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.
The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.
Gallin JI, Farber JM, Holland SM, Nutman TB. Interferon-γ in the Management of Infectious Diseases. Ann Intern Med. ;123:216–224. doi: 10.7326/0003-4819-123-3-199508010-00009
Download citation file:
Published: Ann Intern Med. 1995;123(3):216-224.
Copyright © 2018 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use