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.