Éditeur(s) : HAL CCSD Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists
Résumé : International audience
Hepatic periportal fibrosis, which affects 5–10% of subjects infected by Schistosoma mansoni, is caused by the T cell-dependent granuloma that develop around schistosome eggs. Experimental models of infection have shown that granuloma and fibrosis are tightly regulated by cytokines. However, it is unknown why advanced periportal fibrosis occurs only in certain subjects. The goal of the present study was to evaluate the cytokine response of S. mansoni-infected subjects with advanced liver disease in an attempt to relate susceptibility to periportal fibrosis with an abnormal production of cytokines that regulate granuloma and fibrosis. Fibrosis was evaluated by ultrasound on 795 inhabitants of a Sudanese village in which S. mansoni is endemic: advanced periportal fibrosis was observed in 12% of the population; 35% of the affected subjects exhibited signs of portal hypertension. Age (odds ratio (OR), 11.5), gender (OR, 4.2), and infection levels (OR, 2.2) were significantly (p < 0.01) associated with hepatic fibrosis. Cytokines produced by egg-stimulated blood mononuclear cells from 99 subjects were measured (75 with no or mild fibrosis; 24 subjects with advanced fibrosis). Multivariate analysis of cytokine levels showed that high IFN-γ levels were associated with a marked reduction of the risk of fibrosis (p = ‫OR, 0.1); in contrast, high TNF-α levels were associated with an increased risk (p = 0.05; OR, 4.6) of periportal fibrosis. Moreover, infection levels were negatively associated with IFN-γ production. These results with observations in experimental models strongly suggest that IFN-γ plays a key role in the protection of S. mansoni-infected patients against periportal fibrosis, whereas TNF-α may aggravate the disease.
ISSN: 0022-1767

Droits : http://creativecommons.org/licenses/by-nc-nd/
hal-01211587
https://hal.archives-ouvertes.fr/hal-01211587
https://hal.archives-ouvertes.fr/hal-01211587/document
https://hal.archives-ouvertes.fr/hal-01211587/file/929.full.pdf
DOI : 10.4049/jimmunol.169.2.929

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in granuloma formation. This study analyzed the role of iNKT cells in the hepatic immune response during Leishmania donovani infection, using a murine model of wild-type (WT) and iNKT cell-deficient (Jα18⁻/⁻) C57BL/6 mice sacrificed 15, 30 or 60 days post-infection. We recorded hepatic parasite loads, cytokine expression, and analyzed granulomatous response by immunohistochemistry and hepatic immune cell infiltration by flow cytometry. Whereas WT animals rapidly controlled the infection and developed an inflammatory response associated with a massive influx of iNKT cells observed by flow cytometry, Jα18⁻/⁻ mice had significantly higher parasitic loads on all time points. This lack of control of parasite burden was associated with a delay in granuloma maturation (28.1% of large granulomas at day 60 versus 50.7% in WT). Cytokine transcriptome analysis showed that mRNA of 90/101 genes encoding chemokines, cytokines and their receptors, was underexpressed in Jα18⁻/⁻ mice. Detection of IL-4 and TNF-α by ELISA in liver extracts was also significantly lower in Jα18⁻/⁻ mice. Consistent with flow cytometry analysis, cytokinome profile in WT mice showed a bias of expression towards T cell-chemoattractant chemokines on D15, and displayed a switch towards expression of granulocytes and/or monocytes -chemoattractant chemokines on D60. In Jα18⁻/⁻ mice, the significantly lower expression of CXCL5, MIP-2 and CCL2 mRNA was correlated with a defect in myeloperoxidase positive-cell attraction observed by immunohistochemistry and with a lower granulocyte and monocyte infiltration in the liver, as shown by flow cytometry. These data indicate that iNKT cells play a role in early and sustained pro-inflammatory cytokine response warranting efficient organization of hepatic granulomas and parasite clearance.
ISSN: 1932-6203

hal-00696897
https://hal.archives-ouvertes.fr/hal-00696897
https://hal.archives-ouvertes.fr/hal-00696897/document
https://hal.archives-ouvertes.fr/hal-00696897/file/Invariant_NKT_Cells_Drive-accepted.pdf
DOI : 10.1371/journal.pone.0033413

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte-specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies. Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec-1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries.
ISSN: 0946-2716

hal-01134319
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134319
DOI : 10.1007/s00109-015-1270-6
PUBMED : 25747661

Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
INTRODUCTION: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for regulating expression of several important drug-detoxifying proteins. Besides drug metabolism pathways, cytokines have been recently recognized as targeted by the AhR signaling cascade, which may contribute to toxicity and changes in xenobiotic detoxification caused by AhR agonists. AREAS COVERED: This article summarizes the nature of the main cytokines regulated by AhR ligands and reviews their involvement in toxic effects of AhR ligands, especially in relation with inflammation. The article also discusses the potential implications for drug detoxification pathways. EXPERT OPINION: Even if various cytokines, including inflammatory ones, have already been demonstrated to constitute robust targets for AhR, the exact role played by AhR with respect to inflammation remains to be determined. Further studies are also required to better characterize the molecular mechanisms implicated in regulation of cytokines by AhR ligands and to determine the role that may play AhR-targeted cytokines in alteration of xenobiotic detoxification. Finally, changes in cytokine receptor expression triggered by AhR ligands have additionally to be taken into account to better and more extensively comprehend the role played by AhR in the cytokine/inflammation area.
ISSN: 1742-5255

inserm-00831662
http://www.hal.inserm.fr/inserm-00831662
DOI : 10.1517/17425255.2013.738194
PUBMED : 23230817

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
UNLABELLED: During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33(+) cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L. donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33(+) cells and ST2(+) cells in the mouse liver. In ST2(-/-) BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-γ] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment. IMPORTANCE: Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L. infantum and L. donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host's immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.
ISSN: 2150-7511

inserm-00871493
http://www.hal.inserm.fr/inserm-00871493
http://www.hal.inserm.fr/inserm-00871493/document
http://www.hal.inserm.fr/inserm-00871493/file/mBio.00383-13.pdf
DOI : 10.1128/mBio.00383-13

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.
ISSN: 1932-6203

hal-00874120
https://hal.archives-ouvertes.fr/hal-00874120
https://hal.archives-ouvertes.fr/hal-00874120/document
https://hal.archives-ouvertes.fr/hal-00874120/file/Pathogenic_Mouse_Hepatitis-accepted.pdf
DOI : 10.1371/journal.pone.0074278

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Ethnopharmacological relevancePsidium acutangulum Mart. ex DC is a small tree used by the Wayana Amerindians from the Upper-Maroni in French Guiana for the treatment of malaria.Aim of the studyIn a previous study, we highlighted the in vitro antiplasmodial, antioxidant and anti-inflammatory potential of the traditional decoction of P. acutangulum aerial parts. Our goal was then to investigate on the origin of the biological activity of the traditional remedy, and eventually characterize active constituents.Materials and methodsLiquid-liquid extractions were performed on the decoction, and the antiplasmodial activity evaluated against chloroquine-resistant FcB1 ([3H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains, and on a chloroquine sensitive NF54 ([3H]-hypoxanthine bioassay) P. falciparum strain. The ethyl acetate fraction (D) was active and underwent bioguided fractionation. All the isolated compounds were tested on P. falciparum FcB1 strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) of the ethyl acetate fraction and of an anti-Plasmodium active compound, was concurrently assessed on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the fractions and pure compounds was measured on VERO cells, L6 mammalian cells, PBMCs, and RAW cells.ResultsFractionation of the ethyl acetate soluble fraction (IC50 ranging from 3.4 to <1 µg/mL depending on the parasite strain) led to the isolation of six pure compounds: catechin and five glycosylated quercetin derivatives. These compounds have never been isolated from this plant species. Two of these compounds (wayanin and guaijaverin) were found to be moderately active against P. falciparum FcB1 in vitro (IC50 5.5 and 6.9 µM respectively). We proposed the name wayanin during public meetings organized in June 2015 in the Upper-Maroni villages, in homage to the medicinal knowledge of the Wayana population. At 50 µg/mL, the ethyl acetate fraction (D) significantly inhibited IL-1β secretion (−46%) and NO production (−21%), as previously observed for the decoction. The effects of D and guiajaverin (4) on the secretion of other cytokines or NO production were not significant.ConclusionsThe confirmed antiplasmodial activity of the ethyl acetate soluble fraction of the decoction and of the isolated compounds support the previous results obtained on the P. acutangulum decoction. The antiplasmodial activity might be due to a mixture of moderately active non-toxic flavonoids. The anti-inflammatory activities were less marked for ethyl acetate fraction (D) than for the decoction.
ISSN: 0378-8741

hal-01313006
http://hal.upmc.fr/hal-01313006
http://hal.upmc.fr/hal-01313006/document
http://hal.upmc.fr/hal-01313006/file/Houel_Wayanin_and.pdf
DOI : 10.1016/j.jep.2016.04.053

