Type I interferon: a new player in TNF signaling

Abstract

TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-beta-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells.

Fig. 1

Type I IFN induction by microbial stimuli. The ifnb1 promoter region is shown schematically. Microbial stimuli interact with extra- or intracellular PPRs and lead to the activation of NF-κB, AP-1 and IRFs transcriptional factors which bind to specific PRDs on the promoter region of IFN-β gene and driving the gene expression. The promoter contains four PRDs. PRD I and III are the binding sites for IRFs, PRD II binds NF-κB and PRD IV binds AP-1.

Fig. 2

Kinetics of TNF-induced gene expression. Real-time PCR analysis of expression of indicated genes in mouse bone marrow-derived macrophage treated with mTNF for indicated periods of time, relative to untreated cells at the same time point (set at 1). Genes were divided into three groups according to the kinetics of their response to TNF.

Fig. 3

Model for induction of a gene activation program by TNF. Stimulation with TNF (a) activates NF-κB and MAPK pathways leading to rapid expression of inflammatory genes and to increasing expression of IRF1. IRF1 works together with NF-κB and AP-1 to drive production of low amounts of IFN-β. IFN-β, in turn, activates STAT signaling (b) that synergizes with other TNF-induced signals to sustain inflammatory chemokine expression and Ifnb1 expression, and to induce canonical IFN response genes and increase expression of signaling components such as IKKε, IRF7 and STAT1. ISGF3 = IFN-stimulated gene factor 3.