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(American Journal of Pathology. 2000;157:945-955.)
© 2000 American Society for Investigative Pathology

Regular Articles

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

Matthias Hesse*, Allen W. Cheever{dagger}, Dragana Jankovic{ddagger} and Thomas A. Wynn*

From the Schistosomiasis Immunology and Pathology Unit*
and the Immunobiology Section,{ddagger}
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; and The Biomedical Research Institute{dagger}
, Rockville, Maryland

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-{gamma}-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 oxide-deficient 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.




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