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Purpose The purpose of this review was to examine the comprehensively accumulated data regarding potential therapeutic aspects of exogenous administration of interleukin 33 (IL-33) or its antagonists in allergic, cancerous, infectious, and inflammatory diseases. Methods A selected review was undertaken of publications that examined the protective and exacerbating effects of IL-33 or its inhibitors in different diseases. Mechanisms of action are summarized to examine the putative role of IL-33 in various diseases. Findings IL-33 promoted antibacterial, antiviral, anti-inflammatory, and vaccine adjuvant functions. However, in TH2-biased respiratory, allergic, parasitic, and inflammatory conditions, IL-33 exhibited disease-sensitizing effects. The alarmin cytokine IL-33 induced protective effects in diseases via recruitment of regulatory T cells; antiviral CD8+ cells, natural killer cells, γδ T cells, and nuocytes; antibacterial and antifungal neutrophils or macrophages; vaccine-associated B/T cells; and inhibition of nuclear factor–κB–mediated gene transcription. In contrast, IL-33 exacerbated the disease process by increasing TH2 cytokines, IgE and eosinophilic immune responses, and inhibition of leukocyte recruitment in various diseases. Implications The protective or exacerbated aspects of use of IL-33 or its inhibitors are dependent on the type of infection or inflammatory condition, duration of disease (acute or chronic), organ involved, cytokine microenvironment, dose or kinetics of IL-33, and genetic predisposition. The alarmin cytokine IL-33 acts at cellular, molecular, and transcriptional levels to mediate pluripotent functions in various diseases and has potential therapeutic value to mitigate the disease process
ISSN: 0149-2918

hal-01295637
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01295637
PUBMED : 26992663
DOI : 10.1016/j.clinthera.2016.02.021

Éditeur(s) : HAL CCSD American Physiological Society
Résumé : International audience
The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33(-/-) mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33(-/-) mice was associated with significantly higher levels of TNF-alpha and IL-1 beta and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33(-/-) mice following Con A-hepatitis. The percentage of CD25(+) NK cells was significantly higher in the livers of IL-33(-/-) mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33(-/-) mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4(+) and CD8(+) T cells, and the frequency of ST2(+) Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2(+) Treg cells and control of NK cells.
ISSN: 0193-1857

hal-01366372
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366372
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366372/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01366372/file/Ablation%20of%20interaction%20between%20IL-33%20and%201%20ST2.pdf
DOI : 10.1152/ajpgi.00097.2016

