Biological and Biomedical Reports, 2012, 2(1), 37-43

Review

Cytokines: an ever expanding area

Nadeem Afzal1,*, Romeeza Tahir1, Shah Jahan1
1. Department of Immunology, University of Health Sciences Lahore, Lahore-54600, Pakistan
Corresponding author*: immunology@uhs.edu.pk
__________________________________________________________________________________
ABSTRACT
The article is an overview of different properties
of cytokines. It discusses ways to group these
proteins, major advancements regarding their
structure, functions and significance in the last
three or four decades, the newly diagnosed
cytokines and their major contribution, various
clinical conditions where the role of these
proteins have been established and also the
clinical situations where these cytokines are
being used for therapeutic purposes.
Keywords: autoimmunity; T helper cells;
chemokines; interleukins; T regulatory cells;
immunodeficiency
Cytokines are small secreted signaling proteins
produced de novo in response to an immune
stimulus that mediate and regulate immunity,
inflammation and hematopoiesis. They are
produced by different hematopoietic and nonhematopoietic cells, but the predominant source
is T helper cells and macrophages. They
generally, but not always act over short
distances, for short intervals and at low
concentration. Cytokines are critical for innate
and adaptive immune responses. They activate
and recruit immune cells and increase responses
against foreign pathogens. They also play role in
development and functioning of immune
system. Their aberrant mode of secretion is
documented in a variety of immunological,
inflammatory
and
infectious
diseases.

Cytokines effect on a cell depends on its extra

cellular abundance, complementary receptors
and production of downstream signals. They are
characterized by considerable redundancy, as
many cytokines share similar functions while
over stimulation of cytokines can trigger a
dangerous syndrome known as cytokine strom;
may be the cause of severe adverse events
during a clinical trial (1,2).
Cytokine field is becoming ever more complex
and it is not possible in a single volume to
present all the new facts and concepts, about
these proteins. This review article is an attempt
to cover some of the areas in which new
information has appeared or where new
interpretations and concepts are emerging.
During 19501970 cytokine studies involved
description of protein factors produced by
different cells that mediate particular functions
such as antiviral interferon, fever producing
pyrogens, etc. Later, partial purification,
characterization of many individual cytokines
and production of specific neutralizing antisera
was done. Golden age of cytokine research
occupied 1980s which characterized molecular
cloning, expression of cytokine molecules and
production of specific, monoclonal, neutralizing
antibodies.
These
reagents
allowed
identification of structure and properties of
individual cytokines. Many new cytokines were
discovered
and
previously
unexpected
properties of known cytokines were revealed.
As a result of these studies, there is now a

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

wealth of information about the sources and

biologic activities of particular cytokines (2,3).
Cytokines also called as lymphokine, monokine,
chemokine, and interleukin (IL). They are
autocrine, paracrine or endocrine in action.
There may be pleiotropic, redundant, cascade,
synergistic or antagonistic functions of
cytokines. They are grouped as working on
natural immunity, pro-inflammatory, noninflammatory or involved in lymphocyte
activation, growth and differentiation or
involved in immune mediated inflammation.
Redundancy and pleiomorphism of cytokines is
a consequence of their homologous receptors.
Dysregulation of cytokines is under intensive
study for their possible role in pathogenesis of
autoimmune disorders (2,3,4).
Cytokine bind to specific cell-surface receptors
that lead to subsequent cascade of intracellular
signaling. There is up-regulation or downregulation of several genes and their
transcription factors, production of other
cytokines, an increase of surface receptors, or
suppression of their own effects by feedback
inhibition. Cytokine receptors are classified as
immunoglobulin superfamily, haemopoietic
growth factor (type 1), interferon (type 2),
tumor necrosis factor (type 3) and seven
transmembrane helix family. Cytokine receptors
deficiency has been linked to certain
immunodeficiency states (5,6).
Structural homologies classify cytokines into
four alpha-helix bundle family, which is divided
into three sub-families: IL-2, interferon and IL10 subfamily. IL-2 is a T cell growth factor; it
controls peripheral tolerance and NK cell
activity. IL-2R subfamily consists of receptors
for IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 and IL21, has a common signal-transducing gamma
chain. A defect in IL-2R family gamma chain
may lead to X-linked severe combined
immunodeficiency (XSCID). Lack of T cells
and NK cells in XSCID is explained by lack of

IL-7 and IL-15 signaling respectively, whereas

defective signaling by IL-4 and IL-21
contributes to B cell defect. IL-21 is involved in
proliferation, differentiation and effector
functions of B, T, NK and dendritic cells. It may
promote or inhibit immune responses and its
potential therapeutic capacity in treating cancers
is being investigated (6-10).
T helper cells are broadly divided into Th1 and
Th2; functionally distinct subsets that secrete
different cytokines, rather cytokines are critical
mediators of this polarization. IFN-gamma and
IL-12 promote Th1 activities while IL-4 and IL10 stimulate Th2 cell population. Th1 produces
cytokines that activate cytotoxic T cells,
macrophages and stimulate B cells to secrete
IgG2a and inhibit IgG1 and IgE. Similarly, Th2
cells secrete cytokines that stimulate B cells to
produce antibodies; IgE and IgG1. Th1 and Th2
cytokines are antagonistic in activity (4,11,12).
T regulatory cells (Treg) are a group of cells
that control autoimmunity and T cell
homeostasis. On the basis of distinct phenotype,
cytokine profile and mechanism of action
several types of Treg cells are identified such as
gamma-delta T cell, natural killer T cells, CD4+
and CD8+ T cells. Their suppressive activity is
associated with IL-10, and TGF-b (3,13,14,15).
Th17 is a newly diagnosed subset of CD4+ T
cells
with
significant
pro-inflammatory
functions which produces IL-17; a family of six
cytokines (IL-17A - F). IL-17 play a central role
in autoimmune diseases, promotes cytotoxic T
cells and its mRNA is found in
tissues/biological fluids of RA, SLE,
uveitis/scleritis, inflammatory bowel disorders
and psoriasis patients (2, 16, 17, and 18). IL-17
recruits neutrophils and facilitate granuloma
formation and priming of Th17 cells require IL1beta and IL-6. TGF-beta promotes murine IL17 expression but human IL-17 may be downregulated by this cytokine. IL-17 mobilizes
neutrophils from bone marrow and promotes

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

production of IL-1, IL-6 and TNF, which are

important for controlling acute infections. IL-17
family is not completely characterized yet (13,
14, 15, and 19). Lineage commitment and
functions of various T cell populations has been
shown in Figure 1 (16).

Figure 1. Different T cell populations and their

functions
IL-25 formerly known as IL-17E is a member of
IL-17 family; which is a Th2 like cytokine.
Unlike IL-17, IL-25 is produced by Th2 cells
and mast cells. IL-25-/- mice showed
susceptibility to parasitic helminthes; associates
with impaired IL-4 and IL-13 production and
reduced parasite specific IgG1 and total IgE.
Antihelminth activity of IL-25 depends on its
ability to induce Th2 associated cytokines. It is
also anti-inflammatory in suppressing Th1 and
Th17 responses. IL-25 may not be absolutely
required for the generation of Th2 responses in
some parasitic infections but is important for
timely resolution of infection. Expression of IL25 is very limited; CD4+ and CD8+ in gut
showed existence of effector T cells that
selectively produce IL-25; it suggests a special
role of IL-25 in mucosal immunity (20,21).
IL22 like IL-17, is another pro-inflammatory
cytokine which acts on non-immunological
tissues and is associated with chronic T cell
mediated inflammatory diseases e.g. psoriasis,
Crohns disease and RA. Expression of IL-22
receptor; IL-22R1, is detected in many tissues

