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期刊论文
Novel immunomodulatory properties of cirsilineol through selective inhibition of IFN-g signaling in a murine model of inflammatory bowel disease§
Biochemical Pharmacology 79 (2010) 229-238,-0001,():
Regulation of signal transducer and activator of transcription (STAT) 1 signaling is being explored as a new approach to the treatment of inflammatory bowel diseases. However, few chemicals have been reported to inhibit IFN-g/STAT1 signaling for Crohn's disease therapy. In the present study, we found that cirsilineol, a small natural compound isolated from Artemisia vestita, significantly ameliorated trinitro-benzene sulfonic acid (TNBS)-induced T-cell-mediated experimental colitis in mice, which was closely associated with reduced autoreactive T-cell proliferation and activation. Moreover, the regulatory action of pro-inflammatory and anti-inflammatory cytokine by cirsilineol treatment was found to decrease the activity of effector Th1 cells but increase the activity of regulatory T cells as characterized by down-regulation of IFN-g and corresponding up-regulation of IL-10 and TGF-b. The therapeutic effect of cirsilineol was attributable to a novel regulatory mechanism with selective inhibiting IFN-g signaling in colonic lamina propria CD4+ T cells, which was mediated through downregulating STAT1 activation and T-bet expression. Furthermore, cirsilineol was found to down-regulate the activation of JAK2, a critical kinase for IFN-g/STAT1 signaling, and abrogate the expression of T-bet, resulting in markedly decreased proliferation and activation of T cells in vitro. Importantly, the inhibition of IFN-g/STAT1 signaling by cirsilineol was reversible in the presence of high level of IFN-g. These results strongly suggest that cirsilineol might be potentially useful for treating T-cell-mediated human inflammatory bowel diseases.
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