Abstract
We showed previously that type I interferon causes a down-regulation of mitochondrial gene expression. We show here that IFN treatment leads to functional impairment of mitochondria. Western blot analysis indicated that interferon treatment reduces the steady-state level of cytochrome b in murine L-929 cells. Interferon produced a reduction in cytochrome c oxidase and NADH-cytochrome c reductase activities of isolated mitochondria as well as inhibiting electron transport in isolated mitochondria and in intact cells. Several mitochondrial mRNAs are affected by interferon treatment in human Daudi lymphoblastoid cells, which are highly sensitive to the antiproliferative effects of interferon. Electron transport in Daudi cells was also inhibited by interferon both in intact cells and isolated mitochondria with a dose response identical to that for the antiproliferative response. In contrast, a Daudi strain resistant to the antiproliferative effects of interferon showed no down-regulation of mRNA expression and no inhibition of electron transport. Possibly as a consequence of the inhibitory effect on mitochondrial gene expression, treatment with interferon causes a reduction in cellular ATP levels. The inhibition of cellular growth by interferon may thus be partly a consequence of a reduction in cellular ATP levels.
Highlights
Interferons (IFNs)1 are cytokines that have multiple effects on cell function
IFN Causes a Reduction in Steady-state Mitochondrial Protein Level—Our earlier study showed that in addition to reducing the level of mitochondrial mRNAs, IFN inhibited the synthesis of mitochondrial proteins [3]
Inhibition of Mitochondrial Function by IFN Correlates with Anti-proliferative Responses—In order to test whether a correlation between mitochondrial and anti-proliferative responses exists we studied the effect of IFN on an “IFN-resistant” strain of Daudi cells
Summary
Interferons (IFNs) are cytokines that have multiple effects on cell function. In addition to blocking virus replication they exert regulatory effects on lymphocytes, modulate macrophage function, up-regulate major histocompatability complex class II expression, and inhibit the growth of many different cell types [1]. In common with other cytokines IFNs exert their actions by modulating the expression of multiple genes whose products are responsible for the phenotypic changes observed after treatment. Identification of these genes and the mechanism by which their products function is needed to provide a complete understanding of cytokine action. Perturbation of mitochondrial gene expression could have important phenotypic consequences
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