As a search of PubMed with the key word "interferon-gamma" revealed over 46,000 hits, a thorough review of the biological functions of IFN-y is beyond the scope of this article. The effects of IFN-y on the expression of numerous genes, both positive and negative, have been extensively reported. The signaling pathway triggered by IFN-y is well defined, as the receptor has two chains and receptor-ligand interaction triggers activation of the Janus kinases 1 and 2 with subsequent phosphorylation of Statl. Upon phosphorylation of Statl, dimers are formed, translocate to the nucleus, and activate gene transcription primarily through the interaction with GAS elements (gamma-activated sequences) or in some cases, interferon stimulated response elements (ISREs). Other transcription factors, including NF-kB and c-Jun, have also been identified as playing a role in IFN-y signaling and Statl-independent pathways have been identified and characterized (for a review see Ramana et al. 2002). Furthermore, it has been reported that the IFN-y protein is actually transported to the nucleus and this nuclear localization plays a role in the specificity of IFN-y effects on gene expression (for reviews see Ahmed et al. 2003; Ramana et al. 2002).
IFN-y production is characterized as the hallmark of the Thl phenotype and IFN-y has been shown to downregulate the generation of IL-4- and IL-10-producing Th2 T cells (reviewed in Szabo et al. 2003). Interestingly, IFN-y has been shown to enhance Th2 polarization and the survival of IL-4 producing cells if present during the initial T cell priming (Bocek et al. 2004). Most recently IFN-y has been shown to inhibit the development of a new subset of T cells (Harrington et al. 2005), characterized by their ability to produce IL-17 (Bettelli et al. 2006; Harrington et al. 2005). These cells play an important role in the development of a number of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE) (Bocek et al. 2004). The inhibition of their development by IFN-y begins to shed new light on the role of IFN-y in the development and progression of these diseases.
There is also evidence that IFN-y can control the generation and activation of CD4+/CD25+ regulatory T cells (Tregs). Tregs suppress a wide variety of immune responses and induce immune tolerance (see review Maloy and Powrie 2001). Furthermore, a recent report demonstrated that pretreatment of mice with IFN-y prevented the development of Tregs reactive to immunized self antigens (Nishikawa et al. 2005). Surprisingly, Treg formation appears to be normal in ifng-~ and ifngRr'~ mice, indicating that it is not required for Treg development (Kelchtermans et al. 2005; Sawitzki et al. 2005). Furthermore, Tregs can themselves produce IFN-y and this may trigger apoptosis in naïve and/or Th2 effector T cells (Dalton et al. 2000; Rafaeli et al. 2002), thus indicating that IFN-y may have a more generalized role in regulating host immunosuppression. These new findings, taken together with the classical roles of IFN-y in the pro-inflammatory response, demonstrate the widespread role of IFN-y in regulating the host immune response.
The role of IFN-y in the host immune response to cancer has recently been reevaluated by Robert Schreiber's laboratory (Dunn et al. 2005). This laboratory has found that the tumor response to IFN-y is critical for an effective host response, as they demonstrated that in mice deficient in the IFN-y response (e.g., Stat1~'~ or ifngR1~'~ mice), there was a higher incidence of chemically induced and spontaneous tumors. Insensitivity to IFN-y at the level of the tumor was a major factor contributing to the increased tumor incidence, as IFN-y is required to increase tumor recognition by inducing MHC class 1 antigen processing and presentation pathway. A more thorough description of the role of IFN-y in the host response to tumor challenge and development can be found elsewhere (Dunn et al. 2005).
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