IL-13Ra2 and IL-10 were shown to coordinately suppress the development of hepatic fibrosis following Schistosoma mansoni infection in mice: To investigate the functional role of IL-10 and IL-13Ra2 in a chronic model of fibrosis, mice were infected with 30 cercariae of S. mansoni and granuloma formation and fibrosis were assessed at acute (8 wk) and chronic time points (12 wk) post infection. At week 8 pi, deletion of IL-13Ra2 or IL-10 had little impact on granuloma size or on the cellularity of the lesions. However, granuloma size was exacerbated in mice that were deficient in both IL-10 and IL-13Ra2 (dKO mice) (30% increase versus WT), which suggested that IL-10 and IL-13Ra2 function as cooperative inhibitors of granulomatous inflammation, at least during the acute phase of infection. By week 12, IL-10-/- and IL-13Ra2-/- mice also displayed significantly larger granulomas. Indeed, while WT mice displayed a 20% decrease in granuloma size between wk 8 and 12, IL-10-/- and IL-13Ra2-/- mice exhibited significantly larger granulomas at the chronic time point. The granulomas in dKO mice were approximately 50% larger than WT animals on wk 12 and 20-30% larger than either single KO mice. The progression of liver fibrosis was also monitored by measuring hydroxyproline content in the liver. On wk 8, liver fibrosis was similar in WT and IL-13Ra2-/- mice, but significantly decreased in IL-10-/- mice. Thus, despite displaying signficant inflammation, many other pathological features were reduced in the IL-10-/- mice. The important contribution of IL-13Ra2 was revealed in the dKO mice, which in contrast to IL-10-/- mice developed exacerbated liver fibrosis as early as wk 8 p.i. Thus, deleting IL-13Ra2 on an IL-10-/- background completely reversed the pathological phenotype of the IL-10-/- mice. The combined anti-fibrotic activities of IL-10 and IL-13Ra2 were particularly impressive at the chronic time point. Indeed, by wk 12, fibrosis nearly doubled in the dKO mice when compared with 12 wk-infected WT, IL-10-/- or IL-13Ra2-/- mice. These data demonstrate that chronic Th2-mediated inflammation and fibrosis are down modulated by the combined actions of IL-10 and IL-13Ra2.