InterferonBy uzair hashmi

Overview of Topics to be covered

IntroductionTypesFunctionInduction of Interferon (IFN’s)Downstream SignalingVirus resistance to interferonDiseases

What are Interferon? Interferon (IFN’s) are proteins made and

released by eukaryotic cells in the presence of pathogens- such as viruses, bacteria or parasites- or tumor cells.

They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.

They are not expressed in normal cells but viral infection of a normal cell causes interferon to be made and released from the cell.

They are a part of non-specific immune system and are induced at an early stage in viral infection- before the specific immune system has had time to respond.

IFN’s belong to a large class of Glycoprotein known as Cytokines.

Interferon are named after their ability to ‘interfere’ with viral replication within host cells.

About ten distinct IFN’s have been identified in mammals, seven of these have been described for humans.

Types of Interferon

Based on the type of receptor through which they signal, human interferon have been classified into three major types;

Type l

Type ll

Type lll

Interferon Type l

Type l interferon have two further sub-types: Interferon-alpha or Leukocyte

interferon, which is produced by virus infected leukocytes. They are a family of about twenty related proteins.

Interferon-beta or Fibroblast interferon, produced by virus infected fibroblasts. They are particularly potent as anti-viral agents.

Interferon Type l…

All type l IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR) that consists of IFNAR1 and IFN AR2.

Type ll

Interferon Type ll or interferon-gamma, which is also known as immune interferon, is produced by certain activated T-cells and NK cells.

Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.

It binds to IFNGR.

Type lll

Acceptance of this classification is less universal than that of type l and Type ll.

Unlike the other two, it is not currently included in Medical Subject Headings.

Functions of Interferon All interferon share several common effects, they

are anti-viral agents and can fight tumors. Another function of Interferon is to up regulate

major histocompatibility complex molecules MHC l and MHC ll, and increase immunoproteasome activity.

Higher MHC 1 expression increases presentation of viral peptides to cytotoxic T-cells, while the immunoproteasome processes viral peptides for loading onto the MHC l molecule, thereby increasing the recognition and killing of infected cells by T-cells.

Function of Interferon…

As an infected cell dies from a cytolytic virus, viral parasites are released that can infect nearby cells.

However, the infected cell can warn neighboring cells of a viral presence by releasing interferon.

The neighboring cells, in response to interferon, produce large amounts of an enzyme known as protein kinase R (PKR).

Induction of Interferon Membrane bound toll like

receptors or the cytoplasmic receptors RIG1 or MDA5, can trigger release of IFNs.

Toll Like Receptor 3 (TLR3) is important for inducing interferon in response to the presence of double stranded RNA viruses, the ligand for this receptor is double stranded RNA (dsRNA).

After binding dsRNA, this receptor activates the transcription factors IRF3 and NF-kB, which are important for initiating synthesis of many inflammatory proteins.

Downstream signalling

By interacting with their specific receptors, IFNs activate signal transducer and activators of transcription (STAT) complexes.

STATs are a family of transcription factors, that regulate the expression of certain immune system genes.

Some STATs are activated by both type l and type ll IFNs. However, each type can also activate unique STATs.

Virus resistance to Interferon Many viruses have evolved mechanisms to resist

interferon activity. They circumvent the IFN response by blocking

downstream signaling events that occur after the cytokine binds to its receptor by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.

Viruses that inhibit IFN signaling include Japanese Encephalitis Virus (JEV), dengue type 2 virus (DEN-2), and viruses of the herpes virus family such as Human cytomegalovirus and Kaposi's sarcoma associated herpes virus (KSHV).

Diseases

The immune effects of interferon may help for diseases such as actinic keratosis, superficial basal cell carcinoma, pappiloma and external genital warts.

Synthetic IFNs are also made, and administered as anti-viral, antiseptic and anti carcinogenic drugs, and to treat some autoimmune diseases.