Type I IFN and TNFα: cytokines with pleiotropic functions

functions Th e 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. Th e diff erence in biological function between the multiple subtypes of type I IFN is unclear, especially since the induced genes downstream of the diff erent 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 phos phorylation of signal transducers and activators of trans cription (STATs) and transcription of IFN response genes. Th is results in resistance to viral replication, enhanced MHC class I expression and diff erentiation of monocytes, all of which contribute to clear infection. Besides an essential role in the host antiviral state, type I IFN has immuno regulatory functions by aff ecting cell proliferation and diff erentiation and by inducing antiinfl ammatory res ponses. 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 infl ammation. Th is is illus trated 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-infl ammatory cytokine produced by macrophages, activated T cells, natural killer cells and mast cells. Also non-immune, stromal cells are able to produce signifi cant amounts of TNFα. TNFα is produced as a 26 kDa transmembrane protein, which can be cleaved by TNFα converting enzyme to form the 17 kDa soluble form. Upon binding to TNFR1 (which is constitutively expressed on most cell types) or TNFR2 (which is expressed on immune cells, endothelial cells and fi broblasts), TNFα activates the mitogen-activated protein kinase and NF-κB signaling pathways [3] – which in turn can lead to an amplifi cation of the proinfl ammatory response by increased production of chemokines and cytokines, including TNFα itself. Endothelial cells respond to TNFα by expressing adhesion molecules to facilitate traffi cking of immune cells to the infl amed tissue. Macrophages and neutrophils are attracted to the site, increase their cyto kine production, and enhance phagocytic capacities. Taken together, TNFα initiates and orchestrates diff erent mechanisms that lead to an eff ective immune response in the case of infection. Besides its role in host defense, however, TNFα is recognized to play a key role in many immune-mediated infl ammatory diseases (IMIDs), such as rheumatoid Abstract