Mechanisms of interleukin 1β-induced human airway smooth muscle hyporesponsiveness to histamine -: Involvement of p38 MAPK and NF-κB
Mechanisms of interleukin 1β-induced human airway smooth muscle hyporesponsiveness to histamine -: Involvement of p38 MAPK and NF-κB
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DOI：
10.1164/ajrccm.163.4.9911091
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发表时间：
2001-03-01
影响因子：
24.7
通讯作者：
Verleden, GM
中科院分区：
文献类型：
--
作者：
Pype, JL;Xu, HY;Verleden, GM
我们研究了IL-1 β对组胺H-1受体（H1 R）介导的磷酸肌醇（IP）在人气道平滑肌细胞（HASMC）中的积聚和对组胺诱导的人支气管环收缩的影响。用IL-1 β刺激HASMC 24 h导致组胺诱导的IP形成显著减少，这与IL-1 β处理的人支气管环组胺诱导的收缩减少有关。NF-κ B激活抑制剂吡咯烷二硫代氨基甲酸酯和p38 MAPK抑制剂阻断了IL-1 β诱导的H1 R脱敏，而茴香霉素、SAPK/JNK和p38 MAPK激活剂模拟了IL-1 β的作用。IL-1 β已被证明可诱导考克斯-2表达和PGE（2）合成。在我们的研究中，吲哚美辛（考克斯拮抗剂）完全抑制了IL-1 β对H1 R的作用，而外源性加入PGE（2）能够使H1 R脱敏。PKA选择性抑制剂H-89可拮抗IL-1 β的作用。在这里，我们已经证明IL-1 β使H1 R脱敏，这涉及p38 MAPK和NF-κ B的激活，导致考克斯-2的表达和PGE的合成（2）。PGE（2）增加细胞内cAMP，导致PKA活化，从而磷酸化和功能性解偶联H1 R。我们的研究结果表明，IL-1 β保护气道平滑肌对组胺诱导的收缩反应和支气管高反应性组胺是不相关的促炎性奎宁诱导的增强H1 R信号。
We have investigated the effect of IL-1beta on histamine H-1-receptor (H1R)-mediated inositol phosphate (IP) accumulation in human airway smooth muscle cells (HASMC) and on histamine-induced contraction of human bronchial rings. Stimulation of HASMC for 24 h with IL-1beta resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine-induced contraction of IL-1beta-treated human bronchial rings. An inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1beta-induced H1R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1beta. IL-1beta has been demonstrated to induce cox-2 expression and PGE(2) synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1beta on H1R, whereas exogenously added PGE(2) was able to desensitize H1R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1beta. Here, we have demonstrated that IL-1beta desensitizes H1R, which involves the activation of p38 MAPK and NF-kappaB, leading to the expression of cox-2 and the synthesis of PGE(2). PGE(2) increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H1R. Our results suggest that IL-1beta protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H1R signaling.