IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages.
IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages.
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DOI：
10.4049/jimmunol.1301906
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Falcone DJ
中科院分区：
文献类型：
--
作者：
Kothari P;Pestana R;Mesraoua R;Elchaki R;Khan KM;Dannenberg AJ;Falcone DJ
IL-6在慢性炎症性疾病和癌症发病机制中的作用机制尚不完全清楚。我们先前报道，环氧合酶-2(COX-2)依赖的PGE2合成调节巨噬细胞基质金属蛋白酶-9(MMP9)的表达，MMP9是一种参与多种病理过程的内肽酶。在这些研究中，我们确定了IL-6是否调节小鼠巨噬细胞中COX-2、→、PGE、→、MMP9途径。IL-6共同诱导COX-2和微粒体前列腺素E合成酶-1(mPGES-1)，并抑制15-羟基前列腺素脱氢酶(15-PGDH)的表达，导致PGE2水平升高。此外，IL-6诱导了基质金属蛋白酶-9的表达，提示观察到的蛋白酶表达受PGE2合成的调节。然而，抑制PGE2的合成部分抑制了IL-6介导的基质金属蛋白酶-9的诱导。在IL-6诱导信号的典型模型中，JAK激活触发STAT和MAPKerk1/2信号通路。因此，我们检测了不同结构的JAK抑制剂阻断IL-6诱导的基质金属蛋白酶-9表达的能力。抑制JAK可阻断IL-6诱导的STAT3的磷酸化，但不能阻断MAPKerk1/2的磷酸化，并意外增强MMP9的表达。相反，抑制MEK-1可阻断IL-6诱导的MAPKerk1/2和MMP9表达的磷酸化，而不影响STAT3的磷酸化。因此，IL-6诱导的MMP9的表达依赖于MAPKerk1/2的激活，并受JAK依赖的基因产物的抑制。利用药理学和遗传学方法，JAK依赖的IL-10诱导被确认为控制IL-6诱导的基质金属蛋白酶-9表达的有效反馈机制。综上所述，这些结果揭示了IL-6通过COX-2依赖和非依赖的机制诱导巨噬细胞表达MMP-9，并确定了IL-6与慢性炎症性疾病和癌症发病机制的潜在联系。
The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)-dependent PGE2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE2→MMP-9 pathway in murine macrophages. IL-6 co-induced Cox-2 and microsomal prostaglandin E synthase-1 (mPGES-1), and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), leading to increased levels of PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6–mediated induction of MMP-9. In the canonical model of IL-6-induced signaling, JAK activation triggers STAT and MAPKerk1/2-signaling pathways. Therefore, the ability of structural diverse JAK inhibitors to block IL-6-induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6 induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPKerk1/2, and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6 induced phosphorylation of MAPKerk1/2 and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6-induced MMP-9 expression is dependent on the activation of MAPKerk1/2 and restrained by a JAK-dependent gene product. Utilizing pharmacologic and genetic approaches, JAK-dependent induction of IL-10 was identified as a potent feedback mechanism controlling IL-6 induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2-dependent and -independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.
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影响因子：
15.8
作者：
Danesh, John;Kaptoge, Stephen;Mann, Andrea G.;Sarwar, Nadeem;Wood, Angela;Angleman, Sara B.;Wensley, Frances;Higgins, Julian P. T.;Lennon, Lucy;Eiriksdottir, Gudny;Rumley, Ann;Whincup, Peter H.;Lowe, Gordon D. O.;Gudnason, Vilmundur
通讯作者：
Gudnason, Vilmundur
影响因子：
11.5
作者：
Golijanin, D;Tan, JY;Dannenberg, AJ
通讯作者：
Dannenberg, AJ
影响因子：
1.3
作者：
Iyer SS;Cheng G
通讯作者：
Cheng G
影响因子：
4.4
作者：
Itoh, T;Matsuda, H;Suzuki, R
通讯作者：
Suzuki, R
DOI：
10.1161/01.atv.0000161275.82687.f6
发表时间：
2005-05-01
影响因子：
8.7
作者：
Choi, ET;Collins, ET;Parks, WC
通讯作者：
Parks, WC