such as epithelial cells of lung, implicating its

role in pulmonary inflammation (18). CD4+ T
cells are predominant source of IL-17 and IL-22
but they are distinct from each other and are
distinct from Th1 cytokine producing subsets.
Th1 cytokines inhibit IL-17, but not IL-22,
therefore it is suggested that regulation of IL-17
and IL-22 producing cells are different. T cells
showed a strong tendency for mutually
exclusive production of INF-gamma or IL-17
(12, 15, 22, and 23).
IL-23 a new regulatory cytokine of IL-12 family
is produced by activated macrophages and
dendritic cells. IL-12 and IL-23 bridge innate
and adaptive immunity as IL-12 is required for
antimicrobial
responses
to
intracellular
pathogens, whereas IL-23 recruits and activates
various inflammatory cells for induction of
chronic inflammation and granuloma formation.
IL-12 receptor is composed of IL-12R-beta1 and
IL-12R-beta-2, whereas IL-23 binds to receptor
composed of IL-12R-beta-1 and IL-23.
Therefore targeting IL-12 and IL-23 and their
downstream signaling elements would be
logical strategies for treatment of immune
mediated diseases. IL-12 and IL-23 are indeed
master regulators of innate and adaptive
immunity but we still have to find out design of
effective therapeutics that could specifically
inhibit right target IL-12, IL-17, IL-23 or
others for a range of immune mediated
inflammatory disorders (23). Experimental
autoimmune encephalitis and collagen induced
arthritis develop in mice which are deficient in
either IL-12 or IL-23. Further, mice lacking IL12 receptor complex succumbed to disease
meaning it is IL-23 and not IL-12 required for
the disease. It established an inverse relation
between Th1 induction and disease development
and a positive correlation between IL-23 and
development of effector CD4+ T cells that
produce IL-17; a cytokine linked to IL-23
induced inflammation. Similarly, IL-17
deficient mice demonstrated impaired joint
inflammation and neutralization of IL-17

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

decreases disease severity. Therefore, in some

autoimmune disorders, it is IL-23-IL-17
cytokine axis, and not IL-12-INF-gamma-axis
crucial for disease (14,23,24,25).

macrophages. Increased IL-10 play a role in

early control of viral infection and tumor cell
dissemination but later it decreases both innate
and adoptive responses (27,28).

TNF-alpha, stimulates IL-1 and IL-6 but

suppresses bone marrow stem cell division.
Chronic administration of TNF-alpha may lead
to lymphopenia, immunodeficiency and
rheumatoid arthritis patients showed increased
risk of tuberculosis. IL-1 does not cause tissue
injury by itself, but it can potentiate injury along
with TNF. IL-6 is a growth factor for activated
B and malignant plasma cells. It may serve as a
co-stimulator of T cells and is required for bone
marrow hematopoietic stem cells. TGF-beta is
pleiotropic, inhibit growth of many cells while
stimulate others. It causes angiogenesis and may
act as pro-inflammatory (IL-17 inducing) or
anti-inflammatory (Th3) agent and shut off
immune response but some tumors escape
immune responses by secreting large quantities
of TGF-beta (2,10,13,15,17,26).

IL-27 is structurally and functionally similar

with IL-12, is pro-inflammatory and it may
promote Th1 responses. Its stimulatory and
inhibitory effects are in parallel of many other
cytokines (19, 29).

IL-4 is a growth and differentiation factor for

Th2 cells. It synergizes with IL-3 in stimulating
mast cells in allergic reactions and switching of
B cells to IgE heavy chain isotype. IL-4
stimulates expression of certain adhesion
molecules such as VCAM-1 on endothelial cells
and inhibits macrophage activation (4).
INF-gamma secretion starts with antigen
activation and is enhanced by IL-2 and IL-12.
INF-gamma an anti-viral cytokine stimulates
cytolytic activity of NK cells and is an antitumor agent (with TNF). It increases MHC class
I and II expression, therefore increases cellular
and humoral immune responses. It promotes T
and B cell differentiation; favors Th1 and
inhibits Th2 responses (13,22).
IL-10 may act as immunostimulatory or
immunosuppressive factor. It stimulates innate
immune system; NK and B cells and inhibits
TNF, IL-1, chemokines and IL-12 by

