Enhanced induction of LPS-induced fibroblast MCP-1 by interferon-gamma: involvement of JNK and MAPK phosphatase-1

IFN-gamma has significant immunoregulatory activity and plays an important role in both innate and adaptive immunity. Additive effects of IFN-gamma and the Toll-like receptor ligand LPS has been investigated in macrophages, but in fibroblasts is incompletely understood. IFN-gamma and LPS synergistically induced MCP-1 and NO release in primary murine dermal fibroblasts. IFN-gamma enhanced LPS-induced JNK and p38 MAPK phosphorylation but had no effect on NF-kappaB activity. The induction of both MCP-1 and NO was attenuated by inhibition of JNK but not p38 MAPK. Serine 727 STAT1 phosphorylation by IFN-gamma was increased by LPS, and this was also attenuated by inhibition of JNK but not p38 MAPK. IFN-gamma inhibited the basal expression of MAPK phosphatase-1, a negative regulator of MAPK signaling pathway. These results suggest that enhancement of LPS-induced JNK activation by IFN-gamma associated with inhibition of MAPK phosphatase-1 may be one of the mechanisms of additive effects between IFN-gamma and LPS in fibroblasts.