Selective Expression of Type I IFN Genes in Human Dendritic Cells Infected withMycobacterium tuberculosis

Abstract

Type I IFN regulates different aspects of the immune response, inducing a cell-mediated immunity. We have recently shown that the infection of dendritic cells (DC) with Mycobacterium tuberculosis (Mtb) induces IFN-α. In this work we have monitored a rapid induction of IFN-β followed by the delayed production of the IFN-α1 and/or -α13 subtypes. The Mtb infection rapidly activates the NF-κB complex and stimulates the phosphorylation of IFN regulatory factor (IRF)-3, events known to induce IFN-β expression in viral infection. In turn, the autocrine production of IFN-β induces the IFN-stimulated genes that contain binding sites for activated STATs in their promoters. Among the IFN-stimulated genes induced in DC through STAT activation are IRF-1 and IRF-7. The expression of IRF-1 appears to be dependent on the sequential activation of NF-κB and STAT-1. Once expressed, IRF-1 may further stimulate the transcription of IFN-β. Induction of IRF-7 is also regulated at the transcriptional level through the binding of phosphorylated STAT-1 and STAT-2, forming the IFN-stimulated gene factor-3 complex. In turn, the IRF-1 and IRF-7 expression appears to be required for the delayed induction of the IFN-α1/13 genes. Although correlative, our results strongly support the existence of a cascade of molecular events in Mtb-infected DC. Upon infection, constitutively expressed NF-κB and IRF-3 are activated and likely contribute to the rapid IFN-β expression. In turn, IFN-β-induced IRF-1 and IRF-7 may cooperate toward induction of IFN-α1/13 if infection persists and these factors are activated.

Mechanisms of IL-12 Synthesis by Human Dendritic Cells Treated with the Chemical Sensitizer NiSO4

“…The next question was to elucidate if STAT-1 tyrosine phosphorylation resulted from a direct effect of NiSO 4 on Jak activity or through the synthesis of an intermediate factor. Indeed, type I IFNs are well-known inducers of STAT-1 tyrosine phosphorylation in Mo-DCs (38). We found that NiSO 4 upregulated the ifn-b mRNA, but IFN-b was undetectable in the supernatants of Mo-DC treated for 24 h by NiSO 4 (data not shown).…”

Qualitatively distinct patterns of cytokines are released by human dendritic cells in response to different pathogens

“…31 DCs have also been shown to produce type I interferons in response to micro-organisms as well as in response to viral infection or following interaction with T cells. [32][33][34][35][36][37][38] In mice, enhanced IL-12 or IL-10 production by DCs requires two signals, one from the encounter with the pathogen and the second from the interaction with T cells, [39][40][41] suggesting that the role of the pathogen in mice is to 'sensitize' DCs such that they can be fully activated following encounter with T cells. Similar studies in human-derived DC have not been reported.…”

ESX-1 dependent impairment of autophagic flux byMycobacterium tuberculosisin human dendritic cells

“…In line with these findings, Jagannath and collaborators showed that in a mouse model the stimulation of autophagy by rapamycin enhanced the capacity of DC to present mycobacterial antigens into the MHC class II complex. 13 Given the critical role played by DC in the regulation of the immune response against Mtb, [22][23][24] we sought to investigate the modulation of the autophagic process in human primary DC infected by Mtb and the vaccine strain BCG. We show that Mtb, but not BCG, impairs the late steps of autophagy and a functional ESX-1 secretion system is required for this inhibition.…”