Cytokine inhibition as treatment: In Alzheimers

disease (AD) inflammatory processes lead to
neurotoxicity. It is a group of functionally
interrelated cytokines and TNF-alpha is crucial
as it is elevated in patients cerebrospinal fluid
and serum. There is activation of microglia
which releases many cytokines that may lead to
neuronal death and its dysfunction. A single
nucleotide polymorphism in TNF-alpha gene is
associated with earlier onset of AD. Amyloidspecific IL-10 generation is selectively and
significantly reduced in AD patients. Analyses
of alleles of IL-10 gene revealed, high IL-10
production is extremely infrequent in AD
individuals. Presence of low/intermediate IL10-producing
genotypes
(GCC/ATA;
ATA/ATA) is associated with early age onset of
disease and (ACC/ACC; ACC/ATA) with an
accelerated rate of disease progression.
Therapeutic strategies that affect microglial
activation or proinflammatory cytokine release
or anti-amyloid therapies are in development
(30,31).
Allergic Diseases: extensively used antiinflammatory agent is corticosteroid, which act
on mast cells, eosinophils and effect cytokine
production. TNF-alpha production by mast
cells is down regulated by corticosteroids.
Successful
allergen
immunotherapy
is
characterized by a switch of allergen-specific
Th2 to Th1 expression (13,32).
Recombinant cytokines are studied in a variety
of malignant, infectious, autoimmune and

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

allergic/asthmatic diseases. They are expensive,

toxic and since a disease is an imbalance of
"good" and "bad" cytokines, giving large doses
of recombinant cytokines may create further
imbalances. Recombinant cytokines are
successful in atopic dermatitis; IFN-gamma in
children with severe atopic dermatitis. During
desensitization IFN-gamma to pollens may act
on animal dander-specific TH2 clone to down
regulate its activity. Marillion Pharmaceuticals
Inc has recently got the permission to develop
and commercialize cytokine's treatment for
xerostomia (10). IL-13 regulates inflammation,
mucus production, tissue remodeling and
fibrosis. It induces allergic response via a
complex array rather through immunoglobulinE and eosinophils. It is important therapeutic
target for asthma, idiopathic pulmonary fibrosis,
ulcerative colitis, etc. A schistosomiasis model
illustrated opposing activities for IL-13 and IL13R-alph-2 in health and disease; IL-13R-alpha2 is down regulated in granulomatous
inflammatory response. IL-13 is overproduced
in many chronic and allergic diseases; the
amount of free versus IL-13R-alpha-2-bound
IL-13 may be a key to pathogenesis of a variety
of Th2 mediated diseases (32).
Chronic inflammatory diseases: It is seen that
combination of anti-TNF-alpha and anti-CD4
can be useful in collagen arthritis (CIA). TNF
receptor-1 associated syndrome (TRAPS) is a
chronic inflammatory disorder with mutations in
55 kDa TNFRSFIA gene. IL-1beta blockade
showed improvement in a TRAPS French
patient who failed to respond to anti-TNF-alpha
therapy (13).
Chronic heart failure: Patients have high level of
many cytokines and they may negatively
influence contractility of heart. Intravenous
immunoglobulin (IVIG) therapy showed
improvement as it may down regulate
chemokines and their receptors. Several anticytokine and immunomodulatory therapy, in
addition to conventional cardiovascular

