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首页> 外文期刊>American Journal of Physiology >Calcitonin gene-related peptide inhibits interleukin-1beta-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells.
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Calcitonin gene-related peptide inhibits interleukin-1beta-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells.

机译：降钙素基因相关肽抑制白细胞介素-1β诱导的II型肺泡上皮细胞内源性单核细胞趋化蛋白1分泌。

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摘要

As important multifunctional cells in the lung, alveolar epithelial type II (AEII) cells secrete numerous chemokines on various stimuli. Our previous data showed that AEII cells also express the neuropeptide calcitonin gene-related peptide (CGRP) and the proinflammatory factor interleukin (IL)-1beta induces CGRP secretion in the A549 human AEII cell line. In the present study, the CGRP-1 receptor antagonist human (h)CGRP(8-37) (0.1-1 nM) greatly amplified the production of IL-1beta-induced monocyte chemoattractant protein (MCP)-1. The inhibition of CGRP expression by small interfering RNA significantly increased MCP-1 secretion on IL-1beta stimulation. However, exogenous hCGRP (10-100 nM) suppressed IL-1beta-evoked MCP-1 secretion in MCP-1 promoter activity, and CGRP gene stably transfected cell clones significantly inhibited both the mRNA and protein levels of MCP-1 induced by IL-1beta. These data imply that AEII-derived CGRP suppressed IL-1beta-induced MCP-1 secretion in an autocrine/paracrine mode. Subsequent investigation revealed that CGRP inhibited IL-1beta-evoked NF-kappaB activity by suppressing IkappaBalpha phosphorylation and degradation. Moreover, CGRP attenuated IL-1beta-induced reactive oxygen species (ROS) formation, the early event in proinflammatory factor signaling. We previously showed that the CGRP inhibitory effect was mediated by elevated intracellular cAMP and show here that analogs of cAMP, 8-bromoadenosine 3',5'-cyclic monophosphothioate and the Sp isomer of adenosine 3',5'-cyclic monophosphothioate, mimicked the CGRP suppressive effect on IL-1beta-induced ROS formation, NF-kappaB activation, and MCP-1 secretion. Thus increased endogenous CGRP secretion in lung inflammatory disease might eliminate the excessive response by elevating the cAMP level through inhibiting the ROS-NF-kappaB-MCP-1 pathway.
机译：作为肺中重要的多功能细胞，肺泡上皮II型（AEII）细胞在各种刺激下分泌大量趋化因子。我们以前的数据显示AEII细胞还表达神经肽降钙素基因相关肽（CGRP），促炎因子白介素（IL）-1beta诱导A549人AEII细胞系中CGRP分泌。在本研究中，CGRP-1受体拮抗剂人（h）CGRP（8-37）（0.1-1 nM）大大扩增了IL-1β诱导的单核细胞趋化蛋白（MCP）-1的产生。小干扰RNA对CGRP表达的抑制作用大大增加了IL-1beta刺激下MCP-1的分泌。然而，外源性hCGRP（10-100 nM）抑制了IL-1beta诱发的MCP-1启动子活性中的MCP-1分泌，并且CGRP基因稳定转染的细胞克隆显着抑制了IL-β诱导的MCP-1的mRNA和蛋白水平。 1beta。这些数据表明，AEII衍生的CGRP以自分泌/旁分泌模式抑制了IL-1β诱导的MCP-1分泌。随后的研究表明，CGRP通过抑制IkappaBalpha磷酸化和降解来抑制IL-1beta诱发的NF-kappaB活性。此外，CGRP减弱了IL-1β诱导的活性氧（ROS）的形成，这是促炎因子信号传导的早期事件。我们以前表明CGRP抑制作用是由细胞内cAMP升高介导的，在这里表明cAMP，8-溴腺苷3'，5'-环一硫代磷酸酯和3'，5'-环一硫代腺苷的Sp异构体的类似物模仿了CAMP。 CGRP对IL-1β诱导的ROS形成，NF-κB活化和MCP-1分泌的抑制作用。因此，肺炎性疾病中内源性CGRP分泌的增加可能会通过抑制ROS-NF-kappaB-MCP-1途径来提高cAMP水平，从而消除过度反应。

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