Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes.
Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes.
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表皮生长因子受体的转调介导培养的人角质形成细胞中 IL-1β 诱导的 MMP-1 表达。
DOI：
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发表时间：
2001
影响因子：
5.4
通讯作者：
G. Fisher
中科院分区：
文献类型：
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作者：
Y. Wan;A. Belt;Z. Wang;J. Voorhees;G. Fisher
紫外线 (UV) 辐射通过激活基质金属蛋白酶 (MMP) 导致人体皮肤老化和皮肤癌，而基质金属蛋白酶 (MMP) 负责人体皮肤中胶原蛋白的降解和肿瘤的进展。紫外线诱导 MMP 的分子机制尚未明确。我们之前的研究和其他研究表明，i) 细胞表面受体的瞬时激活和随后的 MAP 激酶级联激活有助于 MMP 的转录上调； ii) 紫外线诱导的促炎细胞因子（例如 IL-1 β 和 TNF-α）的表达也可能是 MMP 表达的原因。然而，细胞因子诱导 MMP 表达的信号通路仍有待阐明。在这项研究中，我们研究了导致人角质形成细胞中 IL-1β 诱导的 MMP-1 上调的途径。 IL-1β 以时间和剂量依赖性方式激活培养的人角质形成细胞中的表皮生长因子 (EGF) 受体。 IL-1β 诱导的 EGF 受体酪氨酸磷酸化在 5 分钟时开始，在 10 分钟时达到峰值，并在 IL-1β 处理后 40 分钟内保持升高状态。 EGF 受体激酶抑制剂 PD153035 和 AG1478 抑制 IL-1 β 诱导的 EGF 受体酪氨酸磷酸化。为了测试 EGF 受体反式激活对下游成分的影响，我们检查了 IL-1 beta 对 ERK 的激活。我们发现IL-1β诱导的ERK磷酸化、PD153035和MEK抑制剂PD98059阻断IL-1β诱导的ERK活性。此外，两种抑制剂还显着降低 IL-1 β 诱导的 c-jun 和 c-fos mRNA 表达，这是 MMP 上调所必需的。 EGF 受体激酶抑制剂 PD153035 和 AG1478 以及 MEK 抑制剂 PD98059 也在培养的人角质形成细胞中阻断 IL-1β 对 MMP-1 的诱导。总的来说，我们的数据表明，IL-1β 诱导的 MMP-1 表达是通过 EGF 受体的反式激活和人角质形成细胞中的 ERK 途径介导的。
Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.