Paradoxical roles of interferon-gamma in autoimmune disease

Interferon (IFN)-gamma has long been known as a critical T helper (Th)1 cytokine in the initiation and perpetuation of inflammation and autoimmune disease. It is considered a 'signature' pro-inflammatory cytokine and a major culprit in Th1 autoimmune pathologies, as well as an attractive drug target for modulating autoimmune disease. However, it is recognized increasingly that IFN-gamma has paradoxical properties that give rise to its unexpected role as a regulator of immune responses, in addition to its known pro-inflammatory activity. There is emerging evidence indicating that the immunoregulatory role of IFN-gamma is of great importance in the self-regulation/control of inflammation in autoimmune disease and that failure of this mechanism may contribute to persistent T-cell activation and inflammation. It is fascinating that the immune system uses the same molecule to both induce and regulate immune responses. In this article, new evidence related to the regulatory properties of IFN-gamma is reviewed. In particular, its implications for the understanding of disease mechanisms and for the treatment of autoimmune disease are discussed.