Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Mucosal Immunol ; 10(6): 1455-1467, 2017 11.
Article in English | MEDLINE | ID: mdl-28327619

ABSTRACT

Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4+ T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from Th cell-driven intestinal inflammation and exhibited increased colonic Treg cells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the Treg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.


Subject(s)
Colitis, Ulcerative/immunology , Colon/immunology , Receptors, Interleukin-1/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Benzofurans , Cell Differentiation , Disease Models, Animal , Forkhead Transcription Factors/metabolism , Humans , Interleukin-2/metabolism , Interleukin-9/metabolism , Mice , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Quinolines , Receptors, Interleukin-1/genetics , STAT Transcription Factors/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction , Transcription Factor RelA/genetics , Transcription Factor RelA/metabolism
2.
Mucosal Immunol ; 10(3): 673-684, 2017 05.
Article in English | MEDLINE | ID: mdl-27624780

ABSTRACT

Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A- and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.


Subject(s)
Bacteria/immunology , Gastrointestinal Microbiome/immunology , Ileum/immunology , Interleukin-17/metabolism , Neutrophils/immunology , Receptors, Interleukin-8B/metabolism , Th17 Cells/immunology , Adaptive Immunity/genetics , Animals , Antimicrobial Cationic Peptides/metabolism , Bacteria/growth & development , Cell Differentiation , Cell Movement/genetics , Cells, Cultured , Homeodomain Proteins/genetics , Ileum/microbiology , Interleukins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Interleukin-22
3.
Mucosal Immunol ; 8(5): 959-68, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26174765

ABSTRACT

The epithelium serves as a highly selective barrier at mucosal surfaces. Upon injury, epithelial wound closure is orchestrated by a series of events that emanate from the epithelium itself as well as by the temporal recruitment of immune cells into the wound bed. Epithelial cells adjoining the wound flatten out, migrate, and proliferate to rapidly cover denuded surfaces and re-establish mucosal homeostasis. This process is highly regulated by proteins and lipids, proresolving mediators such as Annexin A1 protein and resolvins released into the epithelial milieu by the epithelium itself and infiltrating innate immune cells including neutrophils and macrophages. Failure to achieve these finely tuned processes is observed in chronic inflammatory diseases that are associated with non-healing wounds. An improved understanding of mechanisms that mediate repair is important in the development of therapeutics aimed to promote mucosal wound repair.


Subject(s)
Cell Movement/immunology , Epithelial Cells/immunology , Immunity, Innate , Macrophages/immunology , Neutrophils/immunology , Wound Healing/immunology , Animals , Annexin A1/immunology , Docosahexaenoic Acids/immunology , Epithelial Cells/pathology , Humans , Macrophages/pathology , Neutrophils/pathology
4.
Mucosal Immunol ; 7(5): 1221-32, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24621992

ABSTRACT

Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in vitro and in vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc metalloproteases during TEM. Neutrophil-derived soluble JAML binds to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair are reversed with an anti-JAML monoclonal antibody that inhibits JAML-CAR binding. JAML released from transmigrating neutrophils across inflamed epithelia may thus promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophils would compromise intestinal barrier and inhibit mucosal healing. Thus, targeting JAML-CAR interactions may improve mucosal healing responses under conditions of dysregulated neutrophil recruitment.


Subject(s)
Cell Adhesion Molecules/metabolism , Epithelial Cells/immunology , Inflammation/physiopathology , Intestinal Diseases/physiopathology , Neutrophils/immunology , Animals , Apoptosis , CHO Cells , Cell Adhesion Molecules/immunology , Cell Line , Cell Proliferation , Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Cricetulus , Epithelial Cells/cytology , HL-60 Cells , Humans , Inflammation/immunology , Intestinal Diseases/immunology , Models, Immunological , Protein Binding , Wound Healing/immunology
5.
J Immunol ; 167(2): 926-34, 2001 Jul 15.
Article in English | MEDLINE | ID: mdl-11441100

