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Am J Physiol Lung Cell Mol Physiol 277: L49-L57, 1999;
1040-0605/99 $5.00
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Vol. 277, Issue 1, L49-L57, July 1999

Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand interaction

Kazuyoshi Imaizumi1, Tsutomu Kawabe1, Satoshi Ichiyama2, Hitoshi Kikutani3, Hideo Yagita4, Kaoru Shimokata5, and Yoshinori Hasegawa1

1 The First Department of Internal Medicine and 5 Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya 466-8550; 2 Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto 606-8507; 3 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871; and 4 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

CD40-CD40 ligand (CD40L) interaction was originally defined as important molecules for the development of humoral immunity. Thereafter, some investigations have focused on its essential roles for the induction of cell-mediated immunity in host defenses. Here we investigated the antitumor activity of murine alveolar macrophages through CD40-CD40L interaction. The CD40L gene was transfected into murine lung cancer cells (3LLSA), and CD40L-expressing clones (3LLSA-CD40L) were established. Stimulation of CD40 molecules on the surface of alveolar macrophages with 3LLSA-CD40L cells induced the production of nitric oxide, tumor necrosis factor-alpha , and interleukin-12 and the tumoricidal activity of alveolar macrophages in the presence of interferon-gamma , which increased the surface expression of CD40 molecules on alveolar macrophages. These findings were not observed when alveolar macrophages were obtained from CD40-deficient mice. On the other hand, interleukin-6 production by alveolar macrophages did not depend on CD40-CD40L interaction. We also established a murine melanoma cell line expressing CD40L (B16 4A5-CD40L) that could induce tumoricidal activity of alveolar macrophages. Furthermore, when spleen cells were cocultivated with 3LLSA-CD40L cells, specific cytotoxic T lymphocytes for wild-type 3LLSA cells could be induced. These results suggest that CD40L gene transfer into tumor cells may induce antitumor immunity in a tumor-bearing host and may offer a new strategy for cancer gene therapy.

nitric oxide; cytokine production; cytotoxic T lymphocyte; lung cancer; CD40-deficient mice


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