Cyclic AMP suppresses matrix metalloproteinase-1 expression through inhibition of MAPK and GSK-3beta.
Cyclic AMP suppresses matrix metalloproteinase-1 expression through inhibition of MAPK and GSK-3beta.
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DOI：
10.1038/jid.2010.62
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发表时间：
2010-08
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影响因子：
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通讯作者：
Chi-hyun Park;Y. Moon;Chung Min Shin;J. Chung
中科院分区：
文献类型：
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作者：
Chi-hyun Park;Y. Moon;Chung Min Shin;J. Chung
基质金属蛋白酶-1（MMP-1）的表达受多种刺激物的刺激，并可能受到多种信号通路的调节。已知cAMP作为各种细胞外刺激的第二信使，并参与细胞增殖、凋亡和炎症的调节。在此，我们研究了cAMP对肿瘤坏死因子（TNF）-α诱导的人皮肤成纤维细胞MMP-1表达的影响以及参与该过程的分子事件。我们发现cAMP通过蛋白激酶A（PKA）途径抑制TNF-α诱导的MMP-1表达。cAMP可抑制TNF-α刺激的ERK和JNK的激活，而ERK和JNK在MMP-1的表达中起重要作用。然而，即使ERK和JNK活性不受影响，MMP-1表达也可被cAMP抑制，表明可能存在介导cAMP介导的MMP-1表达抑制的其他靶点。进一步的研究表明糖原合成酶激酶（GSK）-3β可通过cAMP/PKA途径失活，并在MMP-1的表达中起重要作用，而GSK-3β的失活是TNF-α处理后cAMP升高抑制MMP-1表达的关键。综上所述，我们的结果表明cAMP/PKA通路可以通过抑制包括MAPK和GSK-3β在内的多个信号通路来抑制MMP-1的表达。
Expression of matrix metalloproteinase-1 (MMP-1) is stimulated by diverse stimuli and is likely to be regulated by many signaling pathways. cAMP is known to act as a second messenger for various extracellular stimuli and to be involved in the regulation of cell proliferation, apoptosis, and inflammation. Here, we investigated the effect of cAMP on tumor necrosis factor (TNF)-α-induced MMP-1 expression and the molecular events involved in the processes in human skin fibroblasts. We showed that cAMP suppresses TNF-α-induced MMP-1 expression via protein kinase A (PKA) pathway. cAMP inhibited TNF-α-stimulated ERK and JNK activation, which was shown to have an important role in MMP-1 expression. However, MMP-1 expression could also be inhibited by cAMP even when ERK and JNK activities were unaffected, indicating that there might be other target(s) that mediate cAMP-mediated suppression of MMP-1 expression. Further studies revealed that glycogen synthase kinase (GSK)-3β can be inactivated by cAMP/PKA pathway and has important roles in MMP-1 expression, and showed that inactivation of GSK-3β is critical for suppression of MMP-1 expression by cAMP elevation after TNF-α treatment. Taken together, our results suggest that cAMP/PKA pathway can suppress MMP-1 expression through inhibition of multiple signaling pathways, including MAPK and GSK-3β.