Mariko Takada, Uma Chandula Pinnawala, Shinichi Hirano, Genji Imokawa
{"title":"白细胞介素-1α通过细胞内ERK/JNK/c-Jun/c-Fos/AP-1信号轴介导,刺激成人真皮成纤维细胞中皱纹诱导弹性蛋白酶神经纤溶酶的表达。","authors":"Mariko Takada, Uma Chandula Pinnawala, Shinichi Hirano, Genji Imokawa","doi":"10.1111/1346-8138.17520","DOIUrl":null,"url":null,"abstract":"<p><p>Neprilysin is a skin wrinkle-inducing membrane bound elastase that is expressed abundantly in UV-exposed and in aged dermal fibroblasts. The overexpression of neprilysin is closely associated with enhanced epithelial-mesenchymal cytokine interactions mainly via interleukin (IL)-1α, which has the distinct potential to stimulate the expression of neprilysin by human dermal fibroblasts (HDFs). The over-expression of neprilysin also accelerates the formation of wrinkles, accompanied by disruptions of the three-dimensional architecture of dermal elastic fibers that are responsible for the loss of skin elasticity. Because the signaling pathway(s) that lead to the IL-1α-stimulated expression of neprilysin in HDFs remain unclear, we characterized the signaling pathway involved, including their related transcription factors, in IL-1α-treated HDFs. Since qRT-PCR analysis revealed that the mRNA expression level of neprilysin is stimulated to a stronger extent in adult HDFs (aHDFs) by IL-1α than in neonatal HDFs, we used aHDFs for the signaling analysis. Western blotting analysis of the phosphorylation of signaling factors revealed that IL-1α significantly stimulated the phosphorylation of ERK1/2, RSK, JNK, p38, MSK1, NFkB, c-Jun, ATF-2, CREB, and STAT3. Analysis using various signaling inhibitors demonstrated that inhibiting ERK and JNK but not p38, MSK1, NFkB, or STAT3 significantly abrogated the IL-1α stimulated expression of neprilysin at the mRNA, protein, and enzyme activity levels. Furthermore, silencing c-Fos significantly down-regulated the IL-1α-increased expression of neprilysin at the protein and enzyme activity levels. These findings strongly suggest that the IL-1α-stimulated expression of neprilysin in aHDFs is mediated via the intracellular signaling axis of ERK/JNK/c-Jun/c-Fos/AP-1.</p>","PeriodicalId":94236,"journal":{"name":"The Journal of dermatology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The interleukin-1α stimulated expression of the wrinkle-inducing elastase neprilysin in adult human dermal fibroblasts is mediated via the intracellular signaling axis of ERK/JNK/c-Jun/c-Fos/AP-1.\",\"authors\":\"Mariko Takada, Uma Chandula Pinnawala, Shinichi Hirano, Genji Imokawa\",\"doi\":\"10.1111/1346-8138.17520\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Neprilysin is a skin wrinkle-inducing membrane bound elastase that is expressed abundantly in UV-exposed and in aged dermal fibroblasts. The overexpression of neprilysin is closely associated with enhanced epithelial-mesenchymal cytokine interactions mainly via interleukin (IL)-1α, which has the distinct potential to stimulate the expression of neprilysin by human dermal fibroblasts (HDFs). The over-expression of neprilysin also accelerates the formation of wrinkles, accompanied by disruptions of the three-dimensional architecture of dermal elastic fibers that are responsible for the loss of skin elasticity. Because the signaling pathway(s) that lead to the IL-1α-stimulated expression of neprilysin in HDFs remain unclear, we characterized the signaling pathway involved, including their related transcription factors, in IL-1α-treated HDFs. Since qRT-PCR analysis revealed that the mRNA expression level of neprilysin is stimulated to a stronger extent in adult HDFs (aHDFs) by IL-1α than in neonatal HDFs, we used aHDFs for the signaling analysis. Western blotting analysis of the phosphorylation of signaling factors revealed that IL-1α significantly stimulated the phosphorylation of ERK1/2, RSK, JNK, p38, MSK1, NFkB, c-Jun, ATF-2, CREB, and STAT3. Analysis using various signaling inhibitors demonstrated that inhibiting ERK and JNK but not p38, MSK1, NFkB, or STAT3 significantly abrogated the IL-1α stimulated expression of neprilysin at the mRNA, protein, and enzyme activity levels. Furthermore, silencing c-Fos significantly down-regulated the IL-1α-increased expression of neprilysin at the protein and enzyme activity levels. These findings strongly suggest that the IL-1α-stimulated expression of neprilysin in aHDFs is mediated via the intracellular signaling axis of ERK/JNK/c-Jun/c-Fos/AP-1.</p>\",\"PeriodicalId\":94236,\"journal\":{\"name\":\"The Journal of dermatology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-10-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of dermatology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1111/1346-8138.17520\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of dermatology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/1346-8138.17520","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
The interleukin-1α stimulated expression of the wrinkle-inducing elastase neprilysin in adult human dermal fibroblasts is mediated via the intracellular signaling axis of ERK/JNK/c-Jun/c-Fos/AP-1.
Neprilysin is a skin wrinkle-inducing membrane bound elastase that is expressed abundantly in UV-exposed and in aged dermal fibroblasts. The overexpression of neprilysin is closely associated with enhanced epithelial-mesenchymal cytokine interactions mainly via interleukin (IL)-1α, which has the distinct potential to stimulate the expression of neprilysin by human dermal fibroblasts (HDFs). The over-expression of neprilysin also accelerates the formation of wrinkles, accompanied by disruptions of the three-dimensional architecture of dermal elastic fibers that are responsible for the loss of skin elasticity. Because the signaling pathway(s) that lead to the IL-1α-stimulated expression of neprilysin in HDFs remain unclear, we characterized the signaling pathway involved, including their related transcription factors, in IL-1α-treated HDFs. Since qRT-PCR analysis revealed that the mRNA expression level of neprilysin is stimulated to a stronger extent in adult HDFs (aHDFs) by IL-1α than in neonatal HDFs, we used aHDFs for the signaling analysis. Western blotting analysis of the phosphorylation of signaling factors revealed that IL-1α significantly stimulated the phosphorylation of ERK1/2, RSK, JNK, p38, MSK1, NFkB, c-Jun, ATF-2, CREB, and STAT3. Analysis using various signaling inhibitors demonstrated that inhibiting ERK and JNK but not p38, MSK1, NFkB, or STAT3 significantly abrogated the IL-1α stimulated expression of neprilysin at the mRNA, protein, and enzyme activity levels. Furthermore, silencing c-Fos significantly down-regulated the IL-1α-increased expression of neprilysin at the protein and enzyme activity levels. These findings strongly suggest that the IL-1α-stimulated expression of neprilysin in aHDFs is mediated via the intracellular signaling axis of ERK/JNK/c-Jun/c-Fos/AP-1.