ABSTRACT

The majority of humans infected with Helicobacter pylori maintain a lifelong infection with strains bearing the cag pathogenicity island (PAI). H. pylori inhibits T cell responses and evades immunity so the mechanism by which infection impairs responsiveness was investigated. H. pylori caused apoptotic T cell death, whereas Campylobacter jejuni did not. The induction of apoptosis by H. pylori was blocked by an anti-Fas Ab (ZB4) or a caspase 8 inhibitor. In addition, a T cell line with the Fas rendered nonfunctional by a frame shift mutation was resistant to H. pylori-induced death. H. pylori strains bearing the cag PAI preferentially induced the expression of Fas ligand (FasL) on T cells and T cell death, whereas isogenic mutants lacking these genes did not. Inhibiting protein synthesis blocked FasL expression and apoptosis of T cells. Preventing the cleavage of FasL with a metalloproteinase inhibitor increased H. pylori-mediated killing. Thus, H. pylori induced apoptosis in Fas-bearing T cells through the induction of FasL expression. Moreover, this effect was linked to bacterial products encoded by the cag PAI, suggesting that persistent infection with this strain may be favored through the negative selection of T cells encountering specific H. pylori Ags.


Subject(s)
Antigens, Bacterial , Helicobacter pylori/immunology , T-Lymphocytes/immunology , T-Lymphocytes/microbiology , Apoptosis/immunology , Bacterial Proteins/immunology , Cell Line , Cytotoxicity, Immunologic , Fas Ligand Protein , Helicobacter pylori/pathogenicity , Humans , Jurkat Cells , Ligands , Membrane Glycoproteins/biosynthesis , Models, Immunological , Protein Biosynthesis , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Tumor Cells, Cultured , Up-Regulation/immunology , fas Receptor/metabolism , fas Receptor/physiology
6.
J Immunol ; 164(6): 2994-3001, 2000 Mar 15.
Article in English | MEDLINE | ID: mdl-10706687

ABSTRACT

T cell responses to self Ags and normal microbial flora are carefully regulated to prevent autoreactivity. Because IL-10-deficient mice develop colitis, and this response is triggered by luminal flora, we investigated whether IL-10 regulates the ability of microbial Ags to induce autoreactive T cells that could contribute to intestinal inflammation. T cells from wild-type mice were primed with staphylococcal enterotoxin B (SEB) in vitro, which induced an autoreactive proliferative response to syngeneic feeder cells. The cells were predominately CD3+ and CD4+. T cells from IL-10-deficient mice were constitutively autoreactive, and SEB priming enhanced this further. The autoreactive, proliferative response of T cells from wild-type mice was suppressed by IL-10 in the primary or secondary culture, and this effect was inhibited by neutralizing Abs to the IL-10R. To confirm that an autoreactive repertoire was expanded after SEB priming, we used CBA/J mice (Mls-1a) in which autoreactive T cells recognizing the endogenous viral superantigen are depleted (Vbeta6, 7, 8.1 TCR-bearing cells). However, SEB rescued these autoreactive T cell repertoires. Adding anti-MHC class II Ab blocked the autoreactive response. SEB-primed splenic or colonic T cells also induced apoptosis in syngeneic intestinal epithelial cells that was blocked significantly by IL-10. Thus, microbial Ags have the potential to abrogate self tolerance by stimulating autoreactive T cells that become cytolytic to target cells. IL-10 plays a protective role in maintaining self tolerance after microbial stimulation by preventing the activation of T cells that contribute to epithelial cell damage.


Subject(s)
Apoptosis/immunology , Enterotoxins/immunology , Interleukin-10/physiology , Intestinal Mucosa/immunology , Lymphocyte Activation/immunology , Staphylococcus aureus/immunology , T-Lymphocyte Subsets/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Clone Cells , Cytotoxicity Tests, Immunologic , Immunity, Cellular , Immunosuppressive Agents/pharmacology , Intestinal Mucosa/cytology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Knockout , T-Lymphocyte Subsets/cytology
7.
Int Immunol ; 12(2): 133-9, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10653848

