title: Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis.
abstract: Mechanisms involved in inflammatory development during acute pancreatitis (AP) are largely vague, especially in the transformation of acute edematous pancreatitis (AEP) into acute necrotizing pancreatitis (ANP). This current study aims to investigate the functions of Traf6 in different AP models in vitro and in vivo, and to identify the possible regulatory mechanism in the progression of inflammation from mild to severe. Our data revealed that the level of Traf6 expression was significantly increased in the mild AP induced by caerulein, and the upregulation of Traf6 played a protective role in acinar cells against caerulein-induced apoptosis. In contrast, only Traf6 protein but not mRNA was downregulated in the severe ANP induced by combination treatment of caerulein and LPS. Mechanistic studies showed that LPS upregulated the levels of Socs1 and Socs3 expressions in acinar cells, Socs1 and Socs3 interacted Traf6 directly and degraded Traf6 protein via polyubiquitination, thereby counteracted the protective function of Traf6. In vivo study further showed that combination treatment of caerulein and LPS failed to induce an ANP model in the TLR4 knockout mice, and the level of Traf6 expression in the pancreatic tissues remained the same as that from the acute edematous pancreatitis (AEP) mouse. Taken together, our study reveals that Traf6 functioned as a protective factor in the progression of AP, and LPS-induced Socs1 and Socs3 exacerbate mild AP to severe AP, which provides evidence for developing a new therapeutic target to combat AP.
authors.affiliation: Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China.
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Sichuan Medical University, Luzhou, Sichuan Province, P. R. China.
authors.forename: F
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China.
authors.forename: Y
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
chemical_list: D008070:Lipopolysaccharides; D050826:Suppressor of Cytokine Signaling Proteins; D048029:TNF Receptor-Associated Factor 6