The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation. (18th August 2020)

• Record Type: Journal Article
• Authors: Gerlach, Katharina; Lechner, Kristina; Popp, Vanessa; Offensperger, Laura; Zundler, Sebastian; Wiendl, Maximilian; Becker, Emily; Atreya, Raja; Rath, Timo; Neurath, Markus F; Weigmann, Benno
• Is Part Of: Journal of Crohn's and colitis. Volume 15:Number 2(2021)
• Page Start: 244
• Page End: 257
• Publication Date: 2020-08-18
• Subjects: Tofacitinib -- T cells -- cytokines -- wound healing -- inflammatory bowel disease; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjaa162
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: The molecular mechanism of action of the Janus kinase [JAK] inhibitor tofacitinib is poorly understood. Methods: 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. Results: 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 humanised mouse model of colitis, were observed. Tofacitinib suppressed acute and chronic oxazolone colitis, compared with 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. Conclusions: 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. Podcast: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast