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Publications (2)7.37 Total impact

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    ABSTRACT: Gamma interferon (IFN-gamma)-induced indoleamine dioxygenase (IDO), which inhibits chlamydial replication by reducing the availability of tryptophan, is up-regulated by interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). The mechanisms by which this occurs include an increase in the synthesis of interferon regulatory factor-1 as well as a nuclear factor-kappaB (NF-kappaB)-dependent increase in the expression of IFN-gamma receptors (IFN-gammaR). Although Chlamydia is susceptible to IDO, it up-regulates IFN-gammaR expression to a greater degree than either IL-1beta or TNF-alpha, perhaps through interaction with Toll-like receptors (TLR). The purpose of this study was to determine the mechanism by which Chlamydia psittaci up-regulates IFN-gammaR expression and evaluate this effect on IDO induction. Infection of HEK 293 cells with C. psittaci increased IFN-gammaR expression only in cells expressing either TLR2 or TLR4 and the adaptor protein MD-2. In addition, up-regulation of IFN-gammaR expression in Chlamydia-infected HeLa cells could be blocked either by neutralizing TLRs with anti-TLR2 and/or anti-TLR4 or by inhibiting NF-kappaB transactivation with a proteasome inhibitor. Although the newly expressed IFN-gammaR in Chlamydia-infected cells were capable of binding IFN-gamma, they did not enhance IFN-gamma-induced IDO activity in a manner similar to those observed for IL-1beta and TNF-alpha. Instead, IDO activation in Chlamydia-infected cells was no different than that induced in uninfected cells, despite the increase in IFN-gammaR expression. Furthermore, the amount of IFN-gamma-induced signal transducer and activator of transcription 1 (STAT-1) activation in infected cells paralleled that observed in uninfected cells, suggesting that STAT-1 activation by these newly expressed receptors was impaired.
    Infection and Immunity 01/2007; 74(12):6877-84. · 4.07 Impact Factor
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    ABSTRACT: Interferon-gamma (IFN-gamma) induces the enzyme indoleamine dioxygenase (IDO) in a variety of human cell types. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synergistically increase IFN-induced IDO activity. Inasmuch as cytokines can upregulate cytokine receptor expression, one mechanism of cytokine synergy may be at the level of receptor expression. To test the hypothesis that this mechanism of IDO regulation is active in epithelial cells, HeLa cells were treated with IFN-gamma, TNF-alpha, or IL-1beta to determine optimal cytokine concentrations and time for maximal cytokine receptor expression. Flow cytometric analysis with antibodies to receptors for IFN-gamma, TNF-alpha, or IL-1beta indicated that each cytokine upregulated expression of the other cytokine receptors by 4 h, with maximal expression observed between 16 and 20 h after cytokine treatment. Furthermore, increases in IFN-gamma receptors (IFNGR) induced by IL-1beta were found to be dependent on NF-kappaB transactivation. To determine if increases in IFNGR expression alone contributes to synergistic IDO induction, cells were stimulated with IL-1beta to upregulate receptor expression, and the NF-kappaB concentration was allowed to return to basal levels. When treated with IFN-gamma, enhanced Stat1 signaling and IDO induction were still observed, indicating that increased cytokine receptor expression contributes to synergistic increases in IDO activity.
    Journal of Interferon & Cytokine Research 02/2006; 26(1):53-62. · 3.30 Impact Factor