| Interferon-gamma (IFNgamma) induces indoleamine dioxygenase (IDO), which effectively inhibits the growth of intracellular Chlamydia in vitro. Furthermore, tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) synergistically increase IFN-induced, anti-chlamydial IDO activity. The mechanism of synergistic IDO activity is multifactorial. While one mechanism is the nuclear factor-kappaB (NF-kappaB)-dependent increase in interferon regulatory factor-1 (IRF-1) activation, increased expression of IFNgamma receptors (IFNgammaR), could also enhance IDO activation. It was found that IFNgammaR expression was up-regulated in epithelial cells upon stimulation with IL-1, also through the transactivation of NF-kappaB. This increase in receptor expression was shown to enhance IDO activity by increasing activation of the transcription factor signal transducer and activator of transcription-1 (STAT-1). Moreover, Chlamydia was found to significantly increase IFNgammaR expression in HeLa cells, even when inactivated, suggesting that chlamydial antigens and not infection up-regulate cytokine receptor expression. Cytokine receptor increase was found to be independent of cytokine secretion as supernatants from infected cells failed to increase IFNgammaR expression. The component of Chlamydia responsible for stimulating the cell to up-regulate cytokine receptor expression is heat stable; receptors increased occurred upon stimulation with Chlamydia inactivated at 100°C. The mechanism by which Chlamydia increases receptor expression requires stimulation of the Toll-like receptors (TLR). While cells either TLR2 or TLR4+MD2 increased IFNgamma receptor expression, cells not possessing TLRs were unresponsive. Similar to IL-1, Chlamydia required TLR-mediated NF-kappaB activation to enhance IFNgammaR expression. However, unlike stimulation with cytokine, no increase in IDO induction was observed. This effect is not due to the inability of IFNgamma to bind to the newly expressed receptors, but rather the impairment in signaling of these receptors. No increase in phosphorylated STAT-1 could be detected in infected cells suggesting that the JAK/STAT pathway was affected. |
