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(Journal of Leukocyte Biology. 2003;73:621-629.)
© 2003 by Society for Leukocyte Biology

Differential effects of IL-12 on the generation of alloreactive CTL mediated by murine and human dendritic cells: a critical role for nitric oxide

Yasuhiko Nishioka^*, Hua Wen^*, Kayo Mitani^*, Paul D. Robbins, Michael T. Lotze^,, Saburo Sone^* and Hideaki Tahara

^* Third Department of Internal Medicine, University of Tokushima School of Medicine, Japan; Departments of
Surgery and
Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh Cancer Institute, Pennsylvania; and
Department of Surgery, Institute of Medical Science, School of Medicine, University of Tokyo, Japan

Correspondence: Yasuhiko Nishioka, Third Department of Internal Medicine, University of Tokushima School of Medicine, Kuramoto-cho 3, Tokushima 770-8503, Japan. E-mail: yasuhiko{at}clin.med.tokushima.u.ac-jp

We examined the mechanisms involved in interleukin (IL)-12-mediated suppression of cellular immunity in mice using allogeneic mixed leukocyte reaction (MLR) stimulated by dendritic cells (DCs) in vitro and compared the effect of IL-12 on MLR in mice and humans. Although IL-12 stimulated human MLR, the addition of IL-12 or interferon- (IFN-) resulted in a dose-dependent suppression of MLR in mice. The treatment with N^G-monomethyl-L-arginine (L-NMMA) completely abrogated IL-12- and IFN--mediated suppression of MLR in mice. Furthermore, IL-12 enhanced the alloreactive cytolytic T lymphocyte (CTL) induction in human MLR, whereas the addition of L-NMMA was required to generate alloreactive CTLs in the presence of IL-12 in mice. Nitric oxide (NO) was detected only in mouse MLR. Murine DCs could produce NO, but neither human CD34⁺ cell- nor monocyte-derived DCs produced a detectable amount of NO. These results suggest that NO produced by DCs might play an important role in IL-12-mediated immune suppression in mice but not in humans.

Key Words: MLR • IFN- • L-NMMA

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