title: Inhibition of p38 pathway suppresses human islet production of pro-inflammatory cytokines and improves islet graft function.
abstract: Nonspecific inflammation is associated with primary graft nonfunction (PNF). Inflammatory islet damage is mediated at least partially by pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced by resident islet macrophages. The p38 pathway is known to be involved in cytokine production in the cells of the monocyte-macrophage lineage. Therefore, inhibition of the p38 pathway may prevent pro-inflammatory cytokine production by resident islet macrophages and possibly reduce the incidence of PNF. Our present study has demonstrated that inhibition of the p38 pathway by a chemical p38 inhibitor, SB203580, suppresses IL-1beta and TNF-alpha production in human islets exposed to lipopolysaccharide (LPS) and/or inflammatory cytokines. Although IL-1beta is predominantly produced by resident macrophages, ductal cells and islet vascular endothelial cells were found to be another cellular source of IL-1beta in isolated human islets. SB203580 also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the treated islets. Furthermore, human islets treated with SB203580 for 1 h prior to transplantation showed significantly improved graft function. These results suggest that inhibition of the p38 pathway may become a new therapeutic strategy to improve graft survival in clinical islet transplantation.
authors.affiliation: Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center/Beckman Research Institute, Duarte, CA, USA.
authors.forename: Takeru
authors.initials: T
authors.lastname: Matsuda
authors.forename: Keiko
authors.initials: K
authors.lastname: Omori
authors.forename: Tommy
authors.initials: T
authors.lastname: Vuong
authors.forename: Michael
authors.initials: M
authors.lastname: Pascual
authors.forename: Luis
authors.initials: L
authors.lastname: Valiente
authors.forename: Kevin
authors.initials: K
authors.lastname: Ferreri
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Craig V
authors.initials: CV
authors.lastname: Smith
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mullen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008070:Lipopolysaccharides / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580