Histamine enhances the production of granulocyte-macrophage colony-stimulating factor via protein kinase Cα and extracellular signal-regulated kinase in human keratinocytes
Histamine enhances the production of granulocyte-macrophage colony-stimulating factor via protein kinase Cα and extracellular signal-regulated kinase in human keratinocytes
复制标题
DOI：
10.1111/j.0022-202x.2004.22432.x
复制
发表时间：
2004-04-01
影响因子：
6.5
通讯作者：
Watanabe, S
中科院分区：
文献类型：
--
作者：
Kanda, N;Watanabe, S
角化细胞中粒细胞-巨噬细胞集落刺激因子（GM-CSF）的产生与特应性皮炎的慢性性有关。肥大细胞源性组胺有助于肥大细胞和角质形成细胞之间的串扰。我们研究了组胺对人角质形成细胞中GM-CSF产生的影响。组胺增加GM-CSF分泌、mRNA稳定性和启动子活性。启动子上的激活蛋白-1 （AP-1）和核因子- kappab （NF-kappaB）元件负责组胺激活。组胺增强AP-1和NF-kappaB的转录活性和DNA结合。组胺将AP-1组成从c-Jun同型二聚体转变为c-Fos/c-Jun异源二聚体，并短暂表达c-Fos蛋白。组胺快速诱导抑制性kappaB的磷酸化和降解。组胺诱导蛋白激酶Calpha的膜易位。组胺诱导的GM-CSF的产生被H1拮抗剂pyrilamine和常规蛋白激酶C抑制剂Go6976完全抑制，并被PD98059部分抑制，PD98059抑制细胞外信号调节激酶的激活。Go6976和PD98059抑制组胺诱导的c-Fos表达和AP-1激活。Go6976和PD98059抑制组胺诱导的NF-kappaB转录活性增强。组胺诱导的抑制性kappaB磷酸化和降解被Go6976抑制，而PD98059不受抑制。这些结果表明，组胺可能通过H1受体、蛋白激酶Calpha和细胞外信号调节激酶在转录和转录后水平上促进GM-CSF的产生。
The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) in keratinocytes is related to the chronicity of atopic dermatitis. Mast cell-derived histamine contributes to the cross-talk between mast cells and keratinocytes. We examined the effects of histamine on GM-CSF production in human keratinocytes. Histamine increased GM-CSF secretion, mRNA stability and promoter activity. Activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) elements on the promoter were responsible for the activation by histamine. Histamine enhanced transcriptional activity and DNA binding of AP-1 and NF-kappaB. Histamine shifted AP-1 composition form c-Jun homodimers to c-Fos/c-Jun heterodimers, and transiently expressed c-Fos protein. Histamine rapidly induced the phosphorylation and degradation of inhibitory kappaB. Histamine induced membrane translocation of protein kinase Calpha. Histamine-induced GM-CSF production was completely abolished by H1 antagonist pyrilamine and conventional protein kinase C inhibitor Go6976, and partially suppressed by PD98059 which inhibits the activation of extracellular signal-regulated kinase. Go6976 and PD98059 suppressed histamine-induced c-Fos expression and AP-1 activation. Go6976 and PD98059 suppressed histamine-induced enhancement of NF-kappaB transcriptional activity. Histamine-induced phosphorylation and degradation of inhibitory kappaB was suppressed by Go6976, but not by PD98059. These results suggest that histamine may enhance GM-CSF production at transcriptional and posttranscriptional levels via H1 receptor, protein kinase Calpha and extracellular signal-regulated kinase.