title: IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.
abstract: To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-gamma, TNF-alpha, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity. In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Hoffmann
authors.forename: A W
authors.initials: AW
authors.lastname: Cheever
authors.forename: T A
authors.initials: TA
authors.lastname: Wynn
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000276:immunology / Q000473:pathology; D008109:Liver Diseases, Parasitic / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D010063:Ovum / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma