Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes

Mol Endocrinol. 2006 Jan;20(1):114-24. doi: 10.1210/me.2005-0107. Epub 2005 Sep 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism*
  • Animals
  • Enzyme Activation
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • Interleukin-6 / pharmacology
  • Interleukin-6 / physiology
  • Mice
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Serine / metabolism*
  • Signal Transduction
  • Tyrosine / metabolism

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Interleukin-1
  • Interleukin-6
  • Irs1 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Tyrosine
  • Serine
  • Oncogene Protein v-akt
  • Protein Serine-Threonine Kinases