An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response

In schistosomiasis, chronic parasite egg-induced granuloma formation can le ad to tissue destruction and fibrosis, which causes much of the morbidity a nd mortality associated with this disease. Here we show the importance of I L-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for t he first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13R alph a 2-Fc, in the control of hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, ye t the specific contributions of IL-13 and IL-4 to the development of fibros is were not previously investigated. Our studies demonstrate that both cyto kines play redundant roles in granuloma formation, which explains the abili ty of IL-4-deficient mice to form granulomas around eggs. More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cyt okine regulating fibrosis. IL-13 stimulated collagen production in fibrobla sts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13R alpha 2-Fc-treated mice. Moreover, the reduction in fibrosis obser ved in IL-4-deficient mice was much less pronounced than that in sIL-13R al pha 2-Fc-treated animals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases. Thus, our findi ngs provide evidence that IL-13 inhibitors may be of general therapeutic be nefit in preventing damaging tissue fibrosis resulting from Th2-dominated i nflammatory responses.