John I. Gallin; Joshua M. Farber; Steven M. Holland; Thomas B. Nutman
Interferon-γ has pleiotropic adjuvant effects on host defenses. These effects have made interferon-γ particularly useful for enhancing host defenses in patients with chronic granulomatous disease of childhood and thus for reducing the incidence of life-threatening infections in these patients. Increasingly, data suggest that interferon-γ will be useful for treating infections characterized by intracellular persistence in macrophages, such as toxoplasmosis, leishmaniasis, and mycobacteriosis. Interferon-γ is emerging as an important cytokine for use in the treatment of infectious diseases.
Interferon-γ has a six-helix monomer structure and exists in solution as an antiparallel homodimer. The interferon-γ receptor consists of at least two chains: the α chain, which is both necessary and sufficient for binding, and the β chain, which is necessary for signaling. Binding of interferon-γ to its receptor leads to receptor dimerization and the phosphorylation of tyrosine residues of interferon-γ-receptor α chain and of two tyrosine kinases, Jak1 and Jak2. The receptor and the kinases probably exist in a preformed complex before activation by ligand binding, but this has not been shown. Activation of the Jak tyrosine kinases leads to phosphorylation of a latent cytoplasmic factor, Stat1 α, which forms dimers that translocate to the nucleus. Probably together with other proteins (represented by X), Stat1 α binds to sequences that include the GAS motif (consensus sequence TTNCNNNAA) in the promoters of interferon-γ-responsive genes, thereby activating transcription. Sequences in addition to the GAS core, indicated by “(and more),” are important for the activation of interferon-γ-responsive genes. Arrows pointing to the latent Stat1 α indicate that activation of various cytokine and growth factor receptors, in addition to the interferon-γ receptor, leads to phosphorylation of Stat1 α or closely related STAT proteins. = phosphorylated tyrosine residue.
A macrophage (MPhi*) that has been activated by encountering a pathogen secretes interleukin-12, which stimulates T cells and natural killer (NK) cells to secrete interferon-γ and biases the differentiation of CD4+ cells into the T phenotype. Interferon-γ produced by natural killer cells and T cells activates macrophages for pathogen killing through the production of mediators such as superoxide (O ), nitric oxide (NO x), and cytokines such as tumor necrosis factor-α (TNF-α). Interferon-γ inhibits the production of CD4+ T cells. These cells are characterized by the production of interleukin-4, interleukin-10, and related cytokines. Interleukin-4 inhibits the development of T cells; interleukin-10 inhibits cytokine production by natural killer and T cells; and interleukin-4 and interleukin-10 both antagonize the effects of interferon-γ on macrophage activation. Although this scheme is based on data from studies in mice, the T /T paradigm is applicable to humans.
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Gallin JI, Farber JM, Holland SM, Nutman TB. Interferon-γ in the Management of Infectious Diseases. Ann Intern Med. 1995;123:216–224. doi: 10.7326/0003-4819-123-3-199508010-00009
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Published: Ann Intern Med. 1995;123(3):216-224.
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