Transcriptional regulators and modulate inflammatory response genes in -infected human macrophages.

UNLABELLED

Understanding the functions of human transcriptional regulatory genes and during infection is crucial; in a mouse model, homologous genes and have been shown to negatively regulate inflammatory response genes, including the type I interferon (IFN) response. The reduction of these genes in mice is associated with susceptibility to infection and the development of necrotizing granulomatous lesions. To investigate the involvement of and in human inflammatory response, we analyzed their regulatory manner in THP-1 macrophages infected with . Genome-wide transcriptional profiling revealed that the depletion of and/or impaired the induction of gene expression associated with inflammatory responses, including IFN response genes, although it had little effect on the intracellular proliferation of . By contrast, genes related to phosphorylation were upregulated in infected macrophages with and/or knockdown, but downregulated in infected control macrophages without their knockdown. Reverse transcription-quantitative PCR and ELISA further confirmed the impairment of the induction of IFN response genes by the depletion of and/or in -infected macrophages. These findings suggest that human and act as positive regulators for genes associated with inflammatory responses in -infected macrophages.

IMPORTANCE

Tuberculosis (TB) is one of the most serious infectious diseases, with high morbidity and mortality worldwide. C3HeB/FeJ mice are widely utilized for evaluating anti-TB drugs because their drug sensitivity and pathology during infection resemble those of human TB, including the development of necrotizing granulomas. Downregulation of the transcriptional regulatory genes and in C3HeB/FeJ mice has been demonstrated to activate gene expression associated with inflammatory responses during infection, resulting in susceptibility to the infection. Here, we examined the regulatory manner of and using transcriptomic analysis in -infected human macrophages. Depletion of and/or in -infected THP-1 macrophages impaired the induction of gene expression associated with inflammatory responses, including interferon response genes, compared with that in control macrophages. These results suggest that human and act as positive regulators for genes associated with inflammatory responses upon infection.