Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells

IL-2-activated killer lymphocytes (LAK cells) secrete inflammatory cytokine s such as interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF alpha) that can induce nitric oxide (NO) synthesis. We evaluated whether L AK cells could activate NO synthesis in human cancer cells. LAK cells and t heir culture supernatants induced NO synthesis in DLD-1 colon cancer cells in a dose-dependent manner. NO synthesis was inhibited completely by blocki ng antibodies to IFN-gamma, demonstrating a key role for this LAK cell cyto kine in regulating NO synthesis. The addition of TNF alpha antibodies resul ted in partial inhibition. Induction of iNOS mRNA and protein expression in DLD-1 cells was detected. Endogenous NO production inhibited DLD-1 cell pr oliferation and induced apoptosis, processes that-were inhibitable by the N O synthase inhibitor N-G-monomethyl-L-arginine. Our study has identified a novel, non-contact-dependent LAK cell cytotoxic mechanism: induction of gro wth inhibition and programmed cell death due to endogenous NO synthesis in susceptible human cancer cells. (C) 2000 Academic Press.