All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes.
All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes.
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发表时间：
2004
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通讯作者：
X. Dai;K. Yamasaki;Y. Shirakata;K. Sayama;K. Hashimoto
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作者：
X. Dai;K. Yamasaki;Y. Shirakata;K. Sayama;K. Hashimoto
视黄酸衍生物已成功地用于治疗各种皮肤病，如牛皮癣;然而，局部施用这些化合物常常引起皮肤刺激。我们假设这种刺激是由于局部产生白细胞介素-8（IL-8）。为了验证这一假设，我们研究了全反式维甲酸（ATRA）是否诱导正常人角质形成细胞产生IL-8。用10（-7）M ATRA刺激增强IL-8 mRNA表达并诱导IL-8产生。我们还研究了ATRA诱导角质形成细胞产生IL-8的细胞内信号转导机制。ATRA增加RelA（p65）、RelB、核因子（NF）-kappaB 2（p52）和NF-kappaB 1（p50）的表达，并提高p65的DNA结合活性和抑制剂kappaB（IkappaB）α的磷酸化。引入IkappaB α的显性负突变体完全消除了ATRA诱导的IL-8产生，这表明该过程是NF-κ B依赖性的。我们还研究了p38丝裂原活化蛋白激酶（MAPK）通路在这种现象中的作用。ATRA可使p38 MAPK磷酸化，SB 202180可抑制ATRA诱导的IL-8产生，提示p38 MAPK也参与了ATRA诱导的IL-8产生。总之，在正常人角质形成细胞中，ATRA以NF-κ B和p38 MAPK依赖的方式诱导IL-8产生。
Retinoic acid derivatives have been used successfully for the treatment of various dermatoses, such as psoriasis; however, topical application of these compounds often elicits skin irritation. We hypothesized that this irritation was as a result of the local production of interleukin-8 (IL-8). To test this hypothesis, we investigated whether all-trans-retinoic acid (ATRA) induced IL-8 production in normal human keratinocytes. Stimulation with 10(-7) M ATRA enhanced IL-8 mRNA expression and induced IL-8 production. We also studied the intracellular signaling mechanisms of ATRA-induced IL-8 production in keratinocytes. ATRA increased the expression of RelA (p65), RelB, nuclear factor (NF)-kappaB2 (p52), and NF-kappaB1 (p50), and elevated the DNA-binding activity of p65 and phosphorylation of inhibitor kappaB (IkappaB) alpha. Introduction of a dominant-negative mutant of IkappaBalpha completely abolished ATRA-induced IL-8 production, which indicates that this process is NF-kappaB-dependent. We also studied the role of the p38 mitogen-activated protein kinase (MAPK) pathway in this phenomenon. ATRA phosphorylated the p38 MAPK, and SB202180 inhibited ATRA-induced IL-8 production, which indicates that the p38 MAPK is also involved in ATRA-induced IL-8 production. In summary, ATRA induces IL-8 production in both NF-kappaB- and p38 MAPK-dependent manners in normal human keratinocytes.