Nitric oxide regulates Th1 cell development through the inhibition of IL-12 synthesis by macrophages

Abstract

We have previously reported that mice lacking inducible nitric oxide synthase (NOS2) developed enhanced Th1 cell responses. We now investigated the mechanism by which NO modulates Th1 cells differentiation. Peritoneal macrophages from NOS2-deficient mice infected with Leishmania major in vivo or stimulated with IFN-gamma or lipopolysaccharide (LPS) in vitro produced significantly higher levels of IL-12 than those from heterozygous or wild-type mice. A macrophage cell line, J774, produced significant amounts of IL-12 following activation with LPS, or LPS plus IFN-gamma. This could be markedly enhanced by the NOS inhibitor L-NG monomethyl arginine (L-NMMA), but profoundly inhibited by the NO-generating compound S-nitroso-N-acetyl-penicillamine (SNAP). The effect of NO in this system is selective, since SNAP enhanced and L-NMMA decreased TNF-alpha synthesis by LPS-activated J774 cells. The differential effect of NO on IL-12 and TNF-alpha is at the transcriptional level and is activation dependent. Since IL-12 is a major inducer of Th1 cells which produce IFN-gamma that can activate macrophages to produce IL-12, our data demonstrate that NO can be an inhibitor of this feedback loop, preventing the excessive amplification of Th1 cells which are implicated in a range of immunopathologies.

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

“…TNFα is known to be a key mediator of pathogenesis in a broad range of infectious and predominantly Th-mediated inflammatory diseases, possibly via macrophage induction of iNOS and thus NO synthesis. However, iNOS has also been shown to enhance induction of TNFα synthesis [23] , contributing to local tissue destruction during the chronic inflammation that is one of the direct consequences of inflammatory processes. A previous study found a positive correlation between iNOS activity levels and disease severity in patients with ulcerative colitis, but this association is less clear in Crohn's disease [24] .…”

Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

“…The mechanisms underlying these effects are not clear. Involvement of NK cells (1) or macrophages (28), or direct activity of NO on T cells (29), are the recently suggested explanations. In the present study, NK cell functions, e.g., cytotoxic activity and production of IFN-␥, are not altered in the absence of NOS2 in the current model.…”

Nitric oxide as a regulator of inflammatory processes

“…The production by macrophages of a variety immunomodulatory cytokines (e.g., IL-12, IL-1) can be inhibited by NO (Huang et al 1998, Obermeier et al 1999. Interestingly, NO can also modulate the actions of macrophage-derived cytokines on target cells.…”