Upadacitinib effectively suppresses IL13RA2 expression in primary human intestinal fibroblasts derived from Crohn's disease tissue.

Abstract

Interleukin-13 receptor alpha 2 (IL13RA2) is highly expressed in intestinal inflammation-associated fibroblasts (IAFs) and is associated with anti-tumor necrosis factor alpha (TNF-α) therapy resistance in inflammatory bowel disease (IBD). Because IL13RA2 inhibition ameliorates experimental colitis in mice, we investigated IL13RA2 regulation in Crohn's disease (CD)-derived primary human intestinal fibroblasts (phIFs) and the effect of anti-TNF-α infliximab and the Janus Kinase (JAK)1 inhibitor upadacitinib. Nineteen independent phIF cultures were established from CD surgical tissue, either from full tissue pieces (explant) or cell suspensions (suspension). phIFs were exposed to IL13, upadacitinib, infliximab, and/or signal transducer and activator of transcription (STAT)3/6 inhibitors. Cellular responses were assessed using viability assays, qRT-PCR, Western blotting and fluorescence microscopy. Suspension-derived phIFs exhibited higher basal IL13RA2 expression than explant-derived phIFs. IL13 strongly enhanced IL13RA2 mRNA and protein levels in phIFs. Upadacitinib effectively suppressed basal and IL13-induced IL13RA2 expression, without affecting phIF viability or proliferation. Infliximab did not reduce IL13-induced IL13RA2 expression. IL13 induced both STAT3 and STAT6 phosphorylation and STAT6 inhibition efficiently suppressed IL13-induced IL13RA2 expression, mirroring the effect of upadacitinib. These results reveal that CD-derived phIFs show marked heterogeneity in basal IL13RA2 expression, which is strongly induced by IL13 and associated with JAK1-STAT6 pathway activation, both of which are effectively suppressed by upadacitinib. This direct effect of JAK inhibition on IL13RA2 expression may contribute to its therapeutic effect in IBD.