ORIGINAL PAPER Kazutoshi Hiyama á Shinjiro Hamano Takahiko Nakamura á Kikuo Nomoto á Isao Tada IL-4 reduces resistance of mice to Trypanosoma cruzi infection Received: 2 October 2000 / Accepted: 5 October 2000 Abstract The role of IL-4 has often been studied, especially in the Leishmania major infection model, but not in Trypanosoma cruzi infection. In the present study, the role of IL-4 in host defense against infection with the TulahueÂn strain of T. cruzi was examined by depleting IL-4 with an anti-IL-4 monoclonal antibody in vivo. In both IL-4 depleted and control C57BL/6 mice, the parasitemia showed peaks on the 21st day of infection. Both parasitemia and mortality were decreased in IL-4 depleted mice compared with control mice when IFN-c and nitric oxide productions were increased in IL-4 depleted mice compared with control mice. The mice treated with N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase, showed increased susceptibility to T. cruzi infection to the same level in both IL-4 depleted and control mice. Thus, it is suggested that endogenous IL-4 induces susceptibility to T. cruzi mainly by suppressing the production of IFN-c and nitric oxide, which has trypanocidal activity. Introduction Trypanosoma cruzi, a hemo¯agellate protozoan para- site, is the causative agent of Chagas' disease, which is a major health problem in Central and South America Brener 1980). Protection against T. cruzi is dependent on both innate and acquired immunities, which are regulated by cytokines Abrahamsohn and Coman 1996). IFN-c, a major Th1 type cytokine, has remark- able capacity to activate macrophages to kill T. cruzi Ho 1975). The administration of recombinant IFN-c increases resistance in mice and the neutralization of endogenous IFN-c increases susceptibility during the acute phase of T. cruzi infection Reed 1988; Torrico et al. 1991). Nitric oxide NO), mainly produced from macrophages in an IFN-c-dependent manner, acts as a trypanocidal agent MunÄ oz-FernaÂndez et al. 1992; Petray et al. 1994; HoÈlscher et al. 1998). In Leishmania major infection, for example, the role of IL-4 is well known to deviate the immune system into Th2 type response, which induces the susceptibility of BALB/c mice Sadick et al. 1990; Chatelain et al. 1992), while C57BL/6 mice continue to be resistant to L. major infection, despite the administration of exogenous IL-4 Sadick et al. 1991). IL-4 is also known to reduce the resistance to infection of the intracellular pathogens Toxoplasma gondii Roberts et al. 1996), Plasmodium chabaudi Von der Weid et al. 1994) and Listeria mono- cytogenes Nakane et al. 1996). However, IL-4 was also reported to be protective against pathological changes induced by T. gondii Roberts et al. 1996; Suzuki et al. 1996). In Trypanosoma cruzi infection, the increase of IL-4 measured by enzyme-linked immuno- sorbent assay ELISA) was in accordance with the peak of parasitemia in susceptible BALB/c mice, but not in C57BL/6 mice Hoft et al. 1993). Furthermore, the number of T. cruzi in BALB/c mice treated with anti- IL-4 monoclonal antibody mAb) was lower than that of untreated mice Petray et al. 1993), and T. cruzi- speci®c IL-4 producing CD4+ lymphocytes successfully transferred susceptibility against T. cruzi infection to resistant C57BL/6 recipient mice Oliveira et al. 1996). Until now there have been few studies to clarify the role of IL-4 in T. cruzi infection. Therefore, we tried to elucidate the role of IL-4 in T. cruzi infection in C57BL/ 6 mice. Parasitol Res 2001) 87: 269±274 Ó Springer-Verlag 2001 K. Hiyama á S. Hamano &) á I. Tada Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, higashi-ku, Fukuoka, 812-8582, Japan e-mail: hamano@parasite.med.kyushu-u.ac.jp Tel.: +81-92-6426118; Fax: +81-92-6426115 T. Nakamura á K. Nomoto Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582 Japan