Éditeur(s) : HAL CCSD
Résumé : Visceral leishmaniasis is a life-threatening systemic disease caused by Leishmania protozoans, L. donovani and L. infantum, which invade mononuclear phagocytes in the lymphoid organs and the liver. The control of the hepatic parasite burden depends on the granuloma formation, which is favored by a Th1 immune response in a Th2 tissue microenvironment. The aim of this work was to study the role of the recently described Th2 cytokine IL-33 in this complex immune response, which remains partially misunderstood. IL-33 dosages in different patient sera and IL-33+ cells detected in the liver of a patient from Rennes suggested that IL-33 could be a biomarker for active visceral leishmaniasis. As IL-33 was described in hepatic stellate cells during chronic hepatitis, these cells were exposed to L. donovani in primary culture. The cell permissivity to L. donovani and the parasite persistence during a long term culture led us to propose hepatic stellate cells as a new type of sanctuary cells, which could partially explain asymptomatic carriage. However, these cells were apparently not the main source of IL-33 during visceral leishmaniasis. In infected BALB/c and C57BL/6 mice, IL-33 was detected in the liver in non stellate cells preferentially localized in granulomas. The presence of cells expressing its specific receptor ST2 in the liver led us to explore the role of the IL-33/ST2 axis. BALB/c mice deficient in ST2 or treated with recombinant IL-33 and infected with L. donovani revealed that IL-33 downregulates the expression of Th1 key cytokines (IL-12, IFN-γ) and the recruitment of neutrophils and monocytes. Finally, IL-33 acts as a susceptibility factor during visceral leishmaniasis. Besides, the model of L. donovani infected C57BL/6 mice deficient in IL-33 or treated with recombinant IL-33 suggests possible differential roles of IL-33 depending on the immune environment related to the host genetic background.
La leishmaniose viscérale est une maladie systémique mortelle en l’absence de traitement. Elle est due aux protozoaires Leishmania donovani et L. infantum, parasites des phagocytes mononucléés, capables d’envahir les organes lymphoïdes et le foie. Le contrôle de l’infection hépatique repose sur la mise en place d’une réponse granulomateuse efficace, promue par une réponse immunitaire Th1, dans un environnement tissulaire Th2. L’objectif de ce travail était l'étude du rôle d’une cytokine Th2 récemment décrite, l’IL-33, dans cette réponse hépatique complexe encore partiellement incomprise. Des dosages d’IL-33 sur des sérums de patients et la détection de cellules IL-33+ dans le foie d’un patient rennais ont placé l’IL-33 comme un biomarqueur possible de la maladie active. L’IL-33 étant exprimée dans les cellules étoilées du foie au cours d’hépatites chroniques, ces cellules ont été exposées à L. donovani. Leur permissivité aux leishmanies sans toxicité apparente ni perturbation de leurs propriétés fonctionnelles, ainsi que la persistance des leishmanies sur une culture de plusieurs semaines, nous ont conduit à proposer les cellules étoilées comme cellules sanctuaires possibles pour les leishmanies viscérotropes, contribuant donc potentiellement au portage asymptomatique. En revanche, elles ne sont pas apparues comme une source majeure d'IL-33 au cours de la leishmaniose viscérale. Chez des souris C57BL/6 et BALB/c infectées par L. donovani, l'IL-33 a été observée dans des cellules ne s'apparentant pas à des cellules étoilées, et principalement localisées dans les granulomes. Des cellules exprimant son récepteur ST2 ayant été également observées dans le foie, un rôle de l’axe IL-33/ST2 a été recherché. Les résultats obtenus chez des souris BALB/c déficientes en ST2 ou traitées par de l'IL-33 recombinante suggèrent que l'IL-33 régule négativement l'expression de cytokines Th1 (IL-12, IFN-γ) et l'infiltrat de neutrophiles et monocytes dans le foie, limitant ainsi le contrôle de la charge parasitaire. Ainsi, l'IL-33 semble être un facteur de susceptibilité pour la leishmaniose viscérale. En parallèle, des travaux entrepris sur des souris C57BL/6 infectées par L. donovani suggèrent de possibles rôles différentiels de l'IL-33 en fonction de l'environnement immunitaire inhérent au fond génétique de l'hôte.
https://tel.archives-ouvertes.fr/tel-01126847

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2013REN1B002
tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847/document
https://tel.archives-ouvertes.fr/tel-01126847/file/2013REN1B002.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.
ISSN: 0041-008X

inserm-00872871
http://www.hal.inserm.fr/inserm-00872871
DOI : 10.1016/j.taap.2012.05.004
PUBMED : 22617429

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Inorganic arsenic is a toxic environmental contaminant to which humans are mainly exposed through drinking water. This metalloid impairs functions of several key immune cells. Particularly, it reduces IL-2 secretion and proliferation of blood peripheral mononuclear cells stimulated by lectins that, however, do not mimic physiological T cell activation. The present study used isolated human T cells activated, in a more physiological manner, through stimulation with CD3/CD28 antibodies, to carefully analyze the impact of arsenic on T cell proliferation and cytokine expression. We demonstrate that non cytotoxic concentrations of sodium arsenite (As(III), 0.25-2μM) significantly reduce T cell proliferation by increasing the percentage of non dividing cells blocked in G1 phase and by preventing cyclin D3 and CDC25A expression. They also markedly, although not totally, reduces IL-2 expression at both mRNA and protein levels; however, metalloid-dependent inhibition of T cells could not be reversed by addition of recombinant IL-2. In addition, As(III) markedly reduces secretion of interferon-γ without impairing that of IL-4 and IL-13; it also decreases interferon-γ mRNA levels but increases those of IL-13. Finally, simultaneously to its immune effects, As(III) rapidly and potently increases expression of the redox-sensitive genes HMOX1, NQO1 and GCLM in activated T cells without altering the levels of reactive oxygen species. In conclusion, our results demonstrate that As(III) inhibits T cell proliferation, independently of IL-2, and alters the Th balance of cytokines secreted by co-stimulated T cells which thus constitute direct targets of this major environmental contaminant.
ISSN: 0300-483X

inserm-00872848
http://www.hal.inserm.fr/inserm-00872848
DOI : 10.1016/j.tox.2012.05.025
PUBMED : 22683347

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The non-classical human leukocyte antigen-G, HLA-G, plays an important role in inducing tolerance, through its immunosuppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. It would therefore appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression. The generation of immune tolerance is a role common to both HLA-G, as a molecule, and the liver, as an organ. This review provides a summary of the evidence implicating HLA-G in liver diseases. In the normal liver, HLA-G transcripts can be detected, but there is no HLA-G protein. However, HLA-G protein is detectable in the liver tissues and/or plasma of patients suffering from hepatocellular carcinoma, hepatitis B or C, or visceral leishmaniasis and in liver transplant recipients. The cells responsible for producing HLA-G differ between diseases. HLA-G expression is probably induced by microenvironmental factors, such as cytokines. The expression of HLA-G receptors, such as ILT2, ILT4, and KIRD2L4, on liver cells has yet to be investigated, but these receptors have been detected on all types of immune cells, and such cells are present in liver. The tolerogenic properties of HLA-G explain its deleterious effects in cancers and its beneficial effects in transplantation. Given the key role of HLA-G in immune tolerance, new therapeutic agents targeting HLA-G could be tested for the treatment of these diseases in the future.
ISSN: 0168-8278

hal-01134468
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134468
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134468/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134468/file/Biology%20of%20the%20immunomodulatory%20molecule%20HLA-G.pdf
DOI : 10.1016/j.jhep.2015.03.007

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
ISSN: 0891-5849

hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/file/Nrf2_expression_and_activity_in_human_T_lymphocytes_accepted.pdf
DOI : 10.1016/j.freeradbiomed.2014.03.006

Éditeur(s) : HAL CCSD
Résumé : International audience
Leishmania parasites induce an immunomodulation by subverting the host immune response towards a CD4(+) Th2 lymphocytic cell response that favors parasite persistence. Here, we report that after successful treatment of visceral leishmaniasis due to Leishmania infantum, an immune reconstitution syndrome revealing hip septic arthritis was associated with a switch from Th2 towards a Th1 cytokine profile, and a decrease in the level of immunomodulating factors, such as soluble HLA-G and indoleamine 2,3-dioxygenase (IDO) activity. We then measured IDO activity in a cohort of 39 patients and uninfected control subjects. Results showed significantly enhanced IDO activity in patients with visceral Leishmania infection, compared with uninfected control subjects (P < 0.001), but also compared with treated patients (P < 0.05). A decrease in IDO activity could constitute a relevant biomarker for the restoration of the immune response during visceral leishmaniasis.
Innate Immunity

inserm-00818884
http://www.hal.inserm.fr/inserm-00818884
DOI : 10.1177/1753425912473170
PUBMED : 23413147

