title: Long-term treatment of Swiss 3T3 fibroblasts with dexamethasone attenuates MAP kinase activation induced by insulin-like growth factor-I (IGF-I).
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Hansson
authors.forename: K
authors.initials: K
authors.lastname: Hehenberger
authors.forename: M
authors.initials: M
authors.lastname: Thorén
mesh_terms: D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D000918:Antibody Specificity; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000276:immunology / Q000494:pharmacology*; D050356:Lipid Metabolism; D051379:Mice; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D011506:Proteins; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D006003:Glycogen; D017871:Calcium-Calmodulin-Dependent Protein Kinases