Submitted on October 24, 2005
Accepted on March 29, 2006
Calcitonin gene-related peptide inhibits interleukin-1
-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells
Wenjing Li1, Tengke Wang2, Chenming Ma1, Tingting Xiong1, Yi Zhu1, and Xian Wang3*
1 Department of Physiology and Pathophysiology, Schoool of Basic Medical Science, Peking University, Beijing, China
2 Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
3 Department of Physiology and Pathophysiology, Schoool of Basic Medical Science, Peking University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Schoool of Basic Medical Science, Peking University, Beijing, China; Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
* To whom correspondence should be addressed. E-mail: xwang{at}bjmu.edu.cn.
As important multifunctional cells in the lung, alveolar epithelial type II (AEII) cells secrete numerous chemokines upon various stimuli. Our previous data have shown that AEII cells also express neuropeptide calcitonin gene-related peptide (CGRP) and pro-inflammatory factor interleukin-1
(IL-1) induces CGRP secretion in the A549 human AEII cell line. In the present study, CGRP-1 receptor antagonist hCGRP8-37 (0.1-1 nM) greatly amplified the production of IL-1-induced monocyte chemoattractant protein-1 (MCP-1). The inhibition of CGRP expression by siRNA significantly increased MCP-1 secretion upon IL-1 stimulation. However, exogenous hCGRP (10-100 nM) suppressed IL-1-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-1. These data imply that AEII-derived CGRP suppressed IL-1-induced MCP-1 secretion in an autocrine/paracrine mode. Subsequent investigation revealed that CGRP inhibited IL-1-evoked NF-
B activity by suppressing IB
phosphorylation and degradation. Moreover, CGRP attenuated IL-1-induced reactive oxygen species (ROS) formation, the early event in pro-inflammatory factor signaling. We previously showed that the CGRP inhibitory effect was mediated by elevated intracellular cAMP and show here that analogs of cAMP, 8-Br-cAMPs and Sp-cAMPs mimicked the CGRP suppressive effect on IL-1-induced ROS formation, NF-B 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-B-MCP-1 pathway.
