In schistosomiasis chronic parasite egg-induced granuloma formation can result in cells

In schistosomiasis chronic parasite egg-induced granuloma formation can result in cells destruction and fibrosis which causes much of the morbidity and mortality associated with this disease. fibrosis can Mouse monoclonal to CD45/CD14 (FITC/PE). lead to portal hypertension which causes much of the morbidity and mortality associated with this disease. Schistosomiasis is caused by several varieties of Icotinib HCl trematode worms and is believed to impact over 200 million people worldwide causing between 500 0 and 800 0 deaths per year (5). Elucidating the mechanisms leading to cells pathology and fibrosis may lead to more effective strategies for immunological treatment with this and a variety of chronic diseases. In the murine model of schistosomiasis several Th2-connected cytokines including IL-4 IL-5 IL-10 and IL-13 are induced after illness with (6-8) and contribute to many aspects of the host’s immune response against the parasite (9-13). Indeed knockout and cytokine ablation studies have clearly shown an important part for Th2-type cytokines in granuloma formation cells eosinophilia IgG1/IgE antibody production and the development Icotinib HCl of hepatic fibrosis (10 13 14 Because IL-4 is the main cytokine traveling the differentiation of CD4+ T cells into the Th2 subset (15 16 it was predicted that much of the pathology associated with schistosome illness would be ameliorated from the removal of IL-4. However IL-4 ablation experiments and studies Icotinib HCl with IL-4-deficient mice failed to demonstrate an indispensable role for this cytokine (8 9 17 18 Indeed these and related studies analyzing Th2 response development in IL-4-deficient mice demonstrated clearly that a significant albeit diminished Th2-type response can develop in the absence of IL-4 (8 19 20 These findings suggest that IL-4 is not the sole mediator of egg-induced pathology and that additional cytokines are compensating and perhaps playing a more essential part in the pathogenesis of schistosomiasis. Because IL-13 shares many functional activities with IL-4 (21) and uses related receptor subunits for signaling (22) it is possible that IL-13 takes on an important part in schistosomiasis pathogenesis. With the recent development of IL-13 transgenic and knockout mice (23 24 as well as soluble IL-13 antagonists (25) the unique functional activities of IL-13 are becoming delineated. Recent in vivo studies with several infectious disease (20 23 24 26 and asthma models (30 31 suggest that IL-13 possesses many important functional activities that are unique from IL-4. The IL-13 receptor complex is composed of at least 3 unique components including the IL-4 receptor the low-affinity binding chain IL-13Rα1 and the high-affinity binding chain IL-13Rα2 (25 32 Recently a soluble IL-13Rα2-Fc fusion protein was prepared and has been used successfully to neutralize IL-13 both in vitro (25) and in vivo (28-31). Because the fusion protein binds IL-13 with high affinity but fails to neutralize IL-4 the protein provided an excellent tool to dissect the specific tasks of IL-13. In the present study we used the IL-13 antagonist in wild-type (WT) and IL-4-deficient mice in order to dissect the contributions of IL-13 and IL-4 to the pathogenesis of schistosomiasis. In these studies liver granuloma formation was examined in detail focusing on eosinophil and mast cell recruitment and the development of egg-induced fibrosis was quantified using biochemical histological and molecular techniques. Whereas the results from this study display that IL-13 and IL-4 show some redundant activities in schistosomiasis pathogenesis unique functions for both cytokines were also clearly elucidated. The most important and novel getting was the observation that IL-13 not IL-4 was the major Th2-type cytokine driving type I and type III collagen mRNA production and hepatic fibrosis in infected Icotinib HCl mice. Thus our findings provide evidence that an IL-13 inhibitor such as sIL-13Rα2-Fc may be of therapeutic benefit in preventing fibrosis associated with chronic infectious disease. Methods Animals parasites and antigen preparations. Six- to 8-week-old female C57BL/6 mice and IL-4-deficient mice (C57BL/6 background 10 backcross) were obtained from Taconic Farms Inc. (Germantown New York USA) and were infected by percutaneous challenge. Cercariae of a Puerto Rican strain of (Naval Medical Research Institute Bethesda Maryland USA) were obtained from infected snails (Biomedical Research Instruments Rockville Maryland USA). Soluble egg antigen (SEA) was purified from homogenized eggs as previously described (9). The soluble IL-13 receptor α2-Fc fusion protein (sIL-13Rα2-Fc) Icotinib HCl and.