title: Involvement of the TLR4 (Toll-like receptor4) signaling pathway in palmitate-induced INS-1 beta cell death.
abstract: Fatty acid-induced cytotoxicity is believed to recapitulate lipotoxicity seen in obese type-2 diabetes, and, thus, contribute to beta cell loss in the disease. These studies were initiated to determine whether the Toll-like receptor (TLR) signaling pathway was involved in palmitate-induced beta cell death. Treatment of INS-1 beta cells with palmitate enhanced interaction between TLR and myeloid differentiation factor88 (MyD88). Concomitant with TLR/MyD88 interaction, the level of phospho-C-Jun N-terminal kinase (phospho-JNK) showed an increase; however, the level of inhibitory factor kappa B alpha (IκBα) showed a decrease. Gene knockdown of TLR4 prevented palmitate-induced INS-1 cell death, while knockdown of TLR2 did not. In addition, gene knockdown of TLR4 prevented palmitate-induced increase of phospho-JNK and decrease of IκBα. JNK inhibitor SP60125 significantly protected against palmitate-induced INS-1 cell death, while IκB kinase (IKK) inhibitor acetylsalicylate did not. These data suggest involvement of JNK activation through the TLR4 signaling pathway in palmitate-induced INS-1 beta cell death.
authors.affiliation: Institutes for Medical Sciences, Ajou University School of Medicine, Suwon 442-749, Republic of Korea.
authors.forename: Sung-Mi
authors.initials: SM
authors.lastname: Lee
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004789:Enzyme Activation; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010168:Palmitates; D010750:Phosphoproteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D055666:Lipopeptides; D053594:Myeloid Differentiation Factor 88; D010168:Palmitates; C508075:Pam(3)CSK(4) peptide; D010750:Phosphoproteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3