title: SOCS3 regulates BAFF in human enterocytes under ribosomal stress.
abstract: Although the activation of B cells in the gastrointestinal tract is of great importance in the context of immunity to pathogens and mucosal inflammatory diseases, little is known about the mechanisms responsible for the local activation of B cells in the subepithelial area of the intestine. Epithelium-derived BAFF is the major modulator of B cell development and Ig class switching. The present study was performed to address the molecular mechanism of BAFF expression in gut epithelial cells in the presence of proinflammatory stimuli. Inflammation-induced BAFF expression in mucosal epithelial cells might be responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Although BAFF was marginally expressed in unstimulated epithelial cells, BAFF mRNA was significantly upregulated by proinflammatory IFN-γ. Furthermore, IFN-γ triggered JAK/STAT1 signals via the cytokine receptor, which contributed to epithelial BAFF upregulation. In terms of signaling intervention, ribosomal insult attenuated IFN-γ-activated JAK/STAT signal transduction and subsequent BAFF induction in gut epithelial cells. Ribosomal insults led to the superinduction of SOCS3 by enhancing its mRNA stability via HuR RNA-binding protein. Upregulated SOCS3 then contributed to the blocking of the JAK/STAT-linked signal, which mediated BAFF suppression by ribosomal stress. All of these findings show that ribosomal stress-induced SOCS3 plays a novel regulatory role in epithelial BAFF production, suggesting that epithelial ribosomal dysfunction in association with SOCS3 may be a promising therapeutic point in BAFF-associated human mucosal diseases.
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, South Korea.
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Do
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ki-Hyung
authors.initials: KH
authors.lastname: Kim
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
chemical_list: D053264:B-Cell Activating Factor; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C505719:TNFSF13B protein, human