NOS-2 Mediates the Protective Anti-Inflammatory and Antifibrotic Effects of the Th1-Inducing Adjuvant, IL-12, in a Th2 Model of Granulomatous Disease

Abstract

Mice sensitized with Schistosoma mansoni eggs and IL-12 develop liver granulomas, on subsequent infection, which are smaller and less fibrotic than those in nonsensitized mice. The protective response is accompanied by a shift in the type-2 cytokine profile to one dominated by type-1 cytokines. The deviated response is associated with marked increases in inducible nitric oxide synthase (NOS-2) activity. Here, we demonstrate, by using NOS-2-deficient mice, that the anti-inflammatory and anti-fibrotic effects of the type-1 response are completely NOS-2-dependent. Strikingly, despite developing a polarized type-1 cytokine response that was similar in magnitude, the egg/IL-12-sensitized NOS-deficient mice developed granulomas 8 times larger than WT mice did. There was also no decrease in hepatic fibrosis in the sensitized mutant animals. Interferon-␥-deficient mice failed to exhibit the exacerbated inflammatory response, despite displaying a marked deficiency in nitric oxide production. However, immune deviation was unsuccessful in the latter animals, which suggested that the increase in inflammation in NOS-deficient mice resulted from a polarized but nitric oxidedeficient type-1 response. These results reveal a beneficial role for NOS-2 in the regulation of inflammation and suggest that the ultimate success of Th2-to-Th1 immune deviation strategies will rely on the efficient activation of NOS-2 expression in downstream effector cells.

Alternatively activated macrophages in helminth infections

“…Both of these activities may augment fibrosis associated with granulomas developing around eggs during S. mansoni infection of mice [26]. Supporting evidence is observed in iNOS-deficient mice, in which pronounced arginase activity by AAMΦs is associated with increased liver fibrosis and granuloma size during S. mansoni infection [27]. However, other mechanisms may also contribute to fibrosis under physiological conditions, as S. mansoni-infected LysM Cre IL-4Rα − /flox mice still develop liver fibrosis [2].…”

Experimental models of Schistosoma mansoni infection

“…larger granulomas are not always associated with greater hepatic fibrosis (Olds et al 1989, Cheever et al 1994c, Phillips et al 1996, Cheever 1997, Chiramonte et al 1999b, Fallon et al 2000b). Hepatic fibrosis in schistosome infected mice is clearly linked to IL-13 and the Th2 response, although fibrosis also clearly sometimes occurs around granulomas formed in the Th1 melieu (Chen & Boros 1999, Hoffmann et al 2000, Hesse et al 2000.…”

“…This effect is dependent on IFN-γ, IL-12 and TNF-α (Hoffmann et al 1999) and mediated through nitric oxide synthase-2 (Hesse et al 2000). Treatment with IFN-γ resulted in a marked decrease in hepatic fibrosis (Czaja et al 1989a) but anti-IFN-γ had no effect on granuloma size or hepatic fibrosis in infected mice (Sher et al 1990).…”

Nitric oxide monocyte production levels in patients with the hepatosplenic form of Scistosoma mansoni infection who underwent splenectomy, ligature of the left gastric vein and auto implantation of spleen tissue in the major omentum

“…NOS-2 remained the dominant although not exclusive, response in mice infected by S. mansoni 18 . For example, when NOS-2 is induced in mice sensitized with S. mansoni eggs and IL-12, the animals develop smaller and much less fibrotic granulomas when subsequently infected 19 . There is a beneficial role for NOS-2 in the regulation of liver inflammation regarding S. mansoni infection, suggesting that the ultimate success of Th2-toTh1 immune deviation strategies of the host will rely on the efficient activation of NOS-2 expression in downstream effector cells 19 .…”

“…For example, when NOS-2 is induced in mice sensitized with S. mansoni eggs and IL-12, the animals develop smaller and much less fibrotic granulomas when subsequently infected 19 . There is a beneficial role for NOS-2 in the regulation of liver inflammation regarding S. mansoni infection, suggesting that the ultimate success of Th2-toTh1 immune deviation strategies of the host will rely on the efficient activation of NOS-2 expression in downstream effector cells 19 . It is important to stress that some eggs laid by adults S. mansoni pairs are trapped in the liver, a process that can lead to marked inflammation, tissue eosinophilia, collagen deposition, and ultimately portal hypertension and severe hepatic fibrosis in some patients 18 .…”