Enhancement of macrophage cytotoxicity against murine gliomas by interferon beta: increase in nitric oxide production in response to glioma-derived soluble factors.

Abstract

In previous studies interferon-beta (IFNbeta) has been shown to suppress tumor growth. In this report, the antitumor effect of macrophages stimulated with IFNbeta is investigated in murine gliomas in vitro. The authors examined the cytotoxic activity of IFNbeta-stimulated peritoneal macrophages in glioma cells labeled with [3H]thymidine. The addition of IFNbeta enhanced cytotoxic activity in gliomas as well as the nitric oxide (NO) production of macrophages in cocultures. Addition of N(G)-monomethyl-L-arginine (L-NMMA) and L-N6-(1-iminoethyl)-lysine, but not D-NMMA (an inactive analog of L-NMMA), blocked this cytotoxic activity. The addition of IFNbeta had no direct effect on the growth of glioma cells. Because NO was not produced from macrophages treated with IFNbeta alone and IFNbeta-induced cytotoxic activity did not need cell-to-cell contact, the authors suspected that gliomas produce some soluble factors that act as cofactors for IFNbeta-induced cytotoxic activity. Macrophages stimulated with IFNbeta in the presence of glioma culture supernatants showed higher cytotoxicity against glioma cells than macrophages stimulated with IFNbeta alone. Furthermore, NO was markedly produced by IFNbeta-stimulated macrophages in the presence of glial culture supernatants. These data indicate that the antiglioma activity of IFNbeta through macrophages is due to NO produced by macrophages and that glioma-derived soluble factors play a role as an essential cofactor in this activity.