Up-regulation of host cell genes during interferon-gamma-induced persistent Chlamydia pneumoniae infection in HL cells.

As a step toward understanding the role played by host gene expression in the development and pathogenesis of persistent Chlamydia pneumoniae infection, modulation of the host-cell transcriptional response during interferon (IFN)- gamma -induced persistent C. pneumoniae infection of HL cells was examined by a cDNA array and then selectively by a real-time quantitative reverse transcription-polymerase chain reaction. We identified 9 host cell genes whose transcription was consistently altered during IFN- gamma -induced persistent C. pneumoniae infection. The strongest up-regulation of persistent infection, compared with controls (active infection and IFN- gamma ) was identified for insulin-like growth factor-binding protein 6, IFN-stimulated protein 15 kDa, cyclin D1, and interleukin-7 receptor genes. These results suggest that, during persistent infection, C. pneumoniae reprograms the host transcriptional machinery that regulates a variety of cellular processes, including adhesion, regulation of the cell cycle, growth, and inflammatory response, all of which might play important roles in the pathogenesis of persistent C. pneumoniae infection.

Differential expression of IFN regulatory factor 4 gene in human monocyte-derived dendritic cells and macrophages.

In vitro human monocyte differentiation to macrophages or dendritic cells (DCs) is driven by GM-CSF or GM-CSF and IL-4, respectively. IFN regulatory factors (IRFs), especially IRF1 and IRF8, are known to play essential roles in the development and functions of macrophages and DCs. In the present study, we performed cDNA microarray and Northern blot analyses to characterize changes in gene expression of selected genes during cytokine-stimulated differentiation of human monocytes to macrophages or DCs. The results show that the expression of IRF4 mRNA, but not of other IRFs, was specifically up-regulated during DC differentiation. No differences in IRF4 promoter histone acetylation could be found between macrophages and DCs, suggesting that the gene locus was accessible for transcription in both cell types. Computer analysis of the human IRF4 promoter revealed several putative STAT and NF-kappaB binding sites, as well as an IRF/Ets binding site. These sites were found to be functional in transcription factor-binding and chromatin immunoprecipitation experiments. Interestingly, Stat4 and NF-kappaB p50 and p65 mRNAs were expressed at higher levels in DCs as compared with macrophages, and enhanced binding of these factors to their respective IRF4 promoter elements was found in DCs. IRF4, together with PU.1, was also found to bind to the IRF/Ets response element in the IRF4 promoter, suggesting that IRF4 protein provides a positive feedback signal for its own gene expression in DCs. Our results suggest that IRF4 is likely to play an important role in myeloid DC differentiation and gene regulatory functions.