Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism
Zanin-Zhorov A., Weiss JM., Nyuydzefe MS., Chen W., Scher JU., Mo R., Depoil D., Rao N., Liu B., Wei J., Lucas S., Koslow M., Roche M., Schueller O., Weiss S., Poyurovsky MV., Tonra J., Hippen KL., Dustin ML., Blazar BR., Liu C-J., Waksal SD.
Significance Rho-associated kinase 2 (ROCK2) is implicated in the regulation of proinflammatory cytokines, such as IL-17 and IL-21, and the development of autoimmunity in mice. However, the role of ROCK2 signaling pathway in regulation of immune responses in humans is still an enigma. Here we show that targeted ROCK2 inhibition down-regulates proinflammatory responses via concurrent regulation of STAT3/STAT5 phosphorylation and shifting Th17/Treg balance in human T cells with a minimal effect on the rest of the immune response. This work provides previously unidentified insights into the molecular mechanism of ROCK2-mediated modulation of the immune response in man and has profound implications for development of a selective ROCK2 inhibitor as a new therapeutic target for autoimmunity treatment.