ABSTRACT

The appearance of chronic intestinal inflammation in IL-10 knockout mice suggests IL-10 may inhibit adverse responses to luminal antigen. Moreover, this inflammation is associated with an increase in class II MHC molecule expression on intestinal epithelial cells. Thus, the role of IL-10 regulation in epithelial cell function was investigated. Using RT-PCR, it was shown that intestinal epithelial cells express mRNA for both subunits of the IL-10 receptor-signaling complex. In addition, biotinylated IL-10 was shown to bind to both cultured and freshly isolated intestinal epithelial cells prepared from the small or large intestine. This binding appeared specific as it was blocked by neutralizing antibodies to IL-10 but not the isotype control. Moreover, an excess of native IL-10 also inhibited the binding of radiolabeled IL-10. To evaluate whether IL-10 mediated any functions through this receptor, epithelial cells were cultured with IL-10 alone or with IFN-gamma plus IL-10. IL-10 alone had no detectable effects on epithelial cell growth or their expression of class II MHC molecules but it did antagonize the effect of IFN-gamma on the viability of cultured cells. In addition, IL-10 blocked the IFN-gamma-induced expression of class II MHC molecules on cultured epithelial cells. These results suggest that IL-10 binds to a specific receptor on intestinal epithelial cells and may regulate the contribution of epithelial cells to the inflammatory and immune response in the digestive tract.


Subject(s)
Interleukin-10/metabolism , Intestinal Mucosa/immunology , Intestine, Large/immunology , Intestine, Small/immunology , Receptors, Interleukin/metabolism , Animals , Cell Line , Cell Survival , Cells, Cultured , Epithelial Cells/cytology , Epithelial Cells/immunology , Flow Cytometry , Gene Expression Regulation , Histocompatibility Antigens Class II/metabolism , Interferon-gamma/pharmacology , Intestinal Mucosa/cytology , Intestine, Large/cytology , Intestine, Small/cytology , Mice , Mice, Inbred C3H , RNA, Messenger/metabolism , Receptors, Interleukin-10 , Reverse Transcriptase Polymerase Chain Reaction
8.
J Immunol ; 162(4): 2275-80, 1999 Feb 15.
Article in English | MEDLINE | ID: mdl-9973504

ABSTRACT

IL-10 plays an important role in preventing excessive inflammation to the normal flora in the intestinal lumen. The purpose of this study was to compare the effect of normal flora on inflammation in mice in which the IL-10 gene was disrupted. IL-10 knock-out mice housed in germfree conditions remained healthy while those housed in conventional conditions developed colitis after weaning, suggesting that IL-10 inhibits the adverse responses to luminal Ag. Crypt abscesses were present in virtually all of the diseased animals as evidenced by flattening of the epithelial cells and a large number of neutrophils in the lumen of the crypt. Since KC is a chemokine that is capable of recruiting neutrophils in mice, mRNA and protein for KC was measured. Increased levels of both KC mRNA and protein were detected in the colon of diseased mice. To determine whether the epithelial cells were capable of synthesizing KC and contributing to neutrophil accumulation in the crypts, a murine intestinal epithelial cell line (Mode-K) was shown to express mRNA and protein for KC. Two cytokines induced in association with colitis in these mice, TNF-alpha and IFN-gamma, increased the expression of KC mRNA and protein in murine epithelial cells. However, IL-10 was incapable of decreasing the induction of KC, even though the cells expressed the IL-10 receptor. These results suggest that the neutrophil chemokine KC is produced by gastrointestinal epithelial cells in response to inflammatory mediators that are expressed following exposure to normal flora in animals lacking IL-10.


Subject(s)
Chemokines, CXC/biosynthesis , Chemotactic Factors/biosynthesis , Colon/microbiology , Cytokines/physiology , Enterocolitis/microbiology , Epithelial Cells/microbiology , Growth Substances/biosynthesis , Intercellular Signaling Peptides and Proteins , Intestinal Mucosa/microbiology , Neutrophils/immunology , Age Factors , Animals , Cell Line , Chemokine CXCL1 , Chemokines, CXC/genetics , Chemotactic Factors/genetics , Colon/immunology , Colon/pathology , Enterocolitis/immunology , Enterocolitis/mortality , Enterocolitis/pathology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Growth Substances/genetics , Interleukin-10/deficiency , Interleukin-10/genetics , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Mice , Mice, Knockout , RNA, Messenger/biosynthesis , Sex Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...