Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance

The family of type I IFN consists of multiple subtypes of IFNα, a single IFNβ and some less characterized family members, such as IFNε, IFNκ and IFNω. The difference in biological function between the multiple subtypes of type I IFN is unclear, especially since the induced genes downstream of the different types of IFN (the IFN response program) are highly similar between, for example, IFNα and IFNβ. In peripheral blood, plasmacytoid dendritic cells (pDC) are the main producers of type I IFN. All nucleated cells, however, can produce type I IFN upon activation by, for example, viral infections that trigger cytoplasmic nucleic acid sensors such as TLR-7 and MDA-5.Binding of type I IFNs to their cognate receptor (a heterodimer of IFNAR1 and IFNAR2) leads to the phosphorylation of signal transducers and activators of transcription (STATs) and transcription of IFN response genes. This results in resistance to viral replication, enhanced MHC class I expression and differentiation of monocytes, all of which contribute to clear infection. Besides an essential role in the host antiviral state, type I IFN has immunoregulatory functions by affecting cell proliferation and differentiation and by inducing anti-inflammatory responses. Considering these important functions of type I IFN in normal homeostasis as well as host response, an aberrant function in type I IFN immunity may contribute to autoimmunity and chronic inflammation. This is illustrated by the observation that melanoma patients treated with IFNα2β developed clinical and serological signs of autoimmunity [1] and that patients with a trisomy of chromosome 9, which contains the type I IFN genes, develop high IFN levels and lupus-like disease [2].TNFα is a pivotal pro-inflammatory cytokine produced by macrophages, activated T cells, natural killer cells and mast cells. Also non-immune, stromal cells are able to produce significant amounts of TNFα. TNFα is produced as a 26 kDa transmembrane protein, which can be cleave