Novel immunomodulatory properties of cirsilineol through selective inhibition of IFN-gamma signaling in a murine model of inflammatory bowel disease.
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-gamma/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-gamma and corresponding up-regulation of IL-10 and TGF-beta. The therapeutic effect of cirsilineol was attributable to a novel regulatory mechanism with selective inhibiting IFN-gamma signaling in colonic lamina propria CD4(+) T cells, which was mediated through down-regulating STAT1 activation and T-bet expression. Furthermore, cirsilineol was found to down-regulate the activation of JAK2, a critical kinase for IFN-gamma/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-gamma/STAT1 signaling by cirsilineol was reversible in the presence of high level of IFN-gamma. These results strongly suggest that cirsilineol might be potentially useful for treating T-cell-mediated human inflammatory bowel diseases.
Sun
Yang
Y
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China.
Wu
Xing-Xin
XX
Yin
Ye
Y
Gong
Fang-Yuan
FY
Shen
Yan
Y
Cai
Tian-Tian
TT
Zhou
Xiao-Bin
XB
Wu
Xue-Feng
XF
Xu
Qiang
Q
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015345:Oligonucleotide Probes; D015398:Signal Transduction / Q000187:drug effects*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D047309:Flavones; D007155:Immunologic Factors; D015345:Oligonucleotide Probes; C057618:cirsilineol; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid