title: Activation of peroxisome proliferator-activated receptor-gamma protects pancreatic beta-cells from cytokine-induced cytotoxicity via NF kappaB pathway.
abstract: Diabetes mellitus is characterized by cytokine-induced insulitis and a deficit in beta-cell mass. Ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) have been shown to have anti-inflammatory effects in various experimental models. We questioned whether activation of endogenous PPAR-gamma by either PPAR-gamma ligands or adenoviral-directed overexpression of PPAR-gamma (Ad-PPAR-gamma) could inhibit cytokine-induced beta-cell death in RINm5F (RIN) cells, a rat insulinoma cell line. Treatment of RIN cells with interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) induced beta-cell damage through NF kappaB-dependent signaling pathways. Activation of PPAR-gamma by PPAR-gamma ligands or Ad-PPAR-gamma inhibited IL-1 beta and IFN-gamma-stimulated nuclear translocation of the p65 subunit and DNA binding activity. NF kappaB target gene expression and their product formation, namely inducible nitric oxide synthase and cyclooxygenase-2 were decreased by PPAR-gamma activation, as established by real-time PCR, Western blots and measurements of NO and PGE(2). The mechanism by which PPAR-gamma activation inhibited NF kappaB-dependent cell death signals appeared to involve the inhibition of I kappa B alpha degradation, evidenced by inhibition of cytokine-induced NF kappaB-dependent signaling events by Ad-I kappaB alpha (S32A, S36A), non-degradable I kappaB alpha mutant. I kappaB beta mutant, Ad-I kappaB beta (S19A, S23A) was not effective in preventing cytokine toxicity. Furthermore, a protective effect of PPAR-gamma ligands was proved by assaying for normal insulin secreting capacity in response to glucose in isolated rat pancreatic islets. The beta-cell protective function of PPAR-gamma ligands might serve to counteract cytokine-induced beta-cell destruction.
authors.affiliation: Department of Biochemistry, Medical School and Institute for Medical Sciences, Chonbuk National University, Jeonju 561-756, Jeonbuk, Republic of Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Kang-Beom
authors.initials: KB
authors.lastname: Kwon
authors.forename: Bon-Sun
authors.initials: BS
authors.lastname: Koo
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Han
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Song
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Do-Gon
authors.initials: DG
authors.lastname: Ryu
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D016207:Cytokines; D020672:I-kappa B Proteins; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D009573:Nitrites; D047495:PPAR gamma; D045162:Thiazolidinediones; D000072000:NF-KappaB Inhibitor alpha; D000077288:Troglitazone; D015232:Dinoprostone; C039671:ciglitazone