Cross-talk between angiotensin II and interleukin-6-induced signaling through Stat3 transcription factor

In cultured neonatal rat cardiac fibroblasts and CHO-K1 cells expressing an giotensin II (Ang II) type 1 receptors (AT(1)) (T3CHO/AT(1A) cell line), An g II induced a delayed tyrosine phosphorylation of Stat3 (Signal Transducer s and Activators of Transcription) with maximal activation at 2 h. This was in contrast to the rapid tyrosine phosphorylation (15-30 min) of Stat3 by the cytokine interleukin-6 (IL-6). Using T3CHO/AT(1A) cells, we tested the hypothesis that the delayed tyrosine phosphorylation of Stat3 by Ang IT res ulted from the induction of an inhibitory pathway (0-30 min) prior to activ ation (1-2 h). In support of this hypothesis, we observed that a short trea tment of cells with Ang Il transiently inhibited the IL-6-induced Stat3 tyr osine phosphorylation. The inhibitory effect of Ang II could be attenuated by exposing the cells to a specific inhibitor of MAP kinase kinase 1, PD980 59. Such modulatory crosstalk between Ang II and IL-6 may have relevance in pathophysiological conditions such as cardiac hypertrophy, and in acute ph ase and inflammatory responses.