Angiotensin II interferes with interleukin 6-induced Stat3 signaling by a pathway involving mitogen-activated protein kinase kinase 1.
We reported recently that angiotensin II (AII) and phorbol 12-myristate 13-acetate (PMA) transiently inhibit interleukin 6 (IL-6)-stimulated tyrosine phosphorylation of signal transducers and activators of transcription 3 (Stat3) and subsequent formation of sis-inducing factor-A (SIF-A). However, the AII-mediated inhibition was independent of PMA-sensitive isoforms of protein kinase C (Bhat, G. J., Thekkumkara, T. J., Thomas, W. G., Conrad, K. M., and Baker, K. M. (1995) J. Biol. Chem. 270, 19059-19065). In this study, we demonstrate that the inhibition of IL-6-induced Stat3/SIF-A by AII is concentration-dependent and does not involve degradation of Stat3 protein. We hypothesized that the activation profile of the AII- and PMA-induced mitogen-activated protein (MAP) kinase cascade may be different from that of IL-6 and could contribute to the inhibitory effect; therefore, blocking the MAP kinase pathway at the level of MAPK kinase (MAPKK) would attenuate this inhibitory effect. AII and PMA rapidly induced high levels of MAP kinase activity (8-fold), which contrasted with the delayed and weak activation by IL-6 (1. 7-fold). Treatment of cells with PD98059, a specific inhibitor of MAPKK1, attenuated the inhibitory effects of AII and PMA on IL-6-induced Stat3 tyrosine phosphorylation and SIF-A formation. These data suggest that differences in magnitude and/or duration of activation of the MAP kinase cascade differentially affects the status of Stat3 tyrosine phosphorylation, and that MAPKK1 or a downstream intermediate is involved in the inhibition of IL-6-induced Stat3 by AII and PMA. Modulatory cross-talk between AII and IL-6 may have relevance in pathophysiological conditions such as cardiac hypertrophy and in acute phase and inflammatory responses.
Bhat
G J
GJ
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Abraham
S T
ST
Baker
K M
KM
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D016350:Leucine Zippers; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000804:Angiotensin II; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005419:Flavonoids; D015850:Interleukin-6; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C083170:sisA protein, Drosophila; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one