Recent data indicate that interleukin (IL)-17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil-mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL-17 induced release of IL-8 and IL-6 in bronchial epithelial cells. Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL-17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular-signal-regulated kinase [ERK] pathway), Ro-31-7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3-kinase [PI 3-kinase] inhibitor) or vehicle. IL-6 and IL-8 levels were measured in conditioned media by ELISA. The IL-17-induced release of IL-6 and IL-8 was concentration-dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival. Ro-31-7549 and LY294002 had no significant effect on IL-17-induced IL-6 or IL-8 release in bronchial epithelial cells. Taken together, these data indicate a role for p38 and ERK kinase pathways in IL-17-induced release of neutrophil-mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL-17-mediated airway neutrophilia. Keywords: Interleukin-17, bronchial epithelial cell, MAP kinase, neutrophil Introduction Airway neutrophilia is a characteristic of several chronic airway diseases such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), bronchial asthma and cystic fibrosis (Balbi et al., 1997; Lamblin et al., 1998; Meyer & Zimmerman, 1993). By releasing proteolytic enzymes and free oxygen radicals, the increased number of neutrophils may contribute to the main features of these diseases such as airway obstruction, hypersecretion and remodelling (Schuster et al., 1992; Venaille et al., 1995; Weinberg & Hayes, 1982). As indicated in murine airways in vivo, the recruitment of neutrophils into the airways can be controlled by activated T-lymphocytes (Gavett et al., 1994; Nakajima et al., 1992). However, the precise mechanisms by which T-lymphocytes achieve this control are not fully understood. Interleukin-17 is a recently characterized proinflammatory cytokine produced exclusively by activated T-lymphocytes (Yao et al., 1995). The IL-17 receptor (R) however, is widely distributed and is expressed in several tissues, including the lung, and on several cell types, including bronchial epithelial cells (Yao et al., 1997). We have recently shown that exogenous IL-17, given intratracheally, causes a selective increase of the neutrophil number paralleled by an increase in the activity of elastase and myeloperoxidase in murine airways (Hoshino et al., 2000; Laan et al., 1999). Hypothetically, IL-17 could thus link the activation of T-lymphocytes to the recruitment and activation of airway neutrophils. This is further supported by the recent observation that inhalation of endotoxin in mice causes increased IL-17 mRNA expression, followed by neutrophil airways (Larsson et al., 2000). In human bronchial cells in vitro, IL-17 induces the production of neutrophil-mobilizing cytokines such as IL-6 and IL-8 (Fossiez et al., 1996; Laan et al., 1999; Yao et al., 1995). Since these cytokines are known to modulate the recruitment, activation and survival of neutrophils (Bank et al., 1995; Richman-Eisenstat et al., 1993), the induced production of these cytokines in airway cells is likely to explain the effect of IL-17 on neutrophils in the airways. However, the intracellular signalling mechanisms mediating these effects of IL-17 in airway cells have not been elucidated. The mitogen-activated protein (MAP) kinase family is central in mediating several changes in cell function such as cytokine expression, proliferation and apoptosis (Puddicombe & Davies, 2000; Robinson & Cobb, 1997). To date, three MAP kinase cascades have been identified and characterized from a molecular standpoint. These comprise the p38 MAP kinase, extracellular signal-regulated kinase (ERK) and c-Jun amino-terminal kinase (JNK). Once activated by their upstream regulators, the MAP kinases translocate to the cell nucleus where they modulate the activity of nuclear transcription factors and kinases which, in turn, cause the changes in cell function such as production of cytokines. Recently, specific cell permeable inhibitors have been developed for two of these MAP kinase pathways. SB203580 and analogues such as SB202190 specifically inhibit the p38 MAP kinase (Badger et al., 1996; Kramer et al., 1996) whereas PD98059 inhibits the upstream activator of ERK kinases, MEKs, resulting in a blockade of ERK mediated signalling (Alessi et al., 1995). Although there is no specific inhibitor available for the JNK MAP kinase pathway, two major upstream activators of JNK, the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI 3-kinase), can be inhibited by specific inhibitors such as Ro-31-7549 and LY 294002, respectively, resulting in downstream inhibition of JNK-mediated signalling (Kawakami et al., 1998; Vlahos et al., 1995; Yano et al., 1995; Zhang et al., 1997). The aim of this study was to characterize the involvement of MAP kinases in IL-17-induced release of two neutrophil-mobilizing cytokines, IL-6 and IL-8, in human bronchial epithelial cells, thereby identifying potential targets for pharmacotherapeutical inhibition of IL-17 mediated airway neutrophilia.