Regulation of inducible nitric oxide synthase messenger RNA expression and nitric oxide production by lipopolysaccharide in vivo: the roles of macrophages, endogenous IFN-gamma, and TNF receptor-1-mediated signaling.

Abstract

To evaluate potential roles for macrophages, IFN-gamma, and TNF receptor 1 (TNFR1) in the regulation of LPS-induced inducible nitric oxide synthase (iNOS) mRNA expression, we used a model of macrophage depletion as well as IFN-gamma (GKO) and TNFR1 (TNFR1 -/-) knockout mice. LPS-induced iNOS mRNA in spleen was ablated in both macrophage-depleted and GKO mice. In livers of macrophage-depleted mice, LPS-induced iNOS mRNA was reduced by 55 to 85%, with the most profound reductions detected 6 and 8 h after LPS injection. In GKO mice, peak iNOS mRNA expression in liver (3 h) was unaffected by the loss of endogenous IFN-gamma. By 6 to 12 h after LPS challenge, however, hepatic LPS-induced iNOS mRNA and serum nitrate/nitrite levels were reduced substantially in GKO mice. Residual LPS-induced iNOS mRNA in livers of GKO mice was nearly ablated by macrophage depletion, indicating that induction of iNOS mRNA in liver requires both endogenous IFN-gamma and either macrophages and/or macrophage-derived factors. TNFR1-mediated signaling was involved in the induction of LPS-induced iNOS mRNA in liver at 3 and 6 h, but not in its maintenance at 8 h. Conversely, induction of iNOS mRNA in spleen by LPS was independent of TNFR1-mediated signaling. Our results indicate that macrophages and/or their secreted products, endogenous IFN-gamma production, and TNFR1-mediated signaling play key roles in the in vivo regulation of iNOS mRNA expression and that the extent of their involvement is both time and organ specific.

The infection-tolerant white-footed deermouse tempers interferon responses to endotoxin in comparison to the mouse and rat

“…Interferon-gamma is a determinant of Nos2 expression ( Lowenstein et al, 1993 ; Salkowski et al, 1997 ). So, the scant transcription of Ifng in P. leucopus conceivably accounted for the low expression of Nos2 in that species.…”

The white-footed deermouse, an infection-tolerant reservoir for several zoonotic agents, tempers interferon responses to endotoxin in comparison to the mouse and rat

“…Interferon-gamma is a determinant of Nos2 expression (55, 81) . So, the scant transcription of Ifng in P. leucopus conceivably accounted for the low expression of Nos2 in that species.…”

“…Interferon-gamma is a determinant of Nos2 expression (Lowenstein et al 1993;Salkowski et al 1997). So, the scant transcription of Ifng in P. leucopus conceivably accounted for the low expression of Nos2 in that species, not only with LPS but also during bacterial infection.…”

Inhibition of LPS-Induced Microglial Activation by the Ethyl Acetate Extract of Pueraria mirifica

“…This could be because IFN-γ is generally produced by NK cells and T cells [25]. Previous studies have found mouse macrophages to produce IFN-γ but not the macrophage cell line [26]. There could be a difference between the in vivo setting versus a cell culture in the cell-line setting [27].…”