Interferon- (IFN-) affects immune responses in a complex fashion. juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS). In particular, we discuss our recent findings in a mouse model of sJIA, in which endogenous IFN- acts as a regulatory agent, and compare with results from mouse models of MAS. Also, we elaborate on the complexity in the activity of IFN- and the resulting difficulty of predicting its value or that of its antagonists as treatment option. demonstrated that IFN- induced the expression of T-bet in FoxP3+ cells, representing a novel subset of Treg cells that dampens Th1 cell responses . The mechanism by which IFN- regulates T RAD001 distributor cell immune circuits is not restricted to the modulation of Th cell commitment. Indeed, IFN- was demonstrated to be essential for the termination of immune responses by inducing apoptotic cell death in the T cell compartment in conditions of chronic inflammation with prolonged antigen stimulation and responses to self-antigens [31,32]. 2.3. Influence on Chemokine Production and Attenuation of Tissue Destruction Chemokines are produced by a variety of cells so as to attract specific immune cells. IFN- upregulates the expression of several chemokines, such as IFN-inducible protein (IP)-10 and monocyte chemoattractant protein (MCP)-1, as well RAD001 distributor as adhesion molecules, including Rabbit polyclonal to AGPS intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. These molecules specifically orchestrate the attraction of mononuclear cells to the inflammation spot . Conversely, neutrophil attracting chemokine production is generally inhibited by IFN- . Acute as well as chronic immune reactions cause collateral damage to the host, certainly when these reactions are not restrained in an appropriate way. IFN- precisely regulates the balance between clearance of pathogens and attenuation of inflammation-associated tissue damage. IFN- confines tissue damage by inhibiting the production of tissue-destructive factors, including matrix metalloproteinases, serine proteases and complement components . Furthermore, tissue infiltration of neutrophils and monocytes is repressed by IFN- via several mechanisms: first, myelopoiesis and granulopoiesis are attenuated; secondly, neutrophil-attracting chemokine production is inhibited; and thirdly, cellular responsiveness to chemokines is altered by IFN-. Also, IFN- reduces damage in bone tissue as it suppresses formation of osteoclasts [7,8,10]. 2.4. Recombinant IFN- as Therapy in Mycobacterial Infections As indicated above, IFN- is indispensable in the immune defense against intracellular pathogens. Patients and mice with mutations in IFN- pathway genes RAD001 distributor are extremely susceptible for mycobacterial disease . Therefore, recombinant IFN- is a conceivable treatment option for tuberculosis. Although previous clinical trials showed only moderate results, more studies are now conducted in different patient subgroups and with other routes of administration. Indeed, the results strongly depend on a combination of factors, including the dose, route and timing of drug administration, the immune status of the host and the type of infection . 3. Interferon- in Autoinflammation: Focus on Systemic Juvenile Idiopathic Arthritis Autoinflammatory syndromes are characterized by episodes of seemingly unprovoked recurrent inflammatory attacks of an innate immune nature. In contrast to the traditionally defined autoimmune disorders, autoinflammatory diseases lack high-titer auto-antibodies or autoreactive T cells . Systemic juvenile idiopathic arthritis (sJIA) is an example of such a disease, in which excessive activation of innate immune pathways RAD001 distributor dominates the inflammatory responses. A cytokine storm plays a signature role in the syndrome, as symptoms can be explained by the high levels of proinflammatory cytokines such as IL-6 and IL-18. Controversy exists, however, on the role of IFN- in sJIA . In this section, we provide an overview of the pathogenesis of sJIA and its complication macrophage activation syndrome (MAS). We further elaborate on a recently developed CFA-induced mouse model of sJIA in which a protective role was assigned to IFN- and compare the model with findings from other CFA-induced experimental models as well as mouse models of MAS. 3.1. Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Current Treatment Recommendations Systemic juvenile idiopathic arthritis (sJIA), originally described by George Frederic Still in 1897  and formerly known as systemic juvenile rheumatoid arthritis, systemic.