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.