Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms

Bradykinin (BK) is a major kinin with well-documented pharmacological prope rties including vascular leakage and induction of a variety of cytokines. H owever, the intracellular signalling mechanisms by which BK induced proinfl ammatory cytokine production have not been fully elucidated. This study inv estigated the role of the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in the BK-in duced interleukin (IL)-6 and IL-8 production by human lung fibroblasts. Lung fibroblasts were stimulated with BK in the presence or in the absence of PD98059, a specific MAPK/ERK kinase-1 inhibitor, or SB203580, a specific p38 MAPK inhibitor, and IL-6 or IL-8 production and their gene expression was examined. BK-induced ERK 1/2 or p38 MAPK phosphorylation was also analysed by Western blot analysis. BK at nanomolar concentrations stimulated lung fibroblasts to produce IL-6 and IL-8 along with increased ERK 1/2 and p38 MAPK phosphor ylation, BK-induced IL-6 and IL-8 synthesis was inhibited by a BZ-type BK r eceptor antagonist. Furthermore, PD98059 or SB203580 significantly suppress ed BK-induced IL-6 and IL-8 production and their gene expression. These results indicate that bradykinin-induced interleukin-6 and interleuki n-8 production are at least partly mediated through the extracellular signa l-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathw ay-dependent activation in human lung fibroblasts, and suggest that bradyki nin appears to be involved in the inflammatory reaction leading to acute lu ng injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts.