Journal Article

Oncostatin M Induces a Pro-inflammatory Phenotype in Intestinal Subepithelial Myofibroblasts

Kokkotis, Georgios, Manolopoulos, Vangelis G, Arvanitidis, Konstantinos, Vradelis, Stergios, Bamias, Giorgos, Drygiannakis, Ioannis, Filidou, Eirini, Spathakis, Michail, Paspaliaris, Vasilis, Dovrolis, Nikolas, Tarapatzi, Gesthimani, Kandilogiannakis, Leonidas, Kolios, George, Valatas, Vassilis

2024

Overview

Abstract Background Oncostatin-M (OSM) is associated with antitumor necrosis factor (anti-TNF)-α resistance in inflammatory bowel disease (IBD) and fibrosis in inflammatory diseases. We studied the expression of OSM and its receptors (OSMR, gp130) on intestinal subepithelial myofibroblasts (SEMFs) and the effect of OSM stimulation on SEMFs. Methods The mRNA and protein expression of OSM, OSMR, gp130, and several fibrotic and chemotactic factors were studied in mucosal biopsies and isolated human intestinal SEMFs of patients with IBD and healthy controls (HCs) and in a model of human intestinal organoids (HIOs). Subepithelial myofibroblasts and HIOs were stimulated with OSM and interleukin (IL)-1α/TNF-α. RNAseq data of mucosal biopsies were also analyzed. Results Oncostatin-M receptors and gp130 were overexpressed in mucosal biopsies of patients with IBD (P < .05), especially in inflamed segments (P < .05). The expression of OSM, OSMR, and gp130 in SEMFs from HCs was increased after stimulation with IL-1α/TNF-α (P < .001; P < .01; P < .01). The expression of CCL2, CXCL9, CXCL10, and CXCL11 was increased in SEMFs from patients with IBD and HCs after stimulation with OSM in a dose-dependent manner (P < .001; P < .05; P < .001; P < .001) and was further increased after prestimulation with IL-1α/TNF-α (P < .01 vs OSM-alone). Similar results were yielded after stimulation of HIOs (P < .01). Oncostatin-M did not induce the expression of collagen I, III, and fibronectin. Oncostatin-M receptor expression was positively correlated with CCL2, CXCL9, CXCL10, and CXCL11 expression in mucosal biopsies (P < .001; P < .001; P = .045; P = .033). Conclusions Human SEMFs overexpress OSMR in an inflammatory microenvironment. Oncostatin-M may promote inflammation in IBD via its stimulatory effects on SEMFs, which primarily involve chemoattraction of immune cells to the intestinal mucosa. Lay Summary Oncostatin-M/OSMR show elevated expression on intestinal fibroblasts that is regulated by IBD-relevant pro-inflammatory stimuli. In turn, OSM induces a pro-inflammatory phenotype on primary intestinal fibroblasts, with prominent overexpression of chemotactic factors, without demonstrating a substantial profibrotic effect.

• Publisher: Oxford University Press
• Subject: Adult / Biopsy / Case-Control Studies / Cells, Cultured / Cytokine Receptor gp130 - metabolism / Female / Humans / Inflammatory bowel disease / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Male / Myofibroblasts - metabolism / Myofibroblasts - pathology / Oncostatin M - metabolism / Oncostatin M Receptor beta Subunit / Organoids - metabolism / Phenotype / Receptors, Oncostatin M - metabolism / Tumor Necrosis Factor-alpha - metabolism