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

Abstract

Bradykinin (BK) is a major kinin with well-documented pharmacological properties including vascular leakage and induction of a variety of cytokines. However, the intracellular signalling mechanisms by which BK induced proinflammatory cytokine production have not been fully elucidated. This study investigated 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-induced 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 phosphorylation. BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist. Furthermore, PD98059 or SB203580 significantly suppressed BK-induced IL-6 and IL-8 production and their gene expression.These results indicate that bradykinin-induced interleukin-6 and interleukin-8 production are at least partly mediated through the extracellular signal-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathway-dependent activation in human lung fibroblasts, and suggest that bradykinin appears to be involved in the inflammatory reaction leading to acute lung injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts. Eur Respir J 2000; 16: 452±458.

In vitro sensitization of human bronchus by β2-adrenergic agonists

“…Ricciardolo and colleagues (49) showed that a combination of the NK 1 and NK 2 tachykinin receptor antagonists abolished the increased bronchoconstriction produced by NKA and inhibited partially the contractile response induced by bradykinin in ovalbumin-sensitized guinea pigs, whereas HOE-140 had no effect on the increase in bronchoconstriction produced by NKA, suggesting that bradykinin induces the release of tachykinins from sensory nerves in guinea pig airways. Moreover, bradykinin may stimulate the MAPK pathways via the activation of the protein Rho GTPase, PKC, and NF-B in human lung (29). Also, our study highlights the role of NF-B, leukotrienes, prostanoids, tachykinin NK 1 and NK 2 receptor agonists, and bradykinin in the mechanisms of sensitization of human bronchi by fenoterol (Fig.…”

“…PKC-enhances the activity of the protein Raf-1 and NF-B, which activate the p38 MAPK and SAPK/JNK pathways (12). Recent publications showed that bradykinin and thromboxane A 2 activate MAPK pathways via PKC-dependent G i ␣ protein coupling in human cells (20,29). In addition, PKC may increase the contractility of the airway smooth muscle by inhibiting caldesmon (via the MAPK pathways) and calponin (directly), which are involved in modulation of the actin-myosin interaction (30,61).…”

Proangiogenic Effect of Angiotensin-Converting Enzyme Inhibition Is Mediated by the Bradykinin B 2 Receptor Pathway

“…19 In the same way, BK stimulated proinflammatory cytokine production by different cellular types. 20,21 Taken together, these studies highlight the putative role of BK in the modulation of the inflammatory reaction and, therefore, in inflammationinduced angiogenesis. BK might also directly activate cyclooxygenase-2, which has been reported to affect the angiogenic process.…”

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Subsequent studies have shown that BK stimulation of NF-B activation proceeds through both G␤␥ and G␣ q to PI-3K and Akt (Xie et al, 2000) as well as RhoA (Pan et al, 1998). BK also stimulates expression of IL-6 and IL-8 (Phagoo et al, 1999;Hayashi et al, 2000). In cultured smooth muscle cells, BK-stimulated expression of IL-8 was dependent on both a prostanoid-independent and -dependent mechanism (Zhu et al, 2003).…”