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Protective Roles of Mast Cells and Mast Cell-Derived TNF in Murine Malaria

Takahisa Furuta^1,*, Takane Kikuchi^2,*, Yoichiro Iwakura and Naohiro Watanabe

^* Department of Microbiology and Immunology, Division of Infectious Genetics, and Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and Department of Tropical Medicine, Jikei University School of Medicine, Tokyo, Japan

TNF plays important roles in the protection and onset of malaria. Although mast cells are known as a source of TNF, little is known about the relationship between mast cells and pathogenesis of malaria. In this study, mast cell-deficient WBB6F₁-W/W^v (W/W^v) and the control littermate WBB6F₁^+/+ (+/+) mice were infected with 1 x 10⁵ of Plasmodium berghei ANKA. +/+ mice had lower parasitemia with higher TNF levels, as compared with W/W^v mice. Diminished resistance in W/W^v mice was considered to be due to mast cells and TNF. This fact was confirmed by experiments in W/W^v mice reconstituted with bone marrow-derived mast cells (BMMCs) of +/+ mice or of TNF^–/– mice. W/W^v mice with BMMCs of +/+ mice exhibit lower parasitemia and mortality accompanying significantly higher TNF levels than those of W/W^v mice. Parasitemia in W/W^v mice with BMMCs of TNF^–/– mice was higher than that in +/+ mice. Activation of mast cells by anti-IgE or compound 48/80 resulted in release of TNF and decrease of parasitemia. In addition, splenic hypertrophy and increased number of mast cells in the spleen were observed after infection in +/+ mice and W/W^v mice reconstituted with BMMCs of +/+ mice as compared with W/W^v mice. These findings propose a novel mechanism that mast cells and mast cell-derived TNF play protective roles in malaria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Takahisa Furuta, University of Tokyo, Division of Infections Genetics, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address: furuta{at}ims.u-tokyo.ac.jp

² Current address: Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, 1925 Coffey Road, Columbus, OH 43210-1093.

³ Abbreviations used in this paper: Ht, hematocrit; BMMC, bone marrow-derived mast cell; MCV, mean corpuscular volume.

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