We identified altered IL-6-induced Jak1-dependent STAT3 phosphorylation in human ileal subepithelial myofibroblasts (SEMF) of patients with stricturing Crohn’s disease. This resulted in co-localization of pSTAT3(Y705) to Rab5+ signaling endosomes along with pIGF-I receptors that jointly mediated excess collagen I production and proliferation in SEMF of strictures. PTPN2 gene variants occur in patients with Crohn’s disease with rs7234029 associated with apparent ‘loss-of-function’ and with stricturing disease.