This document discusses interferons, which are proteins naturally produced in response to viral infections. There are three main types of interferons - alpha, beta, and gamma. Interferons work by binding to receptors on cells and activating signaling pathways that turn on genes to produce antiviral proteins. This inhibits viral replication and helps the immune system clear infections. Interferons are now produced recombinantly for use in treating certain viral infections and cancers. The document provides details on the structure, function, signaling, and clinical applications of the different interferon types.

2. Abdul Mannan
M. Phil Scholar
Deptt. Of Pathobiology
FVS, BZU Multan

3.  Naturally occurring proteins and
glycoproteins
 Secreted by eukaryotoc cells in response
to viral inections, tumors and other
biological inducers
 Structurally, they are part of the helical
cytokine family which are characterized by
an amino acid chain that is 145-166 amino
acids long

4.  1957
 Isaacs and Lindenmann
 Did an experiment using chicken cell cultures
 Found a substance that interfered with viral
replication and was therefore named interferon
(“Interference factors”)
 Nagano and Kojima also independently
discovered this soluble antiviral protein

5.  Interferons play an important role in the first
line of defense against viral infections
 Interferons are part of the non-specific
immune system

6.  First recognized by their ability to interfere with
viral infections in cultured cells.
 Does not protect the virus infected cell that
produces it.
 Itself is not the antiviral agent.
It moves to other cells where it induces an antiviral
state.(By inhibiting viral replication)

7. 7
TYPE I:
Interferon-alpha (leukocyte interferon, about 20 related
proteins)
leukocytes, etc
Interferon-beta (fibroblast interferon)
fibroblasts, epithelial cells, etc
TYPE II:
Interferon-gamma (immune interferon)
certain activated T-cells, NK cells

8. A. IFN-α & β
(Type-I- IFNs)
When prototypic cell of origin is exposed to
-Viruses
-Double stranded RNA
- Cytokines
B. IFN-
(Type-II- IFNs)
Following a number of immunological stimuli
including :-
-T-cell specific antigen
-Staphylococcal enterotoxin -A And
-Mitogens ( Phyto haemagglutinin ,Phorbol
Ester etc)
Morley,Michael.The pharmacology of
lymphocytes.Barlin Heidelberg.Springer.1988.print

9. Properties Alpha Beta Gamma
Current Nomenclature IFN-α IFN-β IFN-
Former Designation Leukocyte Fibroblast Immune
Interferon
Type Designation Type I Type I Type II
No. Of Genes that code for Family ≥20 1 1
Principal Cell Source Most Cell
Types
Most cell Types Lymphocytes
Inducing Agent Viruses;
dsRNA
Viruses;
dsRNA
Mitogens
Stability at pH 2.0 Stable Stable Labile
Chromosomal location of genes 9 9 12
Size of secreted protein (Number of
amino acids)
165 166 143
IFN receptors IFNAR IFNAR IFNGR

10.  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
collaborating JAKs
 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
binding
 Over 100 genes can be induced via interferon signaling
 Rapidity is needed to respond to danger

11. IFN binds with the respective
IFN-Receptors(IFNRs)
Oligomerization of the receptor followed by
phosphorylation of the tail of receptor
molecule
Phosphorylated STAT ( Signal Transducers
and activators of transcription ) released from
the receptor molecules and translocate to the
nucleus
Activation of trancription of
IFN-Stimulated gene. This results in
synthesis of several enzymes

12.  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).

13.  STAT1 and STAT2
phosphorylation results in
their heterodimerization,
dissociation from the
interferon receptor, and
translocation to the nucleus.
 In nucleus, the STAT
complex associates with
DNA-binding protein p48
(interferon-stimulated gene
factor 3) (ISGF3),which binds
to the interferon-stimulated
response element of ά- and β-
responsive genes.
 induction of interferon target
genes, responsible for the
biologic effects of interferons
ά and β .

14.  Interferon-γ binds as a
homodimer to the specific
interferon-γ receptor
 Dimerization of the
receptor activates the
Janus tyrosine kinases
Jak1 and Jak2, which
ultimately results in the
phosphorylation of STAT
proteins.

15.  Instead of activating STAT1
and STAT2( as with type I
interferon receptor)
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
reported so)

16.  However its best understood anti-viral mechanism is:
 1. Block viral mRNA synthesis
 2. Block translation of viral mRNA
 Mx proteins
 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

18.  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.

19. Interferon alfa-n3
(Alferon-N)
genital and perianal warts
Interferon beta-1b
(Betaseron) and beta-
1a(Avonex)
multiple sclerosis
Interferon gamma-1B
(Actimmune)
chronic granulomatous
disease and severe, malignant
osteopetrosis.
Interferon alfa-2b chronic hepatitis C
and chronic hepatitis B

20.  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
regimens

21.  Hematologic toxicities
-anemia, neutropenia, and thrombocytopenia.
Appear to be dose related, rarely reported in lower-dose
regimens.
 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
reductions.

22. o Kidneys
-Reversible proteinuria - 15% to 20% of patients
-Interstitial nephritis.
.
 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.

23. • 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
subcutaneously
• 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

24.  Protein chain that is 165 amino acids
long
 Produced using recombinant DNA
technology
 Non-glycosylated protein
 Short half life, short terminal
elimination of half life, a large volume
of distribution, and a larger reduction
in renal clearance.

25. • Structurally IFNb-2a is a 166 amino acid
glycoprotein.
• 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

26.  Morley,Michael.The pharmacology of lymphocytes.Barlin
Heidelberg.Springer.1988.print
 Zitzmann, Kathrin, et al. SOCS1 silencing enhances antitumor activity of type I IFNs
by regulating apoptosis in neuroendocrine tumor cells. Cancer research 67.10
(2007): 5025-5032
 Jonasch E and Haluska FG. Interferon 2001;6(1):34-55.
 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
experimental rhinoviral colds. J Infect Dis. 2003 ;150(2):174-80.