Interferon: cellular executioner or white knight?
Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.
Maher
S G
SG
Cancer and Inflammation Program, Laboratory of Experimental Immunology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1201, USA.
Romero-Weaver
A L
AL
Scarzello
A J
AJ
Gamero
A M
AM
D000917:Antibody Formation / Q000187:drug effects / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D007155:Immunologic Factors / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007370:Interferon Type I / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D007372:Interferons / Q000009:adverse effects / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use; D007378:Interleukins / Q000502:physiology; D053612:Janus Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D050737:Proto-Oncogene Proteins c-crk / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014777:Virus Diseases / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000095022:Interferon Lambda
D016207:Cytokines; D007155:Immunologic Factors; D055504:Insulin Receptor Substrate Proteins; D007370:Interferon Type I; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D053612:Janus Kinases; D010750:Phosphoproteins; D050737:Proto-Oncogene Proteins c-crk; D011972:Receptor, Insulin; D050791:STAT Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C526292:IRS1 protein, human