Airway epithelial cells which are the initial site of influenza virus (IV) infection are suggested to participate in airway inflammatory response by expressing various cytokines including RANTES; however, the intracellular signal that regulates RANTES expression has not been determined. In the present study, we examined the role of p38 mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase (Erk), and c-Jun-NH2-terminal kinase (JNK) in RANTES production by IV-infected human bronchial epithelial cells. The results showed that IV infection induced increases in p38 MAP kinase, and Erk and JNK phosphorylation and activity. SB 203580, PD 98059, and CEP-1347 attenuated IV-infection induced p38 MAP kinase activity, Erk activity, and JNK activity, respectively. SB 203580 and CEP-1347 attenuated RANTES production by 45.3% and 45.2%, respectively, but a combination of these inhibitors additively attenuated by 69.1%. In contrast, PD 98059 did not attenuate. Anti-IL-1α mAb, anti-IL-1β mAb, anti-TNF-α mAb, anti-IL-8 mAb, anti-IFN-β mAb, anti-RANTES mAb, and a combination of these mAbs did not affect IV infection-induced increases in p38 MAP kinase, Erk, and JNK phosphorylation, indicating that each cytokine neutralized by corresponding Ab was not involved in IV infection-induced phosphorylation of MAP kinases. N-acetylcysteine (NAC) did not affect IV infection-induced increases in MAP kinase phosphorylation, whereas NAC attenuated RANTES production by 18.2%, indicating that reactive oxygen species may act as a second messenger leading to RANTES production via p38 MAP kinase- and JNK-independent pathway. These results indicate that p38 MAP kinase and JNK, at least in part, regulate RANTES production by bronchial epithelial cells.

These results indicate that p38 MAP kinase plays an important role in TNF alpha-, IL-1 alpha- or PAF-activated signalling pathway which regulates RANTES and GM-CSF production by BECs and that the specific inhibitor for p38 MAP kinase activity might be useful for the treatment of allergic inflammation of the airway.

The aim of this study was to examine the role of p38 mitogen‐activated protein (MAP) kinase in interleukin (IL)‐8 expression in tumour necrosis factor (TNF)‐α‐ and IL‐1α‐stimulated human pulmonary vascular endothelial cells. To this end, the phosphorylation and activation of p38 MAP kinase and the effect of SB 203580, a specific inhibitor of p38 MAP kinase activity, on p38 MAP kinase activity and IL‐8 expression in TNF‐α‐ and IL‐1α‐stimulated human pulmonary vascular endothelial cells were examined. TNF‐α‐ and IL‐1α‐ induced phosphorylation and activation of p38 MAP kinase and IL‐8 expression in human pulmonary endothelial cells. Inhibition of TNF‐α‐ and IL‐1α‐induced p38 MAP kinase activity by SB 203580 inhibited TNF‐α‐ and IL‐1α‐induced IL‐8 protein production as well as IL‐8 messenger ribonucleic acid (mRNA) expression, indicating that SB 203580 was effective at the transcriptional level. These results indicate that p38 mitogen‐activated protein kinase plays an important role in the tumour necrosis factor‐α‐ and interleukin‐1α‐activated signalling pathway which regulates interleukin‐8 expression in human pulmonary vascular endothelial cells.

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Abstract

Abstract

1 Amantadine can prevent and decrease airway in¯ammation by inhibiting in¯uenza virus (IV) replication; however, the e ect of amantadine on RANTES production by human bronchial epithelial cells (BEC) has not been determined. In the present study, we examined the e ect of amantadine on RANTES production and also analysed p38 mitogen-activated protein (MAP) kinase and c-Jun-NH 2 -terminal kinase (JNK) activation to clarify the mechanism in the e ect of amantadine on RANTES production, since we have previously shown that p38 MAP kinase and JNK regulate RANTES production by IV-infected BEC. 2 BEC that had been preincubated with amantadine were infected with IV and then p38 MAP kinase and JNK activation in the cells and RANTES concentrations in the culture supernatants were determined. 3 Amantadine-induced inhibition of virus replication resulted in a decrease in p38 MAP kinase and JNK activity and decreased expression of RANTES in IV-infected cells. 4 Amantadine did not inhibit p38 MAP kinase and JNK activation induced by tumour necrosis factor-a (TNF-a) as a non-viral stimulus. 5 These results indicate that amantadine inhibits IV infection-induced RANTES production by human BEC and that the inhibition by amantadine of RANTES production might result from an indirect inhibitory e ect of amantadine on p38 MAP kinase and JNK activation via the inhibition of virus replication, and we emphasize that amantadine may produce a bene®cial e ect on controlling bronchial asthma exacerbation caused by IV infection. British Journal of Pharmacology (2001) 132, 918 ± 924

Background: Interleukin (IL)-4 and IL-13, which play a role in the production of allergic inflammation, can activate fibroblasts to elicit a variety of cellular functions. However, the effect of IL-4 and IL-13 on fibronectin production by human lung fibroblasts (HLF) has not been determined. In the present study, we examined the effect of IL-4 and IL-13 on fibronectin production by HLF in order to clarify these issues. Methods: We stimulated HLF with various concentrations of IL-4 and IL-13 for 12, 24, 48 and 72 h and fibronectin concentrations in the culture supernatants were determined by ELISA. Results: The results showed that IL-4 and IL-13 induced fibronectin production in a time-and a concentration-dependent manner. Anti-transforming growth factor (TGF)-β 1 antibody (ab) inhibited TGF-β 1induced fibronectin production but not IL-4-and IL-13-induced fibronectin production, indicating that TGF-β 1 is not involved in the IL-4-and IL-13-induced fibronectin production by HLF. Conclusions: These results indicate that IL-4 and IL-13 are capable of inducing fibronectin production by HLF and play an important role in the production of airway remodeling by inducing fibronectin production as well as allergic inflammation.