Éditeur(s) : HAL CCSD
Résumé : Inorganic arsenic is an environmental human carcinogen, but is also studied these days because of its potential effectiveness in curing chronic inflammatory disease. Indeed, this metalloid possesses immunosuppressive properties which can dysregulate physiological mechanisms involved in immune defense, or reduce inflammation associated with those inflammatory diseases. Inorganic arsenic is known mainly to alter functions of T cells and macrophages. However, it is unknown whether arsenic targets dendritic cells (DCs). Yet, this antigen presenting cells plays a major role in the immunosurveillance, and is involved in the physiopathology of chronic inflammatory diseases. So, the aim of my thesis work was to study the effects of inorganic arsenic on in vitro differenciation and maturation of dendritic cells from human monocytes. Our results mainly shows that concentrations corresponding to those measured in environmentally exposed people, inhibits DCs secretion of proinflammatory cytokines, which plays a major role in activation and polarization of T cells. Particularly, arsenic strongly impairs expression and secretion of interleukine 12 (IL-12) by an underlying molecular mechanism involving Nrf2. Finally, this work shows that inorganic arsenic has immunosuppressive properties on the physiology in vitro of human dendritic cells. Immunotoxicity may then contribute to the metalloid toxicity in environmentally exposed people. This element could be taken into account when determining arsenic effects in curing some chronic inflammatory diseases.
L’arsenic inorganique est un contaminant environnemental, cancérogène pour l’homme, mais également un métalloïde étudié, aujourd’hui, dans le traitement de maladies inflammatoires chroniques. Il possède des propriétés immunosuppressives pouvant déréguler les mécanismes physiologiques de défense ou bloquer l’exacerbation de réponses inflammatoires chroniques. L’arsenic inorganique altère principalement les fonctions des lymphocytes T et des macrophages. En revanche, l’impact du métalloïde sur la physiologie des cellules dendritiques (DCs) est peu connu. Pourtant, ces cellules présentatrices d’antigène jouent un rôle fondamental dans les processus d’immunosurveillance et sont très impliquées dans la physiopathologie des maladies inflammatoires chroniques. Dans ce contexte, les objectifs de mon travail de thèse étaient d’étudier les effets de l’arsenic inorganique sur la différenciation et la maturation in vitro de DCs générées à partir de monocytes humains. Nos résultats démontrent principalement que des concentrations de métalloïde, compatibles avec les taux plasmatiques d’arsenic mesurés chez les individus exposés, répriment la capacité des DCs à sécréter différentes cytokines pro-inflammatoires jouant un rôle essentiel dans l’activation et la polarisation des lymphocytes T. En particulier, l’arsenic inhibe l’expression et la sécrétion de l’interleukine-12 par un mécanisme moléculaire impliquant le facteur de transcription Nrf2. Au total, ces travaux de thèse démontrent que l’arsenic inorganique possède des propriétés immunosuppressives sur la physiologie in vitro des DCs humaines. Cette immunotoxicité pourrait contribuer à la toxicité du métalloïde chez l’homme exposé par voie environnementale, et être prise en compte pour déterminer les effets de l’arsenic dans le traitement de certaines maladies inflammatoires chroniques
https://tel.archives-ouvertes.fr/tel-01135887

NNT : 2013REN1B013
tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887/document
https://tel.archives-ouvertes.fr/tel-01135887/file/pdf2star-1392896105-Th--se-M--linda-Macoch2.pdf

Éditeur(s) : HAL CCSD American Physiological Society
Résumé : International audience
Interleukin (IL)-33 is crucially involved in liver pathology and drives hepatoprotective functions. However, the regulation of IL-33 by cytokines of the IL-6 family, including oncostatin M (OSM) and IL-6, is not well studied. The aim of the present study was to determine whether OSM mediates regulation of IL-33 expression in liver cells. Intramuscular administration in mice of an adenovirus encoding OSM (AdOSM) leads to increase in expression of OSM in muscles, liver, and serum of AdOSM-infected mice compared with control mice. The increase of circulating OSM markedly regulated mRNA of genes associated with blood vessel biology, chemotaxis, cellular death, induction of cell adhesion molecules, and the alarmin cytokine IL-33 in liver. Steady-state IL-33 mRNA was upregulated by OSM at an early phase (8 h) following AdOSM infection. At the protein level, the expression of IL-33 was significantly induced in liver endothelial cells [liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells] with a peak at 8 days post-AdOSM infection in mice. In addition, we found OSM-stimulated human microvascular endothelial HMEC-1 cells and human LSEC/TRP3 cells showed a significant increase in expression of IL-33 mRNA in a dose-dependent manner in cell culture. The OSM-mediated overexpression of IL-33 was associated with the activation/enrichment of CD4(+)ST2(+) cells in liver of AdOSM-infected mice compared with adenovirus encoding green fluorescent protein-treated control mice. In summary, these data suggest that the cytokine OSM regulates the IL-33 expression in liver endothelial cells in vivo and in HMEC-1/TRP3 cells in vitro and may specifically expand the target CD4(+)ST2(+) cells in liver
ISSN: 0193-1857

hal-01220632
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01220632
DOI : 10.1152/ajpgi.00398.2014
PUBMED : 26251474

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants.
ISSN: 0009-2797

inserm-00818896
http://www.hal.inserm.fr/inserm-00818896
DOI : 10.1016/j.cbi.2013.01.005
PUBMED : 23396138

Éditeur(s) : HAL CCSD
Résumé : International audience
Acute viral hepatitis results from an inefficient innate immune response to clear the virus and a delayed immune adaptive response. Murine hepatitis virus (MHV) infection represents a unique animal model to identify new escape mechanisms in liver of innate immune responses. The objective of this study was to identify early disorders in TLRs, helicases, cytokines and chemokines favoring the development of a fulminant hepatitis. Groups of C57BL/6 WT and TLR2-/- mice were infected with highly hepatotropic MHV3 and/or weakly hepatotropic MHV-A59 viruses. Histopathological analysis of liver and mRNA expression levels of viral nucleoprotein, viral sensors, interferons, cytokines and chemokines assessed by RT-qPCR were done in the first 3 days of infection. The results showed that liver damages, viral replication and mRNA levels of TLR-2, TLR-3, RIG-1, MDA-5, IL-33, IFN-b, CXCL1, CXCL9, CXCL-10, CXCL-11, CCL3, CCL5, IL-6 and TNF-a increased higher or appeared sooner in MHV3-infected WT than in MHV-A59 and TLR2-/- mice. To address the role of hepatocytes in TLR2-dependent viral replication and innate immune factors, in vitro viral infections were performed on FL83B cells. The results showed that viral replication and mRNA levels of TLR-2 and IL-6 occurred sooner than those of other innate immune parameters. Moreover, blockade of TLR-2 by siRNA decreased IFN-b, TNF-a, CXCL-1, CXCL-10 and CCL-2 expression in infected hepatocytes and also inhibited the viral replication of MHV-A59, and at a lesser extent of MHV3, suggesting that TLR-2 signaling promotes simultaneously the viral replication and the production of innate immune factors in hepatocytes, exacerbating viral hepatitis.
Frontiers of Immunology
Milan, Italy

hal-01118155
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118155
DOI : 10.3389/conf.fimmu.2013.02.00648

Éditeur(s) : HAL CCSD
Résumé : Background and objectives.[br/] Dairy propionibacteria are isolated from various ecological niches, including soil, grass, silage, rumen, raw milk and dairy plants, showing great adaptability and robustness. Used as ripening starters in Swiss type cheeses, these food grade bacteria are described as nutraceutical producers and they release into the external medium short chain fatty acids (SCFA), folic acid, cobalamin and the bifidogenic 1,4- dihydroxy-2-naphthoic acid (DHNA). These compounds are known to play a pivotal role in the modulation of intestinal physiology through diet. Considering the pro-apoptotic potential of some of these metabolites, we investigated the potential of dairy products fermented by the main species, Propionibacterium freudenreichii, to prevent colon carcinogenesis. Methods.[br/] We developed a new fermented milk. Taking advantage of milk fractions, high and stable populations of P. freudenreichii were obtained in this product. It was tested in vitro on gastric HGT-1 and colic HT-29 cells with respect to the typical hallmarks of apoptosis. In vivo, the fermented milk was evaluated in piglets with respect to general health parameters and in human microbiota-associated rats, treated or not with dimethylhydrazine (DMH), with respect to intestinal proliferation and apoptosis. Results. Fermented milk induced cell death in both gastric and colon cancer cells. Cellular and molecular characterization of cells dying in response to SCFA treatment revealed cell cycle arrest, drop in intracellular ATP, depolarization of mitochondria, translocation of key apoptosis proteins, processing of caspases and fragmentation of the nucleus. Interestingly, the new fermented milk was shown to potentiate the cytotoxic effect of molecules used in cancer chemotherapy. In accordance, it modulated expression of key apoptotic proteins. In vivo, the fermented milk was evaluated in piglets. Daily oral gavage led to high colic P. freudenreichii populations, to modulation of the intestinal microbiota and modulation of intestinal cytokines. Promotion of piglets’ growth also revealed general probiotic effects of fermented milk. Considering that propionibacteria were metabolically active in the intestine, we further investigated their impact on colon carcinogenesis (induced by dimethylhydrazine, DMH) in human microbiota-associated rats. Consumption of selected strains of propionibacteria resulted in enhanced apoptotic depletion of DMH damaged epithelial cells, yet had no effect on neither proliferation nor apoptosis in healthy rats. Conclusions and perspectives.[br/] These results open new perspectives in the field of colon cancer cells prevention and/or treatment. The synergy with pro-apoptotic chemotherapy molecules suggests that such a fermented product may be proposed as a food supplement to enhance the effects of anticancer treatments.
colloque international « Nutrition and Cancer : Hot topics from biology to public health issues »
Paris, France

hal-01190452
https://hal.archives-ouvertes.fr/hal-01190452
PRODINRA : 201853