Modulation of interferon-gamma receptor expression during infection with Chlamydia psittaci 6bc and its influence on indoleamine 2,3-dioxygenase

by Shirey, Kari Ann.

MODULATION OF INTERFERON-GAMMA RECEPTOR EXPRESSION DURING INFECTION WITH CHLAMYDIA PSITTACI 6BC AND ITS INFLUENCE ON INDOLEAMINE 2,3-DIOXYGENASE by Kari Ann Shirey Interferon-gamma (IFN) induces indoleamine dioxygenase (IDO), which effectively inhibits the growth of intracellular Chlamydia in vitro. Furthermore, tumor necrosis factor-alpha (TNF) 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-B (NF-B)-dependent increase in interferon regulatory factor-1 (IRF-1) activation, increased expression of IFN receptors (IFNR), could also enhance IDO activation. It was found that IFNR expression was up-regulated in epithelial cells upon stimulation with IL-1, also through the transactivation of NF-B. 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 IFNR 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 IFNR 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 IFN receptor expression, cells not possessing TLRs were unresponsive. Similar to IL-1, Chlamydia required TLR-mediated NF-B activation to enhance IFNR expression. However, unlike stimulation with cytokine, no increase in IDO induction was observed. This effect is not due to the inability of IFN 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. Modulation of Interferon-gamma Receptor Expression During Infection with Chlamydia psittaci 6BC and Its Influence on Indoleamine 2,3-dioxygenase