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首页> 外文期刊>Journal of dermatological science >Epidermal growth factor-induced matrix metalloproteinase-1 expression is negatively regulated by p38 MAPK in human skin fibroblasts.
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Epidermal growth factor-induced matrix metalloproteinase-1 expression is negatively regulated by p38 MAPK in human skin fibroblasts.

机译：表皮生长因子诱导的基质金属蛋白酶-1表达在人皮肤成纤维细胞中受p38 MAPK负调控。

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BACKGROUND: Many extracellular stimuli, including epidermal growth factor (EGF), are known to induce MMP-1 expression. Recently, several reports have shown that ERK activity plays an important role in EGF-induced MMP-1 expression. However, EGF is also known to activate many signaling pathways in addition to the ERK pathway, but the roles of these pathways during the induction of MMP-1 by EGF are unclear. OBJECTIVE: We investigated the role of JNK, p38 MAPK, and PI3K/Akt pathways in EGF-induced MMP-1 expression in human skin fibroblasts. Then, we further explored the inhibitory effect of p38 MAPK pathway on EGF-induced MMP-1 expression and studied the molecular mechanisms involved in the processes. METHODS: Human skin fibroblasts were pretreated with various chemical inhibitors or small interfering RNA (siRNA) at the indicated concentrations and then treated with EGF, TNF-alpha, or IL-1beta for the indicated times. Protein and mRNA levels of various target molecules were assessed by Western blotting and quantitative real-time PCR, respectively. RESULTS: We found that EGF-induced MMP-1 expression was positively regulated by JNK as well as ERK but negatively regulated by p38 MAPK in human skin fibroblasts. On the other hand, the PI3K/Akt pathway did not significantly affect MMP-1 induction by EGF. Then we found that the inhibition of p38 MAPK pathway specifically increased the MMP-1 expression stimulated by EGF but not by TNF-alpha or IL-1beta, indicating that the effect of p38 MAPK on MMP-1 expression may be stimulus-type specific in human skin fibroblasts. In addition, the inhibitory effect of p38 MAPK on EGF-induced MMP-1 expression was shown to be mainly mediated by p38-alpha MAPK. Our further studies showed that the inhibition of p38 MAPK but not PI3K specifically increased EGF-induced ERK and JNK activations, and that the augmentation of EGF-induced MMP-1 expression by p38 MAPK inhibition was significantly attenuated by inhibiting the activities of ERK and/or JNK. CONCLUSIONS: Our results indicate that EGF-induced MMP-1 expression is differentially regulated by the JNK, p38 MAPK, and PI3K/Akt pathways, and suggest that p38 MAPK negatively regulates EGF-induced MMP-1 expression by suppressing the activations of ERK and JNK.
机译：背景：包括表皮生长因子（EGF）在内的许多细胞外刺激均可诱导MMP-1表达。最近，一些报道表明ERK活性在EGF诱导的MMP-1表达中起重要作用。但是，除ERK途径外，EGF还可以激活许多信号传导途径，但这些途径在EGF诱导MMP-1的过程中的作用尚不清楚。目的：我们研究了JNK，p38 MAPK和PI3K / Akt通路在EGF诱导的人皮肤成纤维细胞中MMP-1表达中的作用。然后，我们进一步探讨了p38 MAPK途径对EGF诱导的MMP-1表达的抑制作用，并研究了参与该过程的分子机制。方法：将人类皮肤成纤维细胞用指定浓度的各种化学抑制剂或小干扰RNA（siRNA）进行预处理，然后用EGF，TNF-α或IL-1beta处理指定的时间。分别通过蛋白质印迹和定量实时PCR评估各种靶分子的蛋白质和mRNA水平。结果：我们发现人皮肤成纤维细胞中EGF诱导的MMP-1表达受JNK和ERK的正调控，而受p38 MAPK的负调控。另一方面，PI3K / Akt途径并未显着影响EGF对MMP-1的诱导。然后我们发现抑制p38 MAPK途径可特异性增加EGF刺激的MMP-1表达，但不会增加TNF-α或IL-1beta的刺激，表明p38 MAPK对MMP-1表达的影响可能是刺激型特异性的。人皮肤成纤维细胞。此外，p38 MAPK对EGF诱导的MMP-1表达的抑制作用主要由p38-αMAPK介导。我们的进一步研究表明，p38 MAPK的抑制作用而不是PI3K特异性地增加了EGF诱导的ERK和JNK激活，并且p38 MAPK抑制作用增强了EGF诱导的MMP-1表达的增强通过抑制ERK和//的活性而明显减弱。或JNK。结论：我们的结果表明，ENK诱导的MMP-1表达受JNK，p38 MAPK和PI3K / Akt通路的差异调节，并提示p38 MAPK通过抑制ERK和ERK的激活来负调控EGF诱导的MMP-1表达。 JNK。

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