The JAK1/3 inhibitor tofacitinib suppresses T cell homing and activation in chronic intestinal inflammation.

Abstract

The molecular mechanism of action of the Janus kinase (JAK) inhibitor tofacitinib is poorly understood. Here, we analysed the inhibitory effect of tofacitinib on mucosal and blood T cells from patients with ulcerative colitis (UC). Furthermore tofacitinib treatment was analysed in experimental colitis models and wound healing. Additionally, tofacitinib effects were analysed in bioassays. Tofacitinib significantly reduced T cell derived inflammatory cytokine production (Th2, Th9, Th17) in patients with active UC. Additionally, impaired expression of the homing receptors alpha4/beta1 and alpha4/beta7 as well as reduced gut homing capacity of T cells in a humanized mouse model of colitis were observed. Tofacitinib suppressed acute and chronic oxazolone colitis compared to untreated wild-type mice associated with downregulation of cytokines produced by Th2, Th9 and Th17 cells. Functionally, tofacitinib induced apoptosis of intestinal epithelial cells and prevented mucosal wound healing in vivo at higher concentration. Thus, our findings suggest that tofacitinib is quite effective in protecting from colitis by inhibition of a bundle of T cell derived cytokines like IL-5, IL-6, IL-9, IL-13 and IL-17A. Application of tofacitinib emerges as an attractive concept for treatment of chronic intestinal inflammation at lower concentrations, whereas higher concentrations require attention due to prolonged wound healing.