Am. J. Respir. Cell Mol. Biol., Vol 16, No. 2, 02 1997, 178-186.
Differential responsiveness of human and rat mesothelioma cell lines to recombinant interferon-gamma
L Phan-Bich, A Buard, JF Petit, L Zeng, JP Tenu, P Chretien, I Monnet, C Boutin, J Bignon, G Lemaire and MC Jaurand
URA CNRS, Universite Paris Sud, Orsay, France.
Recombinant human interferon-gamma (r-hu-IFN-gamma) has been found to exert
an antitumor action in vivo in early stages of human malignant
mesothelioma, and an antiproliferative effect in vitro. In order to study
the mechanisms of cytostasis in mesothelioma cells, we examined two
IFN-gamma-controlled metabolic pathways known to mediate growth arrest in
various cell types, measuring production of the antiproliferative compound
nitric oxide (NO) and degradation of tryptophan in nine human mesothelioma
cell lines (HMCLs) displaying different sensitivities to the
antiproliferative effect of r-hu-IFN- gamma. Two rat mesothelioma cell
lines were also studied. IFN-gamma receptor was present and functional in
HMCLs, regardless of their sensitivity to the growth-inhibitory 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-gamma and other
cytokines, and/or with lipopolysaccharide (LPS). In responsive 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 IDO induction was not
absolute. In rat mesothelioma cells, NO synthase was induced in response to
murine IFN- gamma + interleukin-1beta (IL-1beta) treatment, and played a
role in the cytokine-mediated antiproliferative 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 the cytostatic effects of IFN-
gamma in rodent cells are not efficient in human mesothelioma cells, and
suggest that cytokine-induced growth inhibition is mediated by a different
pathway in HMCLs.
