Activation of p38, ERK1/2 and NIK pathways is required for IL-1β and TNF-α-induced chemokine expression in human retinal pigment epithelial cells

Chemokine secretion by human retinal pigment epithelium (hRPE) in response to IL-1 beta and TNF-alpha occurs in infectious and noninfectious retinal diseases. In this study, the roles of p38 kinase and extracellular signal-regulated kinase (ERK) signaling pathways were investigated for IL-1 beta- or TNF-alpha -induced IL-8 and MCP-1 secretion by hRPE cells. Treatment of hRPE cells with IL-1 beta or TNF-alpha caused increased steady-state IL-8 and MCP-1 mRNA levels and protein secretion. Stimulation of hRPE with IL-1 beta and TNF-alpha resulted in degradation of I kappaB-alpha, nuclear translocation of IVF-KB, and prominent increases in p38 and ERK1/2 phosphorylation for as little as 3 min. The induced IL-8 and MCP-1 mRNA and proteins were partially suppressed by U0126, a specific MEK inhibitor. and by SB202190, a selective p38 inhibitor. This induction was completely blocked by simultaneous administration of the two drugs or by incubation with inhibitors for activation of NF-kappaB such as BAY11-7085, CAFE. and parthenolide. These results suggest that co-activation of MEK/ERK and p38 pathways as well as activation of NIK pathway are essential for IL-1 beta- and TNF-alpha -stimulation of IL-8 and MCP-1 gene expression in hRPE cells. Furthermore, coadministration of U0126 and SB202190 did not affect the induced degradation of I kappaB-alpha and NF-kappaB nuclear translocation, indicating that NF-kappa -B is activated by IL-1 beta and TNF-alpha independently of activation of MEK/MAPK and p38 pathways in hRPE cells. (C) 2001 Academic Press.