The synthetic functions of airway smooth muscle (ASM) cells play a critical role in modulating airway hyperreactivity and remodelling. Few studies, however, have examined the critical signalling pathways and transcriptional mechanisms that mediate cytokine-induced ASM synthetic function. In response to inflammatory mediators such as TNFa, ASM cells synthesize and secrete IL-6, a pleiotropic cytokine known to regulate inflammatory cell trafficking and the perpetuation of inflammatory responses in asthmatic airways. In this study we sought to define the signalling mechanisms that regulate TNFa-induced IL-6 gene expression and protein synthesis. By inhibiting p38 MAPK with SB203580, TNFa-induced IL-6 protein secretion was significantly reduced by 50%. In contrast, treatment of ASM cells with PD98059, an inhibitor of p42/p44 MAPK, did not affect TNFa-induced IL-6 secretion. Using receptor-specific agonistic and neutralizing antibodies, we found that TNFa appeared to mediate its effects on IL-6 secretion by binding to the TNFR1, but not the TNFR2 receptor. In addition, following transfection of a series of luciferase-tagged IL-6 promoter constructs, we found that deletion of the W-y site, but not the AP-1 or C/EBP sites, completely abrogated TNFa-induced increases in luciferase activity. Taken together, these results suggest that TNFa binding to the TNFR1 receptor increases NF-xB binding activity and promotes IL-6 gene expression via a p38 MAPK-dependent pathway.
|Original language||English (US)|
|Issue number||SUPPL. 1|
|State||Published - 2001|
All Science Journal Classification (ASJC) codes
- Pulmonary and Respiratory Medicine
- Smooth muscle