DIFFERENTIAL RESPONSIVENESS OF HUMAN AND RAT MESOTHELIOMA CELL-LINES TO RECOMBINANT INTERFERON-GAMMA

Recombinant human interferon-gamma (r-hu-IFN-gamma) has been found to exert an antitumor action in vivo in early stages of human malignant m esothelioma, and an antiproliferative effect in vitro. In order to stu dy the mechanisms of cytostasis in mesothelioma cells, we examined two IFN-gamma-controlled metabolic pathways known to mediate growth arres t in various cell types, measuring production of the antiproliferative compound nitric oxide (NO) and degradation of tryptophan in nine huma n mesothelioma cell lines (HMCLs) displaying different sensitivities t o the antiproliferative effect of r-hu-IFN-gamma. Two rat mesothelioma cell lines were also studied. IFN-gamma receptor was present and func tional in HMCLs, regardless of their sensitivity to the growth-inhibit ory effect of r-hu-IFN-gamma. However, no NO synthase activity or the resulting antiproliferative molecule NO were induced in HMCLs treated either with r-hu-IFN-gamma alone or with a combination of r-hu-IFN-gam ma and other cytokines, and/or with lipopolysaccharide (LPS). In respo nsive HMCLs, r-hu-IFN-gamma induced strong indoleamine-2,3-dioxygenase (IDO) activity, which causes rapid degradation of tryptophan; however , the correlation between r-hu-IFN-gamma-mediated growth arrest and ID O induction was not absolute. In rat mesothelioma cells, NO synthase w as induced in response to murine IFN-gamma + interleukin-1 beta (IL-1 beta) treatment, and played a role in the cytokine-mediated antiprolif erative activity. However, NO production did not seem to be the unique antiproliferative mechanism induced by cytokines in these cells. Our results indicate that two classical pathways accounting for some of th e cytostatic effects of IFN-gamma in rodent cells are not efficient in human mesothelioma cells, and suggest that cytokine-induced growth in hibition is mediated by a different pathway in HMCLs.