Results and discussion
IFNγ down-regulates hypoxia-induced CXCR4 mRNA expression
Previous studies have demonstrated that the chemokine receptor CXCR4 is over-expressed in metastatic tumor MG 149 [14] and that expression of CXCR4 is up-regulated in the hypoxic tumor microenvironment [15] and [16]. To determine whether IFNγ could modulate the hypoxia-induced expression of CXCR4 mRNA, we treated A172 human glioblastoma cells with IFNγ under hypoxic conditions and then prepared total RNA from the cells for northern bolt analysis. As shown in Fig. 1A, although a low level of constitutive CXCR4 mRNA expression was detected in cells under normoxia (20% O2, lane 1), the expression was up-regulated under hypoxic conditions (1% O2, lane 2). When the cells were cultured in the presence of IFNγ, hypoxia-induced CXCR4 mRNA expression was inhibited (lanes 3, 6, 9 and 12).
Fig. 1.
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Hypoxia-induced expression of the CXCR4 gene has been shown to be mediated by HIF-1α [15]. The iron chelator deferoxamine (DFX), a hypoxia mimetic, has been shown to inhibit prolyl hydroxylase, thereby stabilizing HIF-1α and inducing hypoxia-inducible gene expression under normoxia [17]. As shown in Fig. 1B, treatment of the cells with DFX induced an increase in CXCR4 mRNA expression in a time-dependent fashion. When the cells were simultaneously treated with DFX and IFNγ, DFX-induced expression of CXCR4 mRNA was suppressed (Fig. 1C). We also observed a similar inhibitory effect of IFNγ on hypoxia- and DFX-induced expression of CXCR4 mRNA in other glioblastoma cell line T98G cells as assessed by real-time qRT-PCR (Fig. 1D). These results indicate that IFNγ inhibits HIF-1α-dependent CXCR4 mRNA expression.
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