ABSTRACT
BACKGROUND: Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear. METHODS: The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88(-/-) mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs). To this end, MyD88(-/-) and wild-type (WT) mice received sterile distilled water containing 1.2% DSS for 8 days. The survival rate, total clinical score (body weight loss, stool consistency, and rectal bleeding), colon length, and histological score were assessed. The expression of surface markers (F4/80 and CD4) on infiltrating lamina propria mononuclear cells was analyzed immunohistochemistrically. RESULTS: MyD88(-/-) mice exhibited increased susceptibility to DSS-induced colitis, as reflected by significantly higher lethality and higher clinical and histological scores, and more severe colonic shortening compared to WT mice. Immunohistochemical analysis revealed a significant increase of both F4/80+ macrophages and CD4+ T cells in the inflamed mucosa in DSS-fed MyD88(-/-) mice compared to DSS-fed WT mice. CONCLUSIONS: These findings suggest that, via MyD88 signaling, the innate immune system in the gut plays an important protective role in colitis.
Subject(s)
Adaptor Proteins, Signal Transducing/drug effects , Adaptor Proteins, Signal Transducing/deficiency , Antigens, Differentiation/drug effects , Antiviral Agents/adverse effects , Colitis/chemically induced , Colitis/metabolism , Dextran Sulfate/adverse effects , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/metabolism , Receptors, Immunologic/drug effects , Receptors, Immunologic/deficiency , Animals , Antigens, CD/drug effects , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/drug effects , Antigens, Differentiation, T-Lymphocyte/metabolism , Antiviral Agents/administration & dosage , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Colitis/mortality , Dextran Sulfate/administration & dosage , Disease Models, Animal , Disease Susceptibility , Dose-Response Relationship, Drug , Immunohistochemistry , Inflammatory Bowel Diseases/mortality , Interleukin-18 Receptor alpha Subunit , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Lectins, C-Type , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Myeloid Differentiation Factor 88 , Receptors, Interleukin/drug effects , Receptors, Interleukin/metabolism , Receptors, Interleukin-18 , Receptors, Interleukin-2/drug effects , Receptors, Interleukin-2/metabolism , Severity of Illness IndexABSTRACT
BACKGROUND AND AIMS: The authors have previously shown that a third member of the CD28 family, inducible costimulator (ICOS), was increased in the inflamed intestinal mucosa of murine experimental colitis, and that the blockade of ICOS ameliorated the development of colitis. However, the role of ICOS in rat intestinal inflammation and its expression profile remains unclear. In the present study, the authors investigated the involvement of ICOS in the development of rat dextran sulfate sodium (DSS)-induced colitis, and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in colitis. METHODS: The authors first examined expression of ICOS protein in normal rat by immunohistochemistry and flow cytometry. Sprague-Dawley rats were fed 3.0% DSS. The expression of ICOS on infiltrating lamina propria mononuclear cells and splenocytes were examined. The DSS-fed rats were then administered anti-ICOS mAb to test its effect on the development of colitis. RESULTS: Unlike mice and human, ICOS was expressed on a part of CD4+ T-cells from the thymus, spleen, mesenteric lymph nodes and lamina propria. Levels of ICOS on CD4+ T-cells from the spleen and colonic lamina propria were significantly upregulated after Concanavalin A (Con A) stimulation. In addition, ICOS was also upregulated on CD4+ T-cells from DSS-fed rats compared with those from non DSS-fed rats. However, anti-ICOS mAb did not ameliorate the development of both acute and chronic DSS colitis. CONCLUSION: These results suggest that the different expression of ICOS in rats plays a distinct role in rat intestinal inflammation.
Subject(s)
Antigens, Differentiation, T-Lymphocyte/metabolism , Colitis/metabolism , Colon/metabolism , Intestinal Mucosa/metabolism , Animals , Antibodies, Monoclonal/administration & dosage , Antigens, Differentiation, T-Lymphocyte/immunology , Colitis/chemically induced , Colitis/pathology , Colitis/prevention & control , Colon/pathology , Dextran Sulfate , Flow Cytometry , Immunohistochemistry , Inducible T-Cell Co-Stimulator Protein , Intestinal Mucosa/pathology , Leukocytes, Mononuclear/metabolism , Rats , Rats, Sprague-Dawley , Spleen/metabolism , Thymus Gland/metabolismABSTRACT
BACKGROUND AND AIM: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. METHODS: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. RESULTS: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. CONCLUSIONS: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.
Subject(s)
Colitis/metabolism , Interleukin-18/metabolism , Analysis of Variance , Animals , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Disease Susceptibility , Flow Cytometry , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, TransgenicABSTRACT
Based on Pasteur's work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gut-associated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).
