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The NF-B RelA Subunit Confers Resistance to Leishmania major by Inducing Nitric Oxide Synthase 2 and Fas Expression but Not Th1 Differentiation

Setsuko Mise-Omata^*, Etsushi Kuroda, Tsutomu Sugiura, Uki Yamashita, Yuichi Obata^* and Takahiro S. Doi^1,*

^* Technology and Development Team for BioSignal Program, Subteam for BioSignal Integration, RIKEN BioResource Center, RIKEN Tsukuba Institute, Tsukuba, Japan; and Department of Immunology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

Although the NF-B transcription factors participate in both innate and adaptive immune responses, little is known about the role of the RelA subunit because mice lacking the rela gene die at embryonic day 14. To elucidate the role of RelA in Leishmania major infection, we prepared fetal liver chimeric mice by adoptively transferring embryonic day 13.5 rela^–/– or rela^+/+ fetal liver into lethally irradiated host mice. About 90% of the peripheral lymphocytes of the chimeric mice had differentiated from rela fetal liver cells. The rela^–/– fetal liver chimeric mice were highly sensitive to infection with L. major and died within 11 wk after infection. Despite the severity of the disease, parasite Ag-reactive Th1 cells developed normally. The rela^–/– macrophages were less able to control intracellular parasite replication than rela^+/+ macrophages, despite showing equally efficient phagocytosis. Both in vitro NO production of macrophages and in vivo expression of NO synthase 2 in the lesions and draining lymph nodes was reduced in rela^–/– fetal liver chimeric mice. Moreover, up-regulation of Fas in rela^–/– macrophages was impaired both after in vitro stimulation with LPS and after in vivo infection with L. major, implying a defect in their ability to eliminate infected cells. Thus, RelA is necessary for macrophages to be resistant to intracellular parasite infection.

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. Takahiro S. Doi, Technology and Development Team for BioSignal Program, Subteam for BioSignal Integration, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba, 305-0074 Japan. E-mail address: bri{at}brc.riken.jp

² Abbreviations used in this paper: NOS2, NO synthase 2; ED, embryonic day; SLA, soluble Leishmania antigen.