Interleukin-1α Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes

Abstract

Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1alpha is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1alpha may also cause insulin resistance. Here, we investigated the effects of IL-1alpha treatment on insulin signaling in 3T3-L1 adipocytes. IL-1alpha treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1alpha stimulation, when several serine kinases, IkappaB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1alpha-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1alpha. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1alpha in the presence of IL-6. Taken together, short-term IL-1alpha treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1alpha may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

“…This was surprising, since the AKT-mediated protection against apoptosis of neurons exposed to an ischaemic event has been shown to be mediated by PRAS40 [47]. Similarly, L-JNKI did not affect p70S6K, although cytokines activated p70S6K similarly to results reported in adipocytes exposed to IL-1β [49]. The lack of regulation of IRS (S312) phosphorylation by L-JNKI was also unexpected.…”

Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes

“…IL-1α, like IL1B, can rapidly decrease IRS-1 insulin-induced tyrosine phosphorylation in 3T3-L1 differentiated adipocytes [39], suggesting that both IL-1α and IL-1β, which act through the same receptor, can trigger insulin resistance in cultured adipocytes.…”

Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo

“…For instance, in high-fat-fed animals, inhibition of NFkB appears to be sufficient to restore insulin sensitivity without inhibition of IKKb activity (Cai et al 2005), suggesting that the insulin resistance is secondary to transcriptional effects of NFkB, which may not be true after short-term lipid infusion. Furthermore, these models are associated with increased release of adipocyte-derived factors other than FFA, such as pro-inflammatory cytokines, tumor necrosis factor a (TNFa), interleukin-1b, and interleukin-6 (Hotamisligil & Spiegelman 1994, Rotter et al 2003, Kim et al 2004a, He et al 2006, Jager et al 2007 which are known to induce insulin resistance. Accordingly, in these studies, insulin resistance on which IKKb inhibition was shown to have a protective effect cannot be attributed only to FFA.…”