Département de Pharmacologie, Université de Montréal, Montreal QC, Canada.
Cytokine. 2012 Nov;60(2):575-82. doi: 10.1016/j.cyto.2012.07.002. Epub 2012 Jul 31.
IL-6 is a pleiotropic cytokine which emerged recently as a key regulator of CD4 T cell function. IL-6 alone or in combination with other cytokines promotes T helper 1, T helper 17 and T follicular helper cell differentiation whilst inhibiting the induction of regulatory T cell generation. IL-6 activates multiple pathways among which JAK/STAT3 is the most clearly validated in the control of CD4 T helper differentiation. Activation of STAT5 by cytokines such as IL-2 can counteract IL-6-induced T helper 17 and T follicular helper cell differentiation and promote the induction of regulatory T cell generation. STAT5 and STAT3 are known to compete for promoter binding sites in CD4 T cells and the two transcription factors are believed to have opposite functions in the control of CD4 T cell differentiation.
We analyzed IL-6-induced STAT1, 3 and 5 activation by flow cytometry (phosflow) in mouse mononuclear cells and its effect on the level of the mRNA coding for cytokine-inducible SH2-containing protein (CIS).
The results show that IL-6 also induces STAT5 activation in both CD4 and CD8 T as well as NK cells. Analysis of STAT5 phosphorylation in CD4 T cells indicates that it is transient and requires higher cytokine concentrations than that of STAT3. CD4 T cell stimulation with IL-6 induces the synthesis of CIS, which is encoded by a gene known to be regulated by STAT5.
Thus, IL-6 at concentrations corresponding to levels observed in the serum during inflammation may activate, in CD4 T cells, a STAT5-negative feedback loop which alters the balance between STAT3-dependent pro-inflammatory helper T cells and STAT5-induced T regulatory cells. STAT5 activation may modulate the differentiation of T helper cells through attenuation of TGF-β stability and production. Since STAT5 is directly activated by Janus kinases, therapeutic approaches designed to inhibit STAT3 activation or to recruit STAT3 phosphatases may be useful in altering the balance of activated STAT3 and STAT5 in favor a profile that would be beneficial in pathologies involving IL-6.
白细胞介素 6（IL-6）是一种多功能细胞因子，最近被认为是调节 CD4 T 细胞功能的关键调节剂。IL-6 单独或与其他细胞因子一起促进辅助性 T 细胞 1（Th1）、辅助性 T 细胞 17（Th17）和滤泡辅助性 T 细胞分化，同时抑制调节性 T 细胞生成的诱导。IL-6 激活多种途径，其中 JAK/STAT3 途径在控制 CD4 T 辅助分化中被最明确地验证。细胞因子如白细胞介素 2（IL-2）激活 STAT5，可以拮抗 IL-6 诱导的 Th17 和滤泡辅助性 T 细胞分化，并促进调节性 T 细胞生成的诱导。已知 STAT5 和 STAT3 竞争 CD4 T 细胞中的启动子结合位点，并且这两个转录因子在控制 CD4 T 细胞分化方面具有相反的功能。
我们通过流式细胞术（phosflow）分析了单核细胞中 IL-6 诱导的 STAT1、3 和 5 的激活及其对细胞因子诱导的含 SH2 结构域蛋白（CIS）mRNA 水平的影响。
结果表明，IL-6 还可诱导 CD4 和 CD8 T 以及自然杀伤（NK）细胞中的 STAT5 激活。在 CD4 T 细胞中分析 STAT5 磷酸化表明，其是短暂的，并且需要比 STAT3 更高的细胞因子浓度。用 IL-6 刺激 CD4 T 细胞可诱导 CIS 的合成，CIS 是由 STAT5 调节的基因编码的。
因此，在炎症期间血清中观察到的浓度的 IL-6 可能在 CD4 T 细胞中激活 STAT5 阴性反馈环，从而改变 STAT3 依赖性促炎辅助性 T 细胞和 STAT5 诱导的调节性 T 细胞之间的平衡。STAT5 激活可能通过衰减 TGF-β 的稳定性和产生来调节辅助性 T 细胞的分化。由于 STAT5 直接被 Janus 激酶激活，因此设计用于抑制 STAT3 激活或募集 STAT3 磷酸酶的治疗方法可能有助于改变激活的 STAT3 和 STAT5 之间的平衡，有利于在涉及白细胞介素 6 的病理中有益的谱。
