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 lead to tissue destruction and fibrosis, which causes much of the morbidity and mortality associated with this disease. Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the control of hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis were not previously investigated. Our studies demonstrate that both cytokines play redundant roles in granuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs. More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokine regulating fibrosis. IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice. Moreover, the reduction in fibrosis observed in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treated animals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases. Thus, our findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses.
Chiaramonte
M G
MG
Schistosomiasis Immunology and Pathology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Donaldson
D D
DD
Cheever
A W
AW
Wynn
T A
TA
D016475:3T3 Cells; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000172:deficiency; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012555:Schistosomiasis mansoni / Q000150:complications / Q000276:immunology / Q000628:therapy*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D018793:Interleukin-13; D011347:Procollagen; D012333:RNA, Messenger; D015847:Interleukin-4