Long-term treatment of Swiss 3T3 fibroblasts with dexamethasone attenuates MAP kinase activation induced by insulin-like growth factor-I (IGF-I).
Bone formation is reduced in hyperglucocorticoid states, e.g. Cushing's syndrome or long-term treatment with synthetic glucocorticoids during rheumatic diseases. possibly related to decreased sensitivity of the target to insulin-like growth factor-I (IGF-I). In this study, we have sought to identify postreceptor-mechanisms for glucocorticoid-induced resistance to insulin-like peptides in a model system. Treatment of Swiss 3T3 fibroblasts with 100 nM dexamethasone for 48h reduced IGF-I- induced activation of mitogen-activated protein kinase (MAP kinase). The level of insulin receptor substrate-1 (IRS-1) was reduced in dexamethasone-treated cells, as measured by Western blot; however, the pattern of tyrosine-phosphorylated protein subsequent to stimulation with IGF-I (1 min) was not altered. No inhibitory effect of dexamethasone was observed on the level of phosphotyrosine in IRS-1 in extracts from IGF-I-treated cells. The amount of IGF-I- induced association of insulin receptor substrate-1 and phosphatidylinositol 3-kinase was increased in steroid treated cells. Addition of IGF-I increased the synthesis of lipid, glycogen and protein, and the reduction of a tetrazolium dye, MTS, in untreated cells. The response to IGF-I in terms of glycogen synthesis was blunted, whereas the effect of IGF-I was unaffected for the other three parameters in cells pretreated with dexamethasone. These findings indicate that the activation of MAP kinase may be dissociated from IGF-I- induced anabolic pathways and tyrosine phosphorylation of IRS-1. The results agree with the previously proposed role for the activation of MAP kinase in the regulation of glycogen synthesis. Furthermore, they suggest that dexamethasone-induced reduction of IRS-1 expression may be important for the impaired activation of MAP kinase by insulin-like peptides in steroid-treated cells.[1]References
- Long-term treatment of Swiss 3T3 fibroblasts with dexamethasone attenuates MAP kinase activation induced by insulin-like growth factor-I (IGF-I). Hansson, A., Hehenberger, K., Thorén, M. Cell Biochem. Funct. (1996) [Pubmed]
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