Interferon-gamma induced proliferation of human myeloid leukaemia cell lines

Abstract

Interferon-gamma (IFN-γ) is a pleiotropic cytokine involved in the regulation of various phases of immune and inflammatory responses; it also has anti-viral and anti-proliferative activity. Using continuous human leukaemia cell lines as model systems, we found that IFN-γ stimulated the proliferation of leukaemic myeloid cells; this effect was specifically neutralized by an anti-IFN-γ monoclonal antibody (McAb). No proliferative response was seen in autonomously growing cell lines; however, 11/19 constitutively growth factor-dependent cell lines showed a significant response in short-term proliferation assays upon incubation with IFN-γ. The stimulation indices ranged from 2 to 37 compared with the untreated control cells; the EC50 values for these cell lines were in the range of 0.1-0.6 ng/ml IFN-γ. Flow cytometric analysis demonstrated heterogeneity in the expression of the IFN-γ, receptor, as it was found on 37-97% of the cells per cell line. The effects of IFN-γ on proliferation triggered by a spectrum of 10 other cytokines were variable, and both stimulation and attenuation of the proliferative responses were seen in different cell lines. Under serum- free culture conditions, IFN-γ acted as a survival factor suppressing apoptosis. As has been described for other functional processes triggered by IFN-γ, the proliferation-inducing activity of IFN-γ also led to activation of the signal transducing element STAT 1. Thus, IFN-γ can induce myeloid leukaemia cells to proliferate and can modulate their proliferative response to other cytokines. Therefore IFN-γ may be a pathologically relevant ligand for leukaemic cell proliferation in vivo. In physiological settings, IFN-γ might be a bifunctional regulator of haemopoietic cell proliferation, depending on other differential co-signals from the micro-environment.