The Benefits and Side Effects of Interferon Alpha

PATH3343: Immunology and Immunopathology

TOPIC: The benefits and side effects of interferon-α therapy. Include molecular mechanisms.

It is well known throughout the medical professions that interferon-alpha (IFN-α) has antiviral and anti-tumour properties, the very name 'interferon' springing from this fact1. Interferon proteins were first described in 1957 by Alick Isaacs and Jean Lindenmann - they discovered that supernatants from virus-infected cell cultures contained a substance that could react with other cells, rendering them resistant to infection by the same or unrelated viruses.2 The interferon family comprises of molecules capable of 'interfering' with viral infection, and form part of the cytokine superfamily. Cytokines carry signals locally from one cell to another, playing an important role in the body's natural defensive system. In this respect, IFN's are considered to be the first line of defence against viral invasion.3

Although IFN's were first recognised for their potent antiviral properties, they were shown to inhibit cell growth and promote differentiation. Other functions included modulation of activity in virtually every component of the immune system, including antibody response, stimulation of cytotoxic lymphocytes, expression of major histocompatibility complex (MHC) and other surface antigens, recruitment of natural killer (NK) cells and activation of macrophages.3,4

Interferon alpha is classified as a type 1 Interferon, a subgroup that comprises IFN-α and IFN-β primarily - as they share the same receptor complex known as the IFN-α receptor, and subsequently have similar activities to each other (60% homology).5 IFN-alpha is produced primarily by dendritic cells and macrophages in response to foreign cells and nucleic acids - leading to a JAK/STAT signalling cascade which leads to viral 'preparation' in influenced cells. As such, IFN-alpha is used in a number of conditions, with various benefits and side effects.4 Due to the efficacy in treatment of previously untreatable conditions - especially in hepatitis infections, IFN-alpha therapy now forms part of a multi-billion dollar industry, distributed to more than 80 countries around the world.4

FORMATION AND STRUCTURE OF IFN-α

IFN-α is encoded by a family of closely related genes - in the human genome there are at least 14 active IFN-α genes. These genes are located within the band p22 on the short arm of chromosome 92. In all mammalian species, these genes are devoid of introns, and encode proteins of 186-190 amino acids, including a signal peptide of 23 amino acids. All IFN-alphas contain four cysteine residues (positions 1, 29, 99 and 139), which are involved in disulfide bridges.2 As stated earlier, IFN-alpha gene expression is induced upon viral infections. This induction is transient, involving transcritiptional activation by several factors that bind to upstream regulatory cis-elements. The region involved in virus inducibility of the human IFN-alpha genes is known as the virus-inducible element or VRE. After viral infection, several events occur, including posttranslational activation by phosphorylation of inactive transcription factor families, including nuclear factor (NF)-kB, ATF-2/c-Jun, and interferon regulatory factors (IRFs), which activate immediate early genes (that encode IFN-alpha).4 This occurs in tandem with activation of multiple signal transduction cascades like the NF-kB/inhibitory factor kB (IkB) kinase complex, and stress-activated mitogen-activated protein kinase pathways, which converge in the nucleus to turn on regulatory genes to produce the antiviral state. In general, no IFN is produced in healthy tissues, though there is some evidence that small amounts are generated by peritoneal macrophages in vivo. 2,4

MECHANISM OF ACTION OF IFN-α

The mechanism by which interferons exert anti-tumour or antiviral activity is not clearly understood. However, it is believed that direct anti-proliferative action against tumour cells, inhibition of virus replication and modulation of the host immune response play important roles in anti-tumour and antiviral activity.6

In order for interferon's to elicit their biological properties, it is necessary that they bind to specific receptors on target cells. The interaction of IFN's with their cognate receptors leads to activation of signalling pathways, in which cytoplasmic activated transcription factors translocate to the nucleus, stimulating the induction of a 'primary gene set' that are central in mediating the biological response. This transcriptional activation is rapid, does not require protein synthesis and is required for most biological actions to be induced.2 After IFN-alpha is transcribed and translated, it activates gene expression in adjacent cells through this binding to cell surface to IFN receptors, triggering activation of the Janus kinase (jak)/signal transducer and activator of transcription (STAT) signalling pathways. This then allows heterodimers of STAT-1/2 to combine with IRF-9 to create IFN-stimulated gene (ISG) factor (ISGF)-3, which then binds to IFN-stimulated response elements (ISREs), which are found in different IFN-induced antiviral genes. This pathway includes IRF-7, which adds to the amplification of the transcriptional response by starting a second wave of IFN gene expression, including other IFN-alpha genes that were not induced during the early events after viral infection. The IRF, STAT and NF-kB transcription factors translocate to the nucleus, working together to activate a network of antiviral genes such as double-stranded ribonucleic acid (RNA), activated protein kinase (PKR), 2'-5'-oligoadenylate synthase, and Mx proteins, which all interfere with viral transcription and translation.2,4,5,7

Picture from: http://www.ambion.com/tools/pathway/images/Interferon%20Pathway.jpg

IMMUNOMODULATION

Interferons modulate the antibody response of the body, positively or negatively, depending on timing, dose and type of IFN1. IFNs also exert antitumour