title: STAT1, STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling drive SOCS3 expression in inactive ulcerative colitis.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, Netherlands. yili1101@hotmail.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Jasper
authors.initials: J
authors.lastname: Deuring
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: Colin
authors.initials: C
authors.lastname: de Haar
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
mesh_terms: D000328:Adult; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D020895:Enterocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463939:protein kinase A Cgamma