Abstract
Treatment of rat hepatoma cells with insulin attenuated the interleukin 6 (IL-6) stimulation of acute phase plasma protein genes. To identify the potential mechanism of this action, the influence of insulin on IL-6 signal transduction was determined. An insulin dose-dependent reduction in signal transducer and activator of transcription 3 (STAT3) gene transcription, mRNA accumulation, protein concentration, and IL-6-inducible DNA binding activity was detected. A reduction in the IL-6-activated sis-inducible element binding of STAT3 was observed within 4 h of insulin treatment, whereas a maximal 3-4-fold lower STAT protein concentration was measured after 8-24 h of insulin treatment. Insulin mediated a similar magnitude reduction in the amount of mRNA encoding the IL-6 receptor alpha subunit and IL-6 binding activity. These effects of insulin appear to contribute to the strongly suppressed transcriptional induction of the IL-6-responsive acute phase plasma protein genes.
Highlights
Several pathways are involved in signaling by hematopoietic cytokine receptors; one such pathway involves ligand-induced receptor aggregation and concomitant activation of the receptor-associated cytoplasmic protein tyrosine kinases, the Janus kinases
interleukin 6 (IL-6) treatment for 4 h resulted in the stimulation of SIE binding activity of the signal transducers and activators of transcription (STATs), which was primarily restricted to SIF-A complex (Fig. 1A, middle panel), previously determined to contain signal transducer and activator of transcription 3 (STAT3) homodimers [25] and verified by antibody supershift assay (Fig. 1B)
Cells pretreated with insulin showed reduced SIE binding activity, which appeared to be in part due to reduced STAT3 proteins as detected by Western blot (Fig. 1A, top panel)
Summary
Several pathways are involved in signaling by hematopoietic cytokine receptors; one such pathway involves ligand-induced receptor aggregation and concomitant activation of the receptor-associated cytoplasmic protein tyrosine kinases, the Janus kinases. Cells pretreated with insulin showed reduced SIE binding activity, which appeared to be in part due to reduced STAT3 proteins as detected by Western blot (Fig. 1A, top panel).
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