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Involvement of Dendritic Cell Response to Resistance of Stomach Carcinogenesis Caused by N-Methyl-N'-nitro-N-nitrosoguanidine in Rats¹

Department of Molecular Oncology [M. O., C. F.] and Human Genome Center [M. O., T. I., Y. S.], Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan [M. O., M. I., K. M.]; Laboratory of Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan [K. K., M. Y., M. T.]; and Institut für Immunologie, Johannes Gutenberg Universität, D-55101 Mainz, Germany [K. R.]

The involvement of immune response in the resistance of chemically induced stomach cancer was studied in a resistant rat strain (Buffalo) and a sensitive rat strain (ACI). Groups of 10 male Buffalo and ACI rats, 6 weeks of age, were given drinking water with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; 100 mg/l) for 14 days. Total RNA was isolated from the stomach pyloric mucosa from five rats, and cDNA was prepared with reverse transcriptase. Tissue sections of the stomach pyloric mucosa from five rats were stained with antibodies recognizing molecules expressed by various immune cells. Reverse transcription-PCR (RT-PCR), competitive RT-PCR, and Northern blot demonstrated that the expression of MHC class II group genes [MHC class II, MHC class II-associated invariant chain (Ii), CD4 and IgM (B cell marker)], MHC class I group genes (MHC class I and CD8), B7-1 (costimulator on dendritic cells), and CD28 (receptor to B7 on T cells) in the pyloric mucosa was elevated by MNNG in both rat strains but was elevated to a 4–7-fold greater extent in Buffalo rats than in ACI rats. These genes were scarcely expressed in control rats. Histochemical antibody staining after MNNG exposure showed a greater number of cells stained with monoclonal antibody to Ii, OX-62 (dendritic cell marker), and ED-1 (dendritic cell and macrophage common marker) in the interstitial tissue of the pyloric mucosa of Buffalo rats compared with ACI rats. Cell proliferation, as measured by 5-bromo-2-deoxyuridine (BrdUrd)-labeling indices, revealed the presence of BrdUrd-labeled cells only among epithelial cells in the proliferative zone; cells in the interstitial tissue were not labeled with BrdUrd. The results suggest the involvement of dendritic cell response in the resistance to the MNNG induction of stomach carcinogenesis in rats.

¹ This study was partly supported by the Tutikawa Memorial Fund for Study in Mammalian Mutagenicity (to C. F.).

² To whom requests for reprints should be addressed, at Department of Molecular Oncology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5623; Fax: 81-3-5449-5423; E-mail: furi@ims.u-tokyo.ac.jp.

Received 4/ 8/98. Accepted 7/17/98.

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