Nitric oxide and prostaglandin E2 participate in lipopolysaccharide/interferon-γ-induced heme oxygenase 1 and prevent RAW264.7 macrophages from UV-irradiation-induced cell death

induction of heme oxygenase (HO)-1 during inflammation has been demonstrated in many cell types, but the contribution of inflammatory molecules nitric oxide (NO) and prostaglandin E-2 (PGE(2)) has remained unresolved. Here we show that NO donors including sodium nitroprusside (SNP) and spermine nonoate (SP-NO), and PGE2 significantly stimulate HO-1 expression in RAW264.7 macrophages, associated with alternative induction on NO and PGE2 in medium, respectively. NO donors also show the inductive effect on cyclo-oxygenase 2 protein and PGE(2) production. In the presence of lipopolysaccha ride and interferon-gamma (LPS/IFN-gamma), HO-1 protein was induced slightly but significantly, and SNP, SP-NO, and PGE2 enhanced HO-1 protein induced by LPS/IFN-gamma. L-Arginine analogs N-nitro-L-arginme methyl ester (L-NAME) and N-nitro-L-arginine (NLA) significantly block HO-1 protein induced by LPS/IFN-gamma associated with a decrease in NO (not PGE(2)) production. And, NSAIDs aspirin and diclofenase dose dependently inhibited LPS/IFN-gamma-induced HO-1 protein accompanied by suppression of PGE(2) (not NO) production. PD98059 (a specific inhibitor of MEKK), but not S13203580 (a specific inhibitor of p38 kinase), attenuated PGE(2) (not SP-NO) induced HO-1 protein. Under UVC (100 J/m(2)) and UVB (50 J/m(2)) irradiation, PGE(2) or SP-NO treatment prevents cells from UVC or UVB-induced cell death, and HO-1 inhibitor tin protoporphyrin (SnPP) reverses the preventive effects of PGE(2) and SP-NO. The protective activity induced by PGE(2) on UVC or UVB irradiation-induced cell death was blocked by MAPK inhibitor PD98059 (not S13203580). These results demonstrated that inflammatory molecules NO and PGE(2) were potent inducers of HO-1 gene, and protected cells from UV-irradiation-induced cell death through HO-1 induction. (C) 2002 Wiley-Liss, Inc.