Laboratory of Immunity and Infection, Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Eur J Immunol. 2010 Sep;40(9):2580-9. doi: 10.1002/eji.201040540.
The role of STAT3 in infectious diseases remains undetermined, in part because unphosphorylated STAT3 has been considered an inactive protein. Here, we report that unphosphorylated STAT3 contributes to cholinergic anti-inflammation, prevents systemic inflammation, and improves survival in sepsis. Bacterial endotoxin induced STAT3 tyrosine phosphorylation in macrophages. Both alpha 7 nicotinic receptor (alpha 7nAChR) activation and inhibition of JAK2 blunt STAT3 phosphorylation. Inhibition of STAT3 phosphorylation mimicked the alpha 7nAChR signaling, inhibiting NF-kappaB and cytokine production in macrophages. Transfection of macrophages with the dominant-negative mutant STAT3F, to prevent its tyrosine phosphorylation, reduced TNF production but did not prevent the alpha 7nAChR signaling. However, inhibition of STAT3 protein expression enhanced cytokine production and abrogated alpha 7nAChR signaling. Alpha 7nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression, but not its tyrosine phosphorylation. In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis. Stattic also prevented the production of late mediators of sepsis and improved survival in established sepsis. These results reveal the immunological implications of tyrosine-unphosphorylated STAT3 in infectious diseases.
STAT3 在传染病中的作用仍不确定，部分原因是未磷酸化的 STAT3 被认为是一种无活性的蛋白质。在这里，我们报告未磷酸化的 STAT3 有助于胆碱能抗炎，防止全身炎症，并改善脓毒症的存活率。细菌内毒素诱导巨噬细胞中的 STAT3 酪氨酸磷酸化。α7 烟碱型乙酰胆碱受体 (α7nAChR) 的激活和 JAK2 的抑制均可使 STAT3 磷酸化减弱。STAT3 磷酸化的抑制模拟了 α7nAChR 信号，抑制了巨噬细胞中的 NF-κB 和细胞因子的产生。用显性失活突变体 STAT3F 转染巨噬细胞，阻止其酪氨酸磷酸化，减少 TNF 的产生，但不能阻止 α7nAChR 信号。然而，抑制 STAT3 蛋白表达增强了细胞因子的产生，并消除了 α7nAChR 信号。α7nAChR 通过需要 STAT3 蛋白表达而不是其酪氨酸磷酸化的机制控制巨噬细胞中 TNF 的产生。在体内，通过抑制 stattic 使 STAT3 酪氨酸磷酸化来防止全身炎症并改善实验性脓毒症的存活率。Stattic 还可以防止脓毒症后期介质的产生，并改善已建立的脓毒症的存活率。这些结果揭示了 STAT3 酪氨酸非磷酸化在传染病中的免疫学意义。
