Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially cytokine signaling 3
Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially cytokine signaling 3
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DOI：
10.4049/jimmunol.170.6.3263
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发表时间：
2003-03-15
影响因子：
4.4
通讯作者：
Müller-Newen, G
中科院分区：
文献类型：
--
作者：
Niemand, C;Nimmesgern, A;Müller-Newen, G
在人类巨噬细胞上，IL-10 是比 IL-6 更有效的抗炎细胞因子，尽管这两种细胞因子主要通过转录因子 STAT3 的激活来发出信号。在这项研究中，我们比较了源自血液单核细胞的原代人巨噬细胞中的 IL-10 和 IL-6 信号传导。用 PNIA 或促炎介质 LPS 和 TNF-α 预处理巨噬细胞可阻断 IL-6 诱导的 STAT3 激活，而 IL-10 诱导的 STAT3 激活基本上不受影响。尽管 LPS 在巨噬细胞中诱导细胞因子信号传导反馈抑制因子 3 (SOCS3)，但 LPS 对 IL-6 信号转导的抑制作用迅速发生，且不依赖于基因转录。我们还发现，用 IL-10 预处理巨噬细胞会抑制 IL-6 随后的 STAT3 激活，而 IL-10 诱导的 STAT3 激活不受 IL-6 预孵育的影响。这种交叉抑制依赖于活性转录，因此可能通过 IL-10 和 IL-6 信号对反馈抑制剂 SOCS3 的不同敏感性来解释，而 SOCS3 是由两种细胞因子诱导的。与 IL-6 信号转导器 gp130 相比，之前已显示其将 SOCS3 招募到其磷酸酪氨酸残基之一 (Y759)，肽沉淀实验表明 SOCS3 不与 IL-10R 的磷酸化酪氨酸基序相互作用。总而言之，IL-10 和 IL-6 信号传导对抑制 Janus 激酶/STAT 途径的机制的不同敏感性定义了导致这两种细胞因子具有不同抗炎效力的重要机制。
On human macrophages IL-10 acts as a more potent anti-inflammatory cytokine, than IL-6, although both cytokines signal mainly via activation of the transcription factor STAT3. In this study we compare IL-10 and IL-6 signaling in primary human macrophages derived from blood monocytes. Pretreatment of macrophages with PNIA or the proinflammatory mediators LPS and TNF-alpha blocks IL-6-induced STAT3 activation, whereas IL-10-induced activation of STAT3 remains largely unaffected. Although LPS induces the feedback inhibitor suppressor of cytokine signaling 3 (SOCS3) in macrophages, inhibition of IL-6 signal transduction by LPS occurs rapidly and does not depend on gene transcription. We also found that pretreatment of macrophages with IL-10 inhibits subsequent STAT3 activation by IL-6, whereas IL-10-induced STAT3 activation is not affected by preincubation with IL-6. This cross-inhibition is dependent on active transcription and might therefore be explained by different sensitivities of IL-10 and IL-6 signaling toward the feedback inhibitor SOCS3, which is induced by both cytokines. In contrast to the IL-6 signal transducer gp130, which has been previously shown to recruit SOCS3 to one of its phosphotyrosine residues (Y759), peptide precipitation experiments suggest that SOCS3 does not interact with phosphorylated tyrosine motifs of the IL-10R. Taken together, different sensitivities of IL-10 and IL-6 signaling toward mechanisms that inhibit the Janus kinase/STAT pathway define an important mechanism that contributes to the different anti-inflammatory potencies of these two cytokines.