Abstract
Ulcerative colitis (UC) is a chronic disease associated with long periods of quiescent disease followed by fulminant exacerbation. Imminent relapse in UC is associated with high mucosal expression of suppressor of cytokine signaling 3 (SOCS3); hence, knowledge of the mechanisms driving mucosal SOCS3 expression may provide important clues as to rational therapy. Thus, here we aim to characterize the molecular forces driving SOCS3 expression in the mucosal compartment, focusing on druggable pathways. The colon epithelial cell line Caco-2 was stimulated with interferon (IFN)-γ, interleukin (IL)-4 or prostaglandin E(2) (PGE(2)) to allow correlations between SOCS3 expression with signal transducer and activator of transcription 1 (STAT1), STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling, respectively. The physiological relevance of the findings obtained was assessed by immunohistochemical staining for the activated forms of STAT1, STAT6, protein kinase A (PKA)-Cγ and cAMP response element-binding protein (CREB) in biopsies from inactive UC patients and controls. Stimulation with IFN-γ, IL-4 or PGE(2) induced activation of STAT1, STAT6 and cAMP, respectively, in colonic cells, without any signs of concomitant STAT3 activation. Forced activation of all these signaling pathways was sufficient for SOCS3 expression. Biopsies from patients with inactive UC showed significant increase of phosphorylated STAT1 (p-STAT1) (p < 0.0001), p-STAT6 (p = 0.0001), p-PKA-Cγ (p = 0.0003) and p-CREB (p = 0.0025) expression compared with controls. STAT3-independent SOCS3 induction in inactive UC involves multiple proinflammatory signaling pathways and contradicts the usefulness of pathway-specific antiinflammatory drugs for preventing relapse. Our findings suggest that broad-spectrum antiinflammatory drugs are essential to counteract increases in SOCS3 expression and exacerbation of disease. Our results highlight the multifactorial nature of the factors that cause exacerbation in UC.
Highlights
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by alternating periods of remission and relapse
There were no significant differences in patient sex and mean age between groups of control and inactive UC patients (Table 1)
We showed for the first time that IL-4 induced STAT6 phosphorylation and subsequent suppressor of cytokine signaling 3 (SOCS3) expression in intestinal epithelial cells (IECs), and p-STAT6 combined with high SOCS3 is expressed in the biopsies from UC patients with inactive disease
Summary
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by alternating periods of remission and relapse. We previously reported that an increase of mucosal suppressor of cytokine signaling 3 (SOCS3) protein levels in colonic epithelium in biopsies otherwise devoid of signs of a mounting inflammatory reaction is a highly reliable predictor of upcoming relapse [2]. This result suggests a causative role of increased SOCS3 expression for disease exacerbation. Characterization of the molecular mechanisms that drive SOCS3 expression in the mucosal epithelium of UC patients is of utmost importance for both our fundamental understanding of processes driving UC relapse and for devising rational strategies for its prevention
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