Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis.

Abstract

IL-12 promotes Th1 cell differentiation and cell-mediated immunity. In the present study, the potential role of IL-12 was analyzed in an experimental colitis model in scid mice reconstituted with syngeneic CD45RBhighCD4+ T cells. Real-time reverse transcription-PCR studies demonstrated that IL-12 p40 mRNA in inflamed colon is induced shortly after T cell transfer and maintained at a stable level after week 4, at the time when wasting disease starts. Administration of anti-IL-12 on days 0,14, and 28 (early treatment) or on days 28, 42, and 56 (delayed treatment) after T cell transfer, effectively prevented or, respectively cured wasting disease and colitis in scid recipients. Anti-IL-12 treatment abrogated mucosal inflammation with significantly diminished leukocyte infiltration (CD4 cells, macrophages) and CD54 expression, and down-regulated proinflammatory cytokines IFN-gamma and IL-2. Of note, although splenic CD4+ T cells are unable to induce disease as a result of the presence of regulatory CD45RBlow cells, splenic CD4+ T cells, preactivated by IL-12 and anti-CD3 in vitro, were highly pathogenic in inducing severe mucosal inflammation, suggesting that IL-12 and anti-CD3 abrogated regulatory T cell function. These findings indicate that IL-12 is important for the induction of experimental colitis through effects on proinflammatory cytokine production and on regulatory T cell function.

• Authors: Z Liu, K Geboes, H Heremans, L Overbergh, C Mathieu, P Rutgeerts, J L Ceuppens
• Journal: European journal of immunology (Eur J Immunol) Vol. 31 Issue 5 Pg. 1550-60 (May 2001) ISSN: 0014-2980 [Print] Germany
• PMID: 11465113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• RNA, Messenger
• Intercellular Adhesion Molecule-1
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Antibodies (immunology, pharmacology, therapeutic use)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism, transplantation)
• Cells, Cultured
• Chemotaxis, Leukocyte (drug effects)
• Chronic Disease
• Colitis (drug therapy, immunology, metabolism, pathology)
• Colon (drug effects, immunology, metabolism, pathology)
• Disease Models, Animal
• Female
• Immunity, Mucosal (immunology)
• Immunohistochemistry
• Inflammation (drug therapy, immunology, metabolism, pathology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Interferon-gamma (metabolism)
• Interleukin-12 (antagonists & inhibitors, genetics, immunology, metabolism)
• Kinetics
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• RNA, Messenger (genetics, metabolism)
• Recurrence
• Spleen (immunology)