The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation

Gerlach K, Lechner K, Popp V, Offensperger L, Zundler S, Wiendl M, Becker E, Atreya R, Rath T, Neurath M, Weigmann B (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Crohns & Colitis Elsevier

Book Volume: 15

Pages Range: 244-257

Journal Issue: 2

DOI: 10.1093/ecco-jcc/jjaa162

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.

Authors with CRIS profile

Katharina Gerlach Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Vanessa Popp Institute of Radiology Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maximilian Wiendl Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Timo Rath Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I Benno Weigmann Medizinische Fakultät

Related research project(s)

None - None

How to cite

APA:

Gerlach, K., Lechner, K., Popp, V., Offensperger, L., Zundler, S., Wiendl, M.,... Weigmann, B. (2021). The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation. Journal of Crohns & Colitis, 15(2), 244-257. https://doi.org/10.1093/ecco-jcc/jjaa162

MLA:

Gerlach, Katharina, et al. "The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation." Journal of Crohns & Colitis 15.2 (2021): 244-257.

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