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Effect of Dominant Negative Transforming Growth Factor-ß Receptor Type II on Cytotoxic Activity of RAW 264.7, a Murine Macrophage Cell Line

¹ Division of Urologic Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey; ² Department of Urology, University of Ulsan College of Medicine, Seoul, Korea; ³ Department of Urology, University of California, Irvine, Orange, California; and ⁴ Department of Urology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois

Requests for reprints: Isaac Yi Kim, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, 4560, New Brunswick, NJ 08901. Phone: 732-235-2043; Fax: 732-235-6596; E-mail: kimiy{at}umdnj.edu.

Transforming growth factor-ß (TGF-ß) is a potent suppressor of the immune system. In the present study, we investigated the effect of TGF-ß resistance on a murine macrophage cell line, RAW 264.7, by overexpressing a dominant negative TGF-ß receptor type II (TßRIIDN) construct. As expected, TßRIIDN-expressing RAW cells, designated as RAW-TßRIIDN, were resistant to TGF-ß signaling. When these cells were cocultured with the murine renal cell carcinoma cell line, Renca, a dramatic increase in apoptosis of Renca cells was observed. Simultaneously, elevated levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor- (TNF-) in association with IFN- were detected in RAW-TßRIIDN cells. When the effects of TNF- and iNOS were neutralized through the use of neutralizing antibody and N^G-methyl-L-arginine, respectively, the enhanced cytotoxicity of TßRIIDN-RAW cells was partially reversed. Taken together, these results show that TGF-ß–resistant RAW 264.7 murine macrophage cells have increased cytotoxic activity that is in part mediated by iNOS and TNF-. [Cancer Res 2007;67(14):6717–24]