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Abstract
Interferons are cytokines that play a complex and central role in the resistance of
mammalian hosts to pathogens. Type I interferon (IFN-alpha and IFN-beta) is secreted
by virus-infected cells. Immune, type II, or gamma-interferon (IFN-gamma) is secreted
by thymus-derived (T) cells under certain conditions of activation and by natural
killer (NK) cells. Although originally defined as an agent with direct antiviral activity,
the properties of IFN-gamma include regulation of several aspects of the immune response,
stimulation of bactericidal activity of phagocytes, stimulation of antigen presentation
through class I and class II major histocompatibility complex (MHC) molecules, orchestration
of leukocyte-endothelium interactions, effects on cell proliferation and apoptosis,
as well as the stimulation and repression of a variety of genes whose functional significance
remains obscure. The implementation of such a variety of effects by a single cytokine
is achieved by complex patterns of cell-specific gene regulation: Several IFN-gamma-regulated
genes are themselves components of transcription factors. The IFN-gamma response is
itself regulated by interaction with responses to other cytokines including IFN-alpha/beta,
TNF-alpha, and IL-4. Over 200 genes are now known to be regulated by IFN-gamma and
they are listed in a World Wide Web document that accompanies this review. However,
much of the cellular response to IFN-gamma can be described in terms of a set of integrated
molecular programs underlying well-defined physiological systems, for example the
induction of efficient antigen processing for MHC-mediated antigen presentation, which
play clearly defined roles in pathogen resistance. A promising approach to the complexity
of the IFN-gamma response is to extend the analysis of the less understood IFN-gamma-regulated
genes in terms of molecular programs functional in pathogen resistance.