treatment regimens, have recently emerged as

possible promising treatment modalities (33).
Endothelial cells are activated by cytokine
treatment to kill an intravascular parasite
Schistosoma mansoni, through production of
nitric oxide: INF-gamma, TNF-alpha, IL-1alpha
and IL-1beta kill Schistosoma mansoni through
an arginine-dependent mechanism involving
production of nitric oxide (NO). NO-dependent
reactions also kill tumor cells and inhibit
intracellular growth of protozoan parasite
Toxoplasma gondii (21).
Autoimmunity from cytokine treatment predicts
long-term survival in metastatic renal cell
cancer: Recombinant IL-2 and INF-alpha-2
showed promising results as they may alter
immune
responsiveness
in
genetically
predisposed patients (27).
Future prospects for anti-cytokine treatment: In
rheumatology an era of anti-cytokine treatment
has just begun. First generation biological
agents block TNF-alpha such as monoclonal
antibodies or receptor Ig fusion proteins are safe
and effective. The efficacy, safety and capacity
of
anti-TNF-alpha
therapeutic
agents
(infliximab, etanercept and D2E7) are widely
documented. Anti-TNF-alpha is effective in all
aspects of rheumatoid arthritis. Interestingly,
there was joint protection even in patients who
did not respond clinically, suggesting no clear
distinction between anti-TNF-alpha responders
and non-responders. Further, IL-1 and not TNFalpha is most important cytokine in joint
destruction. IL-12 is inducer of Th1 and is very
beneficial in early induction phase. Both anti IL12 and TNF-alpha may act in synergy at
inhibiting inflammation and in protecting joints.
IL-15 activates T cells in antigen non-specific
manner and its inhibition might synergize with
anti TNF-alpha. IL-18 (now known to be IL-1)
has much broader effects and is a potential
target, together with IL-12 with which it
synergizes. Oncostatin M is a member of IL-6

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

family and has profound effects on cartilage and

bone. Therefore, it is a possible target,
especially to augment joint protection
(15,30,33).
REFERENCES
1.
Vilcek, J., Feldmann, M. 2004. Historical
review: cytokines as therapeutics and targets of
therapeutics. Trends Pharmacol. Sci. 25:201-209.
2.
Furuzawa-Carballeda J, Vargas-Rojas M, Cabal
A. Autoimmune inflammation from the Th17 perspective.
Autoimmun Rev 2007; 6:169-75
3.
Tato C, Laurence A, OShea J. Helper T cell
differentiation enters a new era. J Exp Med 2006;
203:809-12
4.
Cellular and Molecular Immunology; 5th edition,
updated edition. Abdul K. Abbas and Andrew H.
Lichtman
5.
Basic and Clinical Immunology; 8th edition.
Daniel P. Stites, Abba I. Terr and Tristram G. Parslow
6.
Kovanen P, Leonard WJ. Cytokines and
immunodeficiency diseases: critical roles of the cdependent cytokines interleukins 2, 4, 7, 9, 15 and 21 and
their signaling pathways. Immunol Rev 2004; 202:67-83
7.
Ruber M, Berg A, Ekerfelt C, Olaison G,
Andersson R. Different cytokine profiles in patients with
history of gangrenous or phlegmonous appendicitis. Clin
Exp Immunol 2005; 143:117-24
8.
Immunology; 7th edition. David Male, Jonathan
Brostoff, David B. Roth and Ivan Roitt
9.
Tellez M, Tan E, Lim B. ARDS in SARS:
cytokine mediators and treatment implications. Cytokine
2005; 29:92-94
10.
Kayle S, Chandler D, Griffiths C et al..
Guideline for anti-TNF- therapy in psoriatic arthritis.
Rheumatol 2005; 44: 390-97
11.
Shames RS. Gender Differences in the
Development and Function of the Immune System. J
Adolesc Health 2002; 30:59-70
12.
Annunziato F, Cosmi L, Santarlasci V et al.
Phenotypic and functional features of human Th17 cells.
J Exp Med 2007; 8:1849-61
13.
Albanesi C, Cavani A, Girolomoni G. IL-17 is
produced by Nickel-specific T lymphocytes and regulates
ICAM-1 expression and chemokine production in human
keratinocytes: synergistic or antagonist effects with IFNand TNF-. J Immunol 1999; 162:494-02
14.
Nakae S, Saijo S, Horai R, Sudo K, Mori S,
Iwakura Y. IL-17 production from activated T cells is
required for the spontaneous development of destructive
arthritis in mice deficient in IL-1 receptor antagonist. Pro
Natl Acad Sci 2003; 100:5986-90

