Interferon: Cellular Executioner or White Knight?

Abstract

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.

NF-κB signaling, liver disease and hepatoprotective agents

“…The immune response to hepatitis viruses is mainly regulated by NFkB-and interferon-signaling pathways Hiscott et al, 2003;Malmgaard, 2004). After viral infection, NF-kB, IRF-3 or both, are activated and execute antiviral effects by activating the JAK-STAT pathway (Maher et al, 2007). Although the inflammatory response triggered by viral infection contributes to the pathogenesis of acute and chronic hepatitis, it should not be forgotten that inflammation is a protective response, which in addition to countering viral replication is responsible for repairing the tissue damaged by the virus.…”

Hepatitis C virus infection and apoptosis

“…INFs induce apoptosis in hepatoma cells, activate pro-apoptotic PKR [10] and upregulate death receptor ligands. However, antiapoptotic effects have also been described [7,[31][32][33] .…”

Modulation of IL-12 and IFN-γ Secretions by Eleutheroside E, Tortoside A, and Syringaresinol from Acanthopanax koreanum Nakai

“…The notion currently prevailing is that natural killer (NK) cells can be rapidly activated in the periphery by chemokines and/or inflammatory cytokines in conjunction with NK cell stimulatory factors such as IL-12, interferon (IFN) type 1, or IL-2 (Zitvogel, 2002). In particular, IFN-gamma (γ) is considered the prototypic NK cell cytokine, and its production by NK cells is known to shape the Th1 immune response (Mocikat et al, 2003), activate antigen presenting cells (APC) to further up-regulate MHC class I expression (Wallach et al, 1982), activate macrophage killing of obligate intracellular pathogens (Filipe-Santos et al, 2006), and have anti-proliferative effects on viral-and malignant-transformed cells (Maher et al, 2007).…”