Histamine affects STAT6 phosphorylation via its effects on IL-4 secretion: role of H1 receptors in the regulation of IL-4 production.
Histamine affects STAT6 phosphorylation via its effects on IL-4 secretion: role of H1 receptors in the regulation of IL-4 production.
复制标题
组胺通过影响 IL-4 分泌来影响 STAT6 磷酸化：H1 受体在调节 IL-4 产生中的作用。
DOI：
10.1016/j.intimp.2006.10.006
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发表时间：
2007
影响因子：
5.6
通讯作者：
Khan,ManzoorM
中科院分区：
文献类型：
--
作者：
Kharmate,Geetanjali;Liu,Zhongfeng;Patterson,Eric;Khan,ManzoorM
信号转导和转录激活因子（Signal Transducer and Activator of Transcription，STAT）-6是一种转录因子，主要通过细胞因子IL-4和IL-13激活，导致Th 2细胞分化。Th 2细胞在变态反应性疾病的病因和发病机制中发挥作用。组胺改变Th 1/Th 2细胞因子平衡，使其趋向Th 2细胞因子谱，因此在过敏性疾病和哮喘中起作用。本研究旨在探讨组胺对STAT 6磷酸化的影响。用不同浓度的组胺（10− 4 M至10− 13 M）预处理C57/BL 6脾细胞，然后用PMA+离子霉素或IL-4刺激。通过采用免疫印迹技术评估磷酸化和总基础STAT 6水平。组胺引起STAT 6的过度磷酸化。H1受体拮抗剂吡拉明可逆转组胺对STAT 6磷酸化的影响。然而，H2受体拮抗剂雷尼替丁和H3/H4受体拮抗剂硫代哌丁胺不影响组胺介导的STAT 6的过度磷酸化。此外，H1受体激动剂betahistine增强STAT 6的磷酸化，而H2受体激动剂amthamine不影响STAT 6的磷酸化。酪氨酸激酶抑制剂tyrphostin可抑制PMA+ionomycin诱导的组胺介导的STAT 6磷酸化。组胺对STAT 6磷酸化的影响是间接的，因为它们被IL-4和IL-13的抗体阻断，或者在IL-13抗体存在下在IL-4敲除小鼠中被阻断。这些结果表明，组胺通过影响细胞因子（IL-4）的分泌间接影响STAT 6的磷酸化，H1受体在此过程中发挥作用。
Signal Transducer and Activator of Transcription (STAT)-6 is a transcriptional factor activated mainly through the cytokines IL-4 and IL-13 leading to the Th2 cell differentiation. Th2 cells play a role in the etiology and pathogenesis of allergic disease. Histamine alters the Th1/Th2 cytokine balance towards the Th2 cytokine profile and consequently plays a role in allergic diseases and asthma. This study was designed to investigate the effects of histamine on the STAT6 phosphorylation. C57/BL6 splenocytes were pretreated with different concentrations of histamine (10−4M to 10−13M) followed by stimulation with PMA+ionomycin or IL-4. The phosphorylated and total basal STAT6 levels were assessed by employing the immunoblotting technique. Histamine caused the hyper-phosphorylation of STAT6. H1 receptor antagonist pyrilamine reversed the effect of histamine on STAT6 phosphorylation. However, H2 receptor antagonist ranitidine and H3/H4 receptor antagonist thioperamide did not affect the histamine mediated hyper-phosphorylation of STAT6. Furthermore, H1 receptor agonist betahistine enhanced the phosphorylation of STAT6 whereas H2 receptor agonist amthamine did not affect the phosphorylation STAT6. Furthermore, tyrosine kinase inhibitor, tyrphostin, inhibited the histamine mediated phosphorylation of STAT6 when stimulated with PMA+ionomycin. The effects of histamine on the STAT6 phosphorylation were indirect since they were blocked either by the antibodies to IL-4 and IL-13 or in IL-4 knock out mice in the presence of IL-13 antibody. These observations suggest that histamine indirectly affected the STAT6 phosphorylation via its effects on the secretion of cytokines (IL-4) and H1 receptor played a role in this process.