Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes.
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.
He
Jianying
J
The First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
Usui
Isao
I
Ishizuka
Ken
K
Kanatani
Yukiko
Y
Hiratani
Kazuyuki
K
Iwata
Minoru
M
Bukhari
Agussalim
A
Haruta
Tetsuro
T
Sasaoka
Toshiyasu
T
Kobayashi
Masashi
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D014443:Tyrosine; C526295:Irs1 protein, mouse