Up-regulation of gamma interferon receptor expression due to Chlamydia-toll-like receptor interaction does not enhance signal transducer and activator of transcription 1 signaling.
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.
Shirey
Kari Ann
KA
Department of Microbiology, Miami University, 32 Pearson Hall, Oxford, OH 45056, USA.
Jung
Joo-Yong
JY
Carlin
Joseph M
JM
D002689:Chlamydia / Q000502:physiology*; D018920:Coculture Techniques; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000819:agonists*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000096743:Interferon gamma Receptor; C495377:LY96 protein, human; C494079:STAT1 protein, human