Regulation of Inhibitor of Apoptosis Expression by Nitric Oxide and Cytokines

Abstract

Abstract. Mesangial cells and RAW 264.7 macrophages respond to different nitric oxide (NO) donors within 16 to 24 h or 6 to 8 h, respectively, with apoptotic cell death. RAW 264.7 macrophages also die in response to endogenous NO production. In contrast, endogenous NO production fails to significantly induce cell death in mesangial cells. It was hypothesized that differences in the expression of antiapoptotic proteins, in particular the inhibitor of apoptosis (IAP) protein family, might be responsible for this cell type-specific behavior. Therefore, IAP expression was investigated in relation to apoptosis induction in response to NO and cytokines in both cell types. In mesangial cells, interleukin-1β (IL-1β) and tumor necrosis factor-α induced cellular inhibitor of apoptosis 1 (cIAP1) mRNA expression within 3 h. In contrast, X chromosome-linked inhibitor of apoptosis (XIAP) mRNA levels remained unaffected by cytokines. Although coincubation of cells with IL-1β and tumor necrosis factor-α or IL-1β and basic fibroblast growth factor resulted in synergistic induction of inducible NO synthase, comparable potentiating effects on cIAP1 induction were absent. Exogenously released NO from NO donors promoted cIAP1 mRNA upregulation in mesangial cells, whereas XIAP mRNA was downregulated. However, the changes observed on the mRNA level were not adequately translated to the protein level, and corresponding values for cIAP1 and XIAP were only slightly affected. In contrast, in lipopolysaccharide/interferon-γ-stimulated RAW 264.7 macrophages, massive NO-dependent downregulation of cIAP1 and XIAP protein levels, which correlated temporally with the induction of apoptosis, was observed. This effect was at least partially reversed by NG-monomethyl-L-arginine, an inhibitor of NO synthase activity. In summary, a direct correlation between the downregulation of IAP protein levels and the induction of apoptosis by endogenous NO was observed in macrophages. In contrast, a stable level of IAP protein in mesangial cells might represent a mechanism for the resistance of the cells to endogenously produced NO.

Inducible Nitric Oxide Synthase Mediates the Triglyceride-induced Death of THP-1 Monocytes

“…Moreover, exogenous or endogenous iNOS-derived NO elicits apoptosis in both in vitro and ex vivo monocyte lines (Taylor et al, 2003). NO mediates monocytic apoptosis by downregulating the expression of cellular inhibitor of apoptosis 1 (cIAP1) and X-chromosome-linked inhibitor of apoptosis (XIAP), which inhibit caspases-3, -7, and -9 (Manderscheid et al, 2001). High concentrations of NO suppress survivin, a member of the inhibitor of apoptosis protein family, in rat primary hepatocytes (Wang et al, 2011), and LPS-mediated iNOS induction promotes BAX/BAKdriven mitochondrial apoptosis in IFNγ-treated macrophages (Simpson et al, 2022).…”