15.
Schmidt-Weber C, Akdis M, Akdis C. Th17 cells
in the big picture of immunology. J Allergy Clin Immunol
2007; 120: 247-54.
16.
Cooke A. Th17 cells in inflammatory conditions.
Rev Diabetic Stud 2006; 3:72-75
17.
Harrington L, Mangan P, Weaver C. Expanding
the effector CD4 T cell repertoire: the Th17 lineage. Curr
Opin Immunol 2006; 18:349-56
18.
Ye P, Garvey P, Zhang P et al Interleukin 17 and
lung host defense against Klebsiella pneumoniae
infection. Am J Respir Cell Mol Biol 2001; 25:335-40
19.
Amadi-Obi A, Yu C, Liu X et al Th17 cells
contribute to uveitis and scleritis and are expanded by IL2 and inhibited by IL-27/STAT 1. Nat Med 2007; 13:71118
20.
Fujino S, Andoh A, Bamba S, Ogawa A, Hata K,
Araki Y, Bamba T, Fujiyama Yl. Increased expression of
interleukin 17 in inflammatory bowel disease. Gut 2003:
52; 65-70
21.
Oswald I, Eltoum I, Thomas A. Wynn T,
Schwartz B, Caspar P, Paulin D, Sher A, James S.
Endothelial cells are activated by cytokine treatment to
kill an intravascular parasite, Schistosoma mansoni,
through the production of nitric oxide. Proc Natl Acad Sci
1994; 91:999-03
22.
Scriba T, Kalsdorf B, Abrahamas D. Distinct,
specific IL-17 and IL-22 producing CD4+ T cell subsets
contribute to the human anti-mycobacterial immune
response. J Immunol 2008; 180:1962-70
23.
Kreymbrog K, Etzensperger R, Dumoutier L et
al. IL-22 is expressed by Th17 Cells in an IL-23dependent fashion, but not required for the development
of autoimmune encephalomyelitis. J Immunol 2007;
179:8098-04
24.
Langrish C, McKenzie B, Wilson N, de Waal
Malefyt R, Kastelein R, Cua D. IL-12 and IL23: master
regulators of innate and adaptive immunity. Immunol Rev
2004; 202:96-05
25.
Watford W, Hissong B, Bream J, Kanno Y,
Muul L, OShea J. Signaling by IL-12 and IL-23 and the
immunoregulatory role of STAT4. Immunol Rev 2002;
202:139-56
26.
Nakae S, Nambu A, Sudo K, Iwakura Y.
Suppression of immune induction of collagen induced
arthritis in IL-17 deficient mice. J Immunol 2003;
171:6173-77
27.
Franzke A, Peest D, Probst-Kepper M et al.
Autoimmunity resulting from cytokine treatment predicts
long-term survival in patients with metastatic renal cell
carcinoma. J Clin Oncol 1999; 17:529-33
28.
Vicari A, Trinchieri G. Interleukin 10 in viral
diseases and cancer: exciting the labyrinth. Immunol Rev
2004; 202:223-36
29.
Hunter C, Villarino A, Artis D, Scott P. The role
of IL-27 in the development of T cell responses during
parasitic infections. Immunol Rev 2004; 202:106-14

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

30.
Feldmann M, Miotla J, Paleolog E, Williams R,
Malfait A, Taylor P, Brennan F, Maini R. Future prospect
for anti-cytokine treatment. Ann Rheum Dis 2000;
59:119-22
31.
Inhibition for Treatment of Alzheimer's Disease:
Medscape General Medicine 2006;8:24; Available from
URL:
http://www.medscape.com/viewarticle/530141http://www
.freepatentsonline.com/WO2003102237.html
32.
Wills-Karp M. Interleukin-13 in Asthma
Pathogenesis. Immunol Rev 2004; 202:175-90
33.
Damas J, Gullestad, Aukrust P. Cytokines as a
new treatment in chronic heart failure. Curr Control Trials
Cardiovascular Med 2001; 2:271-77

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43