Comparison of the effects of insulin, PDGF, interleukin-6, and interferon-gamma on glucose transport in 3T3-L1 cells: lack of cross-talk between tyrosine kinase receptors and JAK/STAT pathways.
The effects of insulin, insulin-like growth factor (IGF)-I, platelet-derived growth factor (PDGF), interleukin (IL)-6 and interferon-gamma on 2-deoxyglucose uptake and insulin receptor substrate (IRS)-1 phosphorylation were compared in 3T3-L1 cells at confluence and after differentiation to the adipocyte-like phenotype. Insulin and IGF-I produced the expected stimulation of glucose transport and tyrosine phosphorylation of IRS-1 in both confluent and differentiated cells. In contrast, IL-6 and interferon-gamma failed to stimulate glucose transport or IRS-1 phosphorylation, although a marked stimulation of the JAK/STAT pathways as shown by acute-phase response factor (APRF)/Stat3 or Stat1 activation was observed in fibroblasts (IL-6, interferon-gamma) and adipocytes (IL-6). PDGF-AA and PDGF-BB stimulated glucose transport in confluent, undifferentiated cells to the same extent as insulin (approximately six-fold stimulation), but produced only a small portion of the effect of insulin in differentiated cells. Similarly, mRNA levels and autophosphorylation of PDGF receptors were much lower in differentiated cells than in confluent fibroblasts. In contrast to insulin and IGF-I, PDGF failed to stimulate tyrosine phosphorylation of IRS-1. All effects of insulin, IGF-I, and PDGF on glucose transport were inhibited by Wortmannin; the half-maximally inhibiting concentration (IC50) of Wortmannin was increased by insulin. These data demonstrate distinct signalling potentials of the investigated receptors, and indicate that the IL-6 and interferon-gamma controlled JAK/STAT pathways lack the potential to stimulate glucose transport. IRS-1 does not appear to be involved in the PDGF receptor-mediated effects, whereas activation of phosphatidylinositol (PI) 3-kinase is a crucial event in all pathways leading to stimulation of glucose transport.
Huppertz
C
C
Institut für Pharmakologie und Toxikologie, RWTH Aachen, Germany.
Schwartz
C
C
Becker
W
W
Horn
F
F
Heinrich
P C
PC
Joost
H G
HG
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012313:RNA / Q000032:analysis / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D012313:RNA; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D003847:Deoxyglucose; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor