Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide.

Kundu N, Dorsey R, Jackson MJ, Guiterrez P, Wilson K, Fu S, Ramanujam K, Thomas E, Fulton AM
Int J Cancer. 1998 76 (5): 713-9

PMID: 9610731 · DOI:10.1002/(sici)1097-0215(19980529)76:5<713::aid-ijc17>3.0.co;2-4

Transfection of cDNA for IL-10 into line 66.1 murine mammary tumor cells results in marked suppression of tumor growth and metastasis. Others have reported that nitric oxide has potent antitumor activity and IL-10 is known to regulate the inducible isoform of nitric oxide synthase (iNOS) expressed in macrophages. We identified nitric oxide production in mammary tumors as indicated by electron paramagnetic resonance detection of nitric oxide-hemoglobin (NO-Hb). IL-10 expression resulted in elevated levels of NO-Hb in mammary tumors. Immunohistochemical examination of mammary tumors for iNOS protein revealed few positively staining cells in parental or control neo-transfected tumors but strong iNOS staining in all IL-10 transfected tumors, consistent with the NO-Hb data. To determine if mammary epithelial tumor cells themselves, express nitric oxide synthase activity, cultured tumor cells were treated with pro-inflammatory cytokines and nitrite accumulation was assessed in the conditioned medium. All IL-10 producing cell lines accumulated uM concentrations of nitrite in response to short term (24 hr) cytokine stimulation. Cells not expressing IL-10 (parental and neo-transfectants) accumulated no nitrite under similar culture conditions. After longer stimulation (48 hr), parental and 66-neo cells accumulated lower amounts of nitrite. IL-10 gene transfer is associated with increased iNOS protein expression and enzymatic activity detected both in vitro and in vivo. Our findings suggest that the antimetastatic and antitumor activity of IL-10 is related to enhanced production of nitric oxide.

MeSH Terms (18)

Adenocarcinoma Animals Cell Division Enzyme Induction Female Genetic Therapy Gene Transfer Techniques Interleukin-10 Male Mammary Neoplasms, Experimental Mice Mice, Inbred BALB C Mice, Inbred C3H Neoplasm Transplantation Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type II Tumor Cells, Cultured

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