBA. The differential segregation of Ahr functional Ahr(d)versus Ahr(b1) alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines.
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http://dx.doi.org/10.1002/ijc.24066DOI Listing
March 2009

Bothrops jararaca venom (BjV) induces differential leukocyte accumulation in mice genetically selected for acute inflammatory reaction: the role of host genetic background on expression of adhesion molecules and release of endogenous mediators.

Toxicon 2008 Oct 6;52(5):619-27. Epub 2008 Aug 6.

Laboratório de Imunogenética, Instituto Butantan, Av. Vital Brasil 1500 - cep 05503-900, São Paulo, SP, Brazil.

The dynamics of the local inflammatory events induced by Bothrops jararaca venom (BjV) inoculation in footpad of mice genetically selected for maximal (AIRmax) and minimal (AIRmin) acute inflammatory reactivity (AIR) was investigated. The BjV injection induced a marked inflammatory cell infiltrate with predominance of neutrophils, with increased blood cell numbers before its accumulation, suggesting a stimulatory action of BjV on mechanisms of cell mobilization from bone marrow. The process of cell migration is regulated by different cell-adhesion molecules (CAM). Our results showed that neutrophil cells from both lines had the same pattern of response concerning CAMs expression, presenting the involvement of l-selectin, Mac-1 and PECAM-1 adhesion molecules in BjV-induced neutrophil accumulation. The effect of BjV on the release of pro-inflammatory cytokines and chemokines related with cellular migration was also studied and IL-1beta, IL-6, TNF-alpha and MIP-2 levels could be detected after venom injection. The AIRmax mice were shown to be more responsive than AIRmin with respect to leukocyte influx, expression of MIP-2 and release of IL-1beta and IL-6. These results demonstrate the importance of host genetic background in the local response and the involvement of alleles accumulated in AIRmax mice in the inflammatory events induced by BjV.
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http://dx.doi.org/10.1016/j.toxicon.2008.07.012DOI Listing
October 2008

Slc11a1 (Nramp1) alleles interact with acute inflammation loci to modulate wound-healing traits in mice.

Mamm Genome 2007 Apr 8;18(4):263-9. Epub 2007 May 8.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Lines of mice were obtained by selective breeding for maximum (AIRmax) or minimum (AIRmin) acute inflammation. They present distinct neutrophil influx and show frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) alleles. This gene is involved in ion transport at the endosomes within macrophages and neutrophils, interfering in their activation. Homozygous AIRmax and AIRmin sublines for the Slc11a1 gene were produced to examine the interaction of this gene with the acute inflammatory loci. The present work investigated wound-healing traits in AIRmax and AIRmin mice, in F(1) and F(2) intercrosses, and in Slc11a1 sublines. Two-millimeter ear punches were made in the mice and hole closure was measured during 40 days. AIRmax mice demonstrated significant tissue repair while AIRmin mice did not. Significant differences between the responses of male and female mice were also observed. Wound-healing traits demonstrated a correlation with neutrophil influx in F(2) populations. AIRmax( SS )showed higher ear-wound closure than AIRmax( RR ) mice, suggesting that the Slc11a1 S allele favored ear tissue repair. QTL analysis has detected two inflammatory loci modulating ear wound healing on chromosomes 1 and 14. These results suggest the involvement of the acute inflammation modifier QTL in the wound-healing phenotype.
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http://dx.doi.org/10.1007/s00335-007-9012-xDOI Listing
April 2007

Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines.

Microbes Infect 2006 Oct 7;8(12-13):2766-71. Epub 2006 Sep 7.

Laboratório de Imunogenética - Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05503900, Brazil.

Two lines of mice selected to produce maximal (AIRmax) or minimal (AIRmin) acute inflammatory reactions (AIR) differ in their susceptibility to infection by Salmonella enterica serotype Typhimurium (S. Typhimurium). The LD(50) for AIRmax mice is 1000 times higher than that observed for AIRmin mice, and higher frequencies of Slc11a1 alleles (known to confer either resistance (R) or high susceptibility (S) to S. Typhimurium) were consistently found in AIRmax and AIRmin mouse lines, respectively. In order to evaluate the effect of the quantitative trait loci (QTL) segregated in AIRmax and AIRmin mice on Slc11a1 dependent susceptibility to S. Typhimurium, the R and S alleles were fixed in homozygosity in AIRmax and AIRmin backgrounds by genotype assisted breedings. These new lines were named AIRmax(RR), AIRmax(SS), AIRmin(RR), and AIRmin(SS). Acute inflammation of Slc11a1(RR) animals was more severe in comparison to their Slc11a1(SS) counterparts, implicating Slc11a1 (or other linked genes) in AIR regulation. The LD(50) of S. Typhimurium was 800-times higher for AIRmax(SS) than for AIRmin(SS), demonstrating that AIR QTL can act as modifiers of the Slc11a1(SS) susceptibility gene. Four microsatellite markers for S. Typhimurium susceptibility QTL described in other mouse lines showed specific allele fixation in AIRmax or AIRmin mice, suggesting that these chromosomal regions also segregate with inflammatory phenotypes.
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http://dx.doi.org/10.1016/j.micinf.2006.08.005DOI Listing
October 2006