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

Abstract

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 PGE(2) significantly stimulate HO-1 expression in RAW264.7 macrophages, associated with alternative induction on NO and PGE(2) in medium, respectively. NO donors also show the inductive effect on cyclo-oxygenase 2 protein and PGE(2) production. In the presence of lipopolysaccharide and interferon-gamma (LPS/IFN-gamma), HO-1 protein was induced slightly but significantly, and SNP, SP-NO, and PGE(2) enhanced HO-1 protein induced by LPS/IFN-gamma. L-Arginine analogs N-nitro-L-arginine 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 SB203580 (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 SB203580). 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.

NO Modulates NADPH Oxidase Function Via Heme Oxygenase-1 in Human Endothelial Cells

“…Studies in both ECs and macrophages have shown that proinflammatory cytokine-induced HO-1 expression is at least partly dependent on iNOS expression and subsequent NO generation. 27,28 In a rat model of adjuvant arthritis, blockade of NO production from iNOS suppressed HO-1 upregulation at the site of inflammation. 29 These findings suggest that NO-mediated HO-1 expression may have important roles in preventing tissue damage associated with inflammation.…”

Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice

“…JNK pathways are also involved in the phosphorylation and activation of several transcription factors, including c-Jun (Derijard et al, 1994), ATF-2 (Read et al, 1997), Elk-1 (Cavigelli et al, 1995), and p53 (Milne et al, 1995). Studies have demonstrated that cell exposure to UV irradiation causes activation of the MAPK pathway (Chen et al, 2002;Chouinard et al, 2002;Iordanov et al, 2002;She et al, 2002). JNK1/2 and p38 kinases are potently activated by various forms of stress, such as UV, heat shock, and inflammation Figure 7 Inhibitory effect of green tea polyphenol on UVBinduced activation of IKKa, and phosphorylation and degradation of IkBa in SKH-1 hairless mice.…”

“…of 12 mice (*Po0.001 vs UVB). ns, nonspecific Suppression of UVB effects in mouse skin by GTP F Afaq et al (Derijard et al, 1994;Chen et al, 2002;Chouinard et al, 2002;Iordanov et al, 2002). Experimental studies have shown that ERK1/2 and p38 are involved in the transcriptional activation of NF-kB (Adderley and Fitzgerald, 1999;Carter et al, 1999).…”

Disease tolerance and immunity in host protection against infection

“…The pathophysiological relevance of this defense strategy is supported by the number of mechanisms deployed by intracellular pathogens to promote or inhibit host genetic programs controlling programmed cell death, presumably as a strategy to escape resistance to infection 70 . Clearance of damaged and dying cells is associated with macrophage polarization towards the production of cytokines and pro-resolving lipid mediators 71 including IL-10 and 15-Deoxy-Δ-prostaglandin J 2 (15d-PGJ 2 ), respectively, which induce the expression HO-1 72,73 . This macrophage response is also associated with the production of growth factors, such as platelet-derived growth factor (PDGF) and cytokines, such as transforming growth factor-β1 (TGFβ1), which can act directly on parenchyma cells to promote tissue regeneration, orchestrating yet another layer of tissue damage control 23 .…”