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1 Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
2 Dept. of Chemical Engineering, National Taiwan University, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: lingwang{at}ibms.sinica.edu.tw.
Endothelial cells (ECs) are constantly exposed to shear stress, the action of which triggers signaling pathways and cellular responses. During inflammation, cytokines such as IL-6 increase in plasma. In this study, we examined the effects of steady flow on IL-6-induced endothelial responses. ECs exposed to IL-6 exhibited Stat3 activation via phosphorylation of Tyr705. However, when ECs were subjected to shear stress, a shear force-dependent suppression of IL-6-induced Stat3 phosphorylation was observed. IL-6 treatment increased the phosphorylation of JAK2, an upstream activator of Stat3. Consistently, shear stress significantly reduced IL-6-induced JAK2 activation. ECs pretreated with an inhibitor to MEK1 did not alter this suppression by shear stress indicating that extracellular signal-regulated protein kinase (ERK1/2) was not involved. However, ECs pretreated with an eNOS inhibitor (L-NAME) attenuated this inhibitory effect of shear stress on STAT3 phosphorylation. Shear-treated ECs displayed decreased nuclear transmigration of Stat3 and reduced Stat3 binding to DNA. Intriguingly, ECs exposed to IL-6 entered the cell cycle as evidenced by increasing G2/M phase, and shear stress to these ECs significantly reduced IL-6-induced cell cycle progression. Stat3 mediated IL-6-induced cell cycle was confirmed by the inhibition of cell cycle in ECs infected with adenovirus carrying the inactive mutant of Stat3. Our study clearly shows that shear stress exerts its inhibitory regulation by suppressing IL-6-induced JAK2/Stat3 signaling pathway and thus inhibits IL-6-induced endothelial proliferation. This shear force-dependent inhibition of IL-6-induced JAK2/Stat3 activation provides new insights for the vaso-protective effects of steady flow on ECs against ctokine-induced responses.
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