NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease

Mice sensitized with Schistosoma mansoni eggs and IL-12 develop liver granu lomas, on subsequent infection, which are smaller and less fibrotic than th ose in nonsensitized mice. The protective response is accompanied by a shif t in the type-2 cytokine profile to one dominated by type-1 cytokines. The deviated response is associated with marked increases in inducible nitric o xide synthase (NOS-2) activity. Here, we demonstrate, by using NOS-2-defici ent 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 tha n WT mice did. There was also no decrease in hepatic fibrosis in the sensit ized mutant animals. Interferon-gamma-deficient mice failed to exhibit the exacerbated inflammatory response, despite displaying a marked deficiency i n nitric oxide production. However, immune deviation was unsuccessful in th e latter animals, which suggested that the increase in inflammation in NOS- deficient mice resulted from a polarized but nitric oxide-deficient type-1 response. These results reveal a beneficial role for NOS-2 in the regulatio n of inflammation and suggest that the ultimate success of Th2-to-Th1 immun e deviation strategies will rely on the efficient activation of NOS-2 expre ssion in downstream effector cells.