Epidermal growth factor synergistically enhances interleukin-8 production in human gingival fibroblasts stimulated with interleukin-1β

The chemokine interleukin-8 (IL-8) has been implicated in inflammatory diseases including periodontitis. In this study the effect of epidermal growth factor (EGF) on the production and regulation of interteukin-8 (IL-8) in human gingival fibroblasts challenged with interleukin-1 beta (IL-1 beta) was investigated. EGF, in comparison to the effect of IL-1 beta, weakly increased the mRNA and protein expression of IL-8 in gingival fibroblasts. When the cells were treated simultaneously with EGF and IL-1 beta, however, EGF synergistically enhanced them RNA expression and production of IL-8. The stimulatory effect of EGF on IL-1 beta-induced IL-8 production was completely abolished by the broad range tyrosine kinase inhibitor Herbimycin A, and considerably reduced by the receptor tyrosine kinase specific inhibitor PD 153035. Herbimycin A abolished IL-8 production induced by IL-1 beta, whereas PD 153035 had no effect on the cytokine-induced IL-8 production. Furthermore, the p38 mitogen-activated protein (MAP) kinase inhibitor SB 203580 reduced IL-8 production induced by IL-1 beta as well as by the combination of EGF and IL-1 beta but had no effect on EGF-induced IL-8 production. In conclusion, the study demonstrates that EGF synergistically stimulates IL-8 production in the presence of IL-1 beta and that tyrosine kinase(s) seem to be involved in the signalling pathway of IL-1 beta and EGF. The synergistic interactions between EGF and IL-1 beta on IL-8 production may play an essential rote in the pathogenesis of the inflammatory disease periodontitis. (c) 2006 Elsevier Ltd. All rights reserved.