Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice

Abstract

Cytokines may be crucially involved in the pathogenesis of inflammatory bowel diseases (IBD), but it remains controversial whether interferon (IFN)-gamma, a typical proinflammatory cytokine, is an essential mediator to cause the disorders. In the present study, IFN-gamma(-/-) and wild-type (WT) C57BL/6 mice were fed 2.5% dextran sodium sulphate (DSS) in drinking water for 7 days, in order to investigate DSS-induced intestinal inflammation. The DSS-treated WT mice exhibited a robust production of IFN-gamma in the gut, a remarkable loss of body weight, as well as high rate of mortality (60%). In striking contrast, IFN-gamma deficient mice did not develop DSS-induced colitis, as indicated by the maintenance of body weight and survival rate of 100%. Severe intestinal inflammation was demonstrated exclusively in WT animals in terms of the shortening of the bowel as well as the elevation of the disease activity index, myeloperoxidase (MPO) activity and serum haptoglobin level. Histological study of DSS-treated WT intestine revealed disruption of mucosal epithelium and massive infiltration of inflammatory cells, while the organ from IFN-gamma(-/-) mice remained virtually normal in appearance. Enzyme-linked immunosorbent assay (ELISA) analyses indicated abundant production of three chemokines, i.e. monokine induced by interferon-gamma (MIG), interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), in the DSS-irritated intestine of WT but not of IFN-gamma(-/-) mice. The present results demonstrate clearly that IFN-gamma plays indispensable roles in the initiation of DSS colitis, and some chemokines are produced in an IFN-gamma-dependent fashion.

Hyaluronan-Mediated Leukocyte Adhesion and Dextran Sulfate Sodium-Induced Colitis Are Attenuated in the Absence of Signal Transducer and Activator of Transcription 1

“…40 -43 A contradictory report appeared recently however, that indicates IFN-␥-null mice are less susceptible to DSS-induced colitis. 44 We showed greater deposition of HA in DSS-treated wild-type mouse colon. This result is consistent with our in vitro studies in which we observed increased HA deposition with a unique cable-like structure that binds more leukocytes.…”

Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction

“…In vitro, administration of IL1b is reported to induce DNA methylation through induction of Nos2 (Hmadcha et al, 1999) and in CDH1 promoter (Qian et al, 2008). INFg is reported to be involved in initiation of DSS-induced colitis (Ito et al, 2006) and in development of colon tumors in Socs1-deficient mice (Hanada et al, 2006), but its role in induction of aberrant DNA methylation is still unknown. Il6 is known to induce DNA methyltransferase expression (Hodge et al, 2001), and its deficiency in mice leads to decreased tumor number and size after AOM and DSS treatment (Grivennikov et al, 2009).…”

ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

“…Although an increased level of IFN-␥ is protective against acute viral infection, excessive production of IFN-␥ by NK cells can lead to increased pathology in the Shwartzman reaction to LPS, inflammatory bowel disease, and atherosclerosis (37)(38)(39)(40)(41)(42). Negative regulators such as ATF3 serve to modulate inflammation to a level appropriate for clearing a pathogen while preventing pathology caused by unrestrained inflammatory responses.…”