Salicylic Acid Reverses Phorbol 12-Myristate-13-Acetate (PMA)- and Tumor Necrosis Factor α (TNFα)-induced Insulin Receptor Substrate 1 (IRS1) Serine 307 Phosphorylation and Insulin Resistance in Human Embryonic Kidney 293 (HEK293) Cells

• Published in: The Journal of biological chemistry 2003-01, Vol.278 (1), p.180-186
• Main Authors: Jiang, Guoqiang, Dallas-Yang, Qing, Liu, Franklin, Moller, David E., Zhang, Bei B.
• Format: Article
• Language: English
• Subjects: Animals; Anthracenes - pharmacology; Cell Line; Enzyme Activation; Humans; I-kappa B Kinase; Insulin Receptor Substrate Proteins; Insulin Resistance - physiology; Isoenzymes - metabolism; JNK Mitogen-Activated Protein Kinases; Kidney - cytology; Kidney - drug effects; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Salicylic Acid - pharmacology; Serine - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M205565200

Salicylates, including aspirin, have been shown to improve insulin sensitivity both in human and animal models. Although it has been suggested that salicylates sensitize insulin action by inhibiting IκB kinase β (IKKβ), the detailed mechanisms remain unclear. Protein kinase C isoforms and tumor necrosis factor α (TNFα) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKβ and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFα-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. The results showed that both PMA and TNFα inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. Salicylic acid pretreatment completely reversed the effects of PMA and TNFα on both Akt and IRS1. Whereas PMA activated protein kinase C isoforms and IKKβ, TNFα activated neither. On the other hand, both PMA and TNFα activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. SP600125, a JNK inhibitor, prevented PMA and TNFα-induced IRS1 Ser-307 phosphorylation. Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFα. Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFα on insulin signaling via an IKKβ-independent mechanism(s), potentially involving the inhibition of JNK activation. The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity.