Biological Effects of IFNg

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).

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment