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


METHODS
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.


CONCLUSIONS
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.
Kito
Tomohiro
T
Department of Immunology, University of Occupational and Environmental Health, Kitakyusyu, Japan.
Kuroda
Etsushi
E
Yokota
Akira
A
Yamashita
Uki
U
D000818:Animals; D001932:Brain Neoplasms; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003603:Cytotoxins / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism*; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000473:pathology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D017077:Culture Media, Conditioned; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016899:Interferon-beta