Elevated levels of several cytokines including interleukin-1β (IL-1β) have been detected in airway fluid of asthmatic patients. Inhalation of IL-1β induced a bronchial hyper-reactivity to contractile agonists. However, the implication of IL-1β in the pathogenesis of bronchial hyper-reactivity is not completely understood. Therefore, we investigated the effect of IL-1β on bradykinin (BK)-induced inositol phosphate [Ins(X)P] accumulation and Ca2+ mobilization, and up-regulation of BK receptor density in canine cultured tracheal smooth-muscle cells (TSMCs). Treatment of TSMCs with IL-1β potentiated BK-induced Ins(X)P accumulation and Ca2+ mobilization. However, there was no effect on the Ins(X)P response induced by endothelin-1, 5-hydroxytryptamine or carbachol. Treatment with platelet-derived growth factor B-chain homodimer (PDGF-BB) also enhanced the BK-induced Ins(X)P response. These enhancements by IL-1β and PDGF-BB might be due to an up-regulation of BK B2 receptor density (Bmax), since [3H]BK binding to TSMCs was inhibited by the B2-selective agonist and antagonist, BK and Hoe 140, but not by B1-selective reagents. The enhancing effects of IL-1β and PDGF-BB on Ins(X)P accumulation, Ca2+ mobilization and Bmax were attenuated by PD98059 [an inhibitor of activation of mitogen-activated protein kinase (MAPK) kinase, MEK] and cycloheximide (an inhibitor of protein synthesis), suggesting that IL-1β may share a common signalling pathway with PDGF-BB via protein synthesis. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed the up-regulation of BK receptors induced by IL-1β, indicating that Ras and Raf may be required for activation of these kinases. These results suggest that the augmentation of BK-induced responses produced by IL-1β might be, at least in part, mediated through activation of the Ras/Raf/MEK/MAPK pathway in TSMCs.
Interleukin-1β enhances bradykinin-induced phosphoinositide hydrolysis and Ca2+ mobilization in canine tracheal smooth-muscle cells: involvement of the Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway
- Views Icon Views
- PDF LinkPDF
- Share Icon Share
- Cite Icon Cite
Chuen-Mao YANG, Chin-Sung CHIEN, Chuan-Chwan WANG, Yan-Mei HSU, Chi-Tso CHIU, Chih-Chung LIN, Shue-Fen LUO, Li-Der HSIAO; Interleukin-1β enhances bradykinin-induced phosphoinositide hydrolysis and Ca2+ mobilization in canine tracheal smooth-muscle cells: involvement of the Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway. Biochem J 1 March 2001; 354 (2): 439–446. doi: https://doi.org/10.1042/bj3540439
Download citation file: