M. Phil Scholar
Deptt. Of Pathobiology
FVS, BZU Multan
Naturally occurring proteins and
Secreted by eukaryotoc cells in response
to viral inections, tumors and other
Structurally, they are part of the helical
cytokine family which are characterized by
an amino acid chain that is 145-166 amino
Isaacs and Lindenmann
Did an experiment using chicken cell cultures
Found a substance that interfered with viral
replication and was therefore named interferon
Nagano and Kojima also independently
discovered this soluble antiviral protein
Interferons play an important role in the first
line of defense against viral infections
Interferons are part of the non-specific
First recognized by their ability to interfere with
viral infections in cultured cells.
Does not protect the virus infected cell that
Itself is not the antiviral agent.
It moves to other cells where it induces an antiviral
state.(By inhibiting viral replication)
Interferon-alpha (leukocyte interferon, about 20 related
Interferon-beta (fibroblast interferon)
fibroblasts, epithelial cells, etc
Interferon-gamma (immune interferon)
certain activated T-cells, NK cells
A. IFN-α & β
When prototypic cell of origin is exposed to
-Double stranded RNA
Following a number of immunological stimuli
-T-cell specific antigen
-Staphylococcal enterotoxin -A And
-Mitogens ( Phyto haemagglutinin ,Phorbol
Morley,Michael.The pharmacology of
Properties Alpha Beta Gamma
Current Nomenclature IFN-α IFN-β IFN-
Former Designation Leukocyte Fibroblast Immune
Type Designation Type I Type I Type II
No. Of Genes that code for Family ≥20 1 1
Principal Cell Source Most Cell
Most cell Types Lymphocytes
Inducing Agent Viruses;
Stability at pH 2.0 Stable Stable Labile
Chromosomal location of genes 9 9 12
Size of secreted protein (Number of
165 166 143
IFN receptors IFNAR IFNAR IFNGR
Interferon signaling mediated by JAKs and STATS
JAKs (Janus Kinases) or just another kinase!
STATS (Signal transducers and activators of transcription)
Binding of Interferon to receptor causes receptor dimerization
JAKs associate to receptor before interferon binding
Binding causes them to get activated and phosphorylate receptor and
Phosphorylated receptors behave as docking sites for STATs
JAKs phosphorylate STATs once they dock to receptors
Phosphorylated STATs dimerize and translocate to nucleus
JAK-STAT pathway is extremely rapid
STAT binding to DNA can be detected within minutes of interferon receptor
Over 100 genes can be induced via interferon signaling
Rapidity is needed to respond to danger
IFN binds with the respective
Oligomerization of the receptor followed by
phosphorylation of the tail of receptor
Phosphorylated STAT ( Signal Transducers
and activators of transcription ) released from
the receptor molecules and translocate to the
Activation of trancription of
IFN-Stimulated gene. This results in
synthesis of several enzymes
Interferons ά and β bind to the
same receptor, which is
composed of two subunits
The binding of either
interferon- ά or interferon- β
to this receptor results in the
activation of Janus tyrosine
kinases Jak1 and Tyk2, which
results in the phosphorylation
of signal transducers and
activators of transcription 1
and 2 (STAT1 and STAT2).
STAT1 and STAT2
phosphorylation results in
dissociation from the
interferon receptor, and
translocation to the nucleus.
In nucleus, the STAT
complex associates with
DNA-binding protein p48
factor 3) (ISGF3),which binds
to the interferon-stimulated
response element of ά- and β-
induction of interferon target
genes, responsible for the
biologic effects of interferons
ά and β .
Interferon-γ binds as a
homodimer to the specific
Dimerization of the
receptor activates the
Janus tyrosine kinases
Jak1 and Jak2, which
ultimately results in the
phosphorylation of STAT
Instead of activating STAT1
and STAT2( as with type I
interferon-γ activates two
separate STAT1 molecules.
form a homodimer known as
the - γ activated factor (GAF)
translocates to the nucleus
and binds to γ -activating
sequences (GAS), elements
of interferon- γ inducible
genes (Zitzmann, Kathrin, et al. in 2008 als0
However its best understood anti-viral mechanism is:
1. Block viral mRNA synthesis
2. Block translation of viral mRNA
2',5' oligo(A) synthetase and ribonuclease L
PKR, double stranded RNA dependent protein kinase
Mx proteins (myxovirus proteins) are induced by interferon
Block viral RNA polymerase
Block transport of viral nucleoproteins (influenza virus) into nucleus
2',5' oligo(A) synthetase and ribonuclease L
This enzyme gets activated by dsRNA
Unique ability to synthesize oligos of A in the 2'- 5' linkage, norm is 3'-5' linkage
Poly(A) oligos bind ribonuclease L and activate it mRNA is destroyed
Both cellular and viral cells may die
Interferons-alpha and -beta have been used to treat
various viral infections.
One currently approved use of interferon- IFN-α
is in the treatment of certain cases of acute and chronic
hepatitis C and chronic hepatitis B.
Interferon-gamma has been used to treat a variety of
disease in which macrophage activation might play an
important role in recovery, eg. lepromatous leprosy, .
Since interferons have anti-proliferative effects, they
have also been used to treat certain tumors such as
melanoma and Kaposi’s sarcoma.
genital and perianal warts
(Betaseron) and beta-
disease and severe, malignant
Interferon alfa-2b chronic hepatitis C
and chronic hepatitis B
Most common toxicities
Schedule and dose dependent.
Acute administration can result in
-fever, , headache, nausea, vomiting, and fatigue.
- Fatigue usually increases with repetitive dosing .
Appropriate timing of administration (e.g., at or just
before bedtime) can limit the impact of symptoms.
Anorexia and weight loss -commonly seen with higher-dose
-anemia, neutropenia, and thrombocytopenia.
Appear to be dose related, rarely reported in lower-dose
Neutropenia requiring dosage reduction reported in 26% to
60% of patients receiving high-dose interferon-α.
Neutropenic fevers or infections requiring antibiotic
administration or hospitalization are quite rare.
Thrombocytopenia -rarely severe enough to warrant dosage
-Reversible proteinuria - 15% to 20% of patients
Skin -macular rashes ,
skin reactions –resolve
Acute hepatic toxicity
High-dose interferon regimens
- manifested as increase in serum levels
Alanine transaminase (ALT)
Aspartate aminotransferase (AST).
- fatal complications can be avoided with careful monitoring and
appropriate dosage modification.
with discontinuation of therapy.
• Interferons are broken down into recombinant versions of a specific
interferon subtype and purified blends of natural human interferon.
• Many of these are in clinical use and are given intramuscularly or
• Recombinant forms of alpha interferon include:
• Alpha-2a drug name Roferon
• Alpha-n3 drug name AlferonN
• Recombinant forms of beta interferon include:
• Beta-1a drug name Avonex
• Beta-1b drug name Betaseron
• Recombinant forms of gamma interferon include:
• Gamma-1b drug name Acimmune
Protein chain that is 165 amino acids
Produced using recombinant DNA
Short half life, short terminal
elimination of half life, a large volume
of distribution, and a larger reduction
in renal clearance.
• Structurally IFNb-2a is a 166 amino acid
• Produced by recombinant DNA technology using
genetically engineered mammalian cells which the
human beta gene has been introduced into
• Amino acid sequence is the same as human beta
interferon. They are both glycosylated at the
asparagines residue at position 80
Morley,Michael.The pharmacology of lymphocytes.Barlin
Zitzmann, Kathrin, et al. SOCS1 silencing enhances antitumor activity of type I IFNs
by regulating apoptosis in neuroendocrine tumor cells. Cancer research 67.10
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Rijckborst V and Janssen Harry L.A. The Role of Interferon in Oncological
Practice: Review of Interferon Biology, Clinical Applications, and Toxicities.
Oncologist in Hepatitis B therapy. Curr Hepatitis Rep 2010;9:231-238.
Kanda T, Imazeki F and Yokosuka O. New Antiviral Therapies for Chronic
Hepatitis C. Hepatol Int 2010;4:548-561
Hayden FG and Gwalthey JM jr. Intranasal interferon-alpha 2 treatment of
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