Cytokines are proteins that are critical for immune responses and their dysregulation can contribute to cardiovascular diseases. The document discusses several families of cytokines including interleukins, tumor necrosis factors, chemokines and interferons. It describes the roles that various cytokines play in processes like atherosclerosis, varicose veins, hypertension, and myocardial ischemia. Cytokines are produced by immune cells and vascular cells, can have pro-inflammatory or anti-inflammatory effects, and signal through multiple receptor families. Their involvement in cardiovascular disorders makes them potential therapeutic targets.

1. Role of Cytokines in
Cardiovascular diseases

2. • Introduction
• Properties of Cytokines
• Cytokines Families
• Cytokine Receptors
• Cytokine Receptors Signaling Pathways
• Chemokines
• Chemokine receptors
• Interferons
• Implication of cytokines in CVS disorders
• Clinically available cytokines
• References
TABLE OF CONTENTS

3. Introduction
 Cytokines are a diverse group of short acting proteins, glycoproteins and
peptides produced by various immune cells and vascular cells.
 Circulate in picomolar to nanomolar concentrations to activate specific
receptors and modulate the function of many cells and tissues.
 They are critical for normal innate and adaptive immune
responses and their expression may be perturbed in most immune,
inflammatory and infective diseased state.

4. Properties of Cytokines
• Cytokines bind to specific receptors on the membrane
of target cells, triggering signal-transduction pathways
that ultimately alter gene expression in the target
cells.
• The susceptibility of the target cell to a particular
cytokine is determined by the presence of specific
membrane receptors.
• In general, the cytokines and their receptors exhibit
very high affinity for each other, with dissociation
constants ranging from 10–10 to 10–12 M. Because
their affinities are so high, cytokines can mediate
biological effects at picomolar concentrations.

5. Pleiotropy
Redundancy
Synergy
Antagonism

6. Actions of Cytokines
IL-2 for
T-cell activation
T-cell help
for B cells
Inflammatory cytokines

7. Cascade induction occurs when the action of one
cytokine on a target cell induces that cell to
produce one or more other cytokines, which in turn
may induce other target cells to produce other
cytokines.

8. CYTOKINES
INTERLEUKINS
TUMOR
NECROSIS
FACTOR
CHEMOKINES
INTERFERONS
LYMPHOKINES
MONOKINES

9. Sources Of Cytokines
• Cytokines are produced in response to inflammatory stimuli mainly by
macrophages and TH cells, but are also produced by other inflammatory
cells, as well as vascular cells and adipocytes.
• Macrophages are the main source of cytokines. They produce the pro-
inflammatory cytokines TNF-α, IL-1, -6, -12, -15, -18, and -32, as
well as the anti-inflammatory cytokines IL-10 and TGF-β.
• An autocrine activation loop in macrophages may involve self stimulation by
IL-12 and IL-18 to produce IFN-γ.
• Macrophages also express a number of chemokines such as MCP-1/CCL2,
MCP-4/CCL13, and IL-8/CXCL8.
• T-cells secrete numerous cytokines including IFN-γ and IL-4.
 Platelets are a rich source of cytokines, chemokines and growth
factors.

10. Pro And Anti inflammatory Cytokines

11. Cytokines Families
The hematopoietin
family
The interferon family
The chemokine
family
The tumor necrosis
factor family

12. Cytokine Receptor Families
The immunoglobulin super family receptors
Class I cytokine receptors (Hematopoietic)
ClassII cytokine receptors (Interferons)
TNF receptors
Chemokine receptors

13. Class I cytokine receptor family
• Many of the cytokine-binding receptors
that function in the immune and
hematopoietic systems belong to the
class I cytokine receptor family.
• Have conserved amino acid sequence
motifs in the extracellular domain
consisting of four positionally conserved
cysteine residues (CCCC) and a conserved
sequence of tryptophanserine-(any amino
acid)-tryptophan-serine (WSXWS,where
X is the nonconserved amino acid).

14. Class II cytokine receptors
• The class II cytokine receptors possess the
conserved CCCC motifs, but lack the
WSXWS motif present in class I cytokine
receptors.
• Initially only the three interferons, a, b, and g,
were thought to be ligands for these receptors.
However, recent work has shown that the IL-10
receptor is also a member of this group.
• Another feature common to most of the
hematopoietin (class I cytokine) and the class
II cytokine receptor families is multiple
subunits, often including one subunit that binds
specific cytokine molecules and another that
mediates signal transduction.

15. Immunoglobulin Superfamily
Receptors
•It includes the receptor for IL-1.
•Two forms of IL-1α and IL-1β, have been well
characterized.

16. TNF Receptor Family
• These receptors have four
extracellular domains.
• Include receptors for soluble
TNFα and TNFβ as well as
membrane-bound CD40 and Fas.
• Two TNF receptors, TNFR1 and
TNFR2, have been described.
• The TNF receptors CD40 and Fas
bind cell the surface ligands
CD40L and FasL on effector T-
cells.

17. Cytokine Receptors Signaling Pathways

18. Chemokines
• Chemokines are small cytokines with selective chemoattractant
properties, coordinating the homeostatic circulation of leukocytes as well
as their movement to sites of inflammation or injury
• Dysregulated expression of chemokines and their receptors is involved in
the development of many human diseases
CHEMOKINE
SUPERFAMILY
XC
SUBFAMILY
CC
SUBFAMILY
CXC
SUBFAMILY
CX3C
SUBFAMILY

19. Chemokine Receptor Family
•These receptors have seven transmembrane
helices and are coupled with G protein.
•Chemokine superfamily is divided into four
subfamilies(XC,CC,CXC, and CX3C).

20. Interferons
• Interferons (IFNs) are a class of antiviral proteins produced by certain animal cells
after viral stimulation
• One of the principal function of interferons is to interfere with viral multiplication
• Human interferons are of three principal types:
• In human body interferons are produced by fibroblast in connective tissue, by
lymphocytes and by other leukocytes.
Alpha- interferon
Beta- interferon
Gamma-interferon

21. Mechanism Of Interferon Action

22. Clinically available interferons

23. Cytokines In CVS Disorders

24. Cytokines And Atherosclerosis
• Studies on cytokine-deficient animals have provided direct evidence for a role
of cytokines in atherosclerosis
• In vitro cell culture experiments further support the suggestion that cytokines
contribute to atherogenesis.
• Innate cytokines such as IL-1 or TNF may activate ECs, VSMCs, monocytes/
macrophages, lymphocytes (T, B, NK), dendritic cells, and mast cells.
These vascular cells can actively contribute to :
The inflammatory cytokine-dependent response in the
vessel wall by production of cytokines.
Involved in cytokine-mediated interaction with invading
cells such as monocytes, T-cells, or mast cells.
Activation of these pathways results in accumulation of
cells and increased LDL- and ECM-deposition which
may facilitate subsequent invasions.
Thus, vascular cells contribute to the inflammatory
pathways involved in both the development and
acceleration of atherosclerosis.

25. Cytokines And Varicose Vein
• In varicose veins, there are reflux,
incompetent valves and vein wall dilation
resulting in an increase in venous pressure.
• Inflammatory cytokines and adhesions
molecules, especially TGF-β, IL-6, IL-8
and VCAM-1, may be involved in vein
valve insufficiency.
• Increased expression of bFGF and TGF1 by
varicose vein cells may play a pivotal role in
the hypertrophy of the venous wall, but the
exact mechanisms leading to dilatation are
unclear.

26. Cytokines And Hypertension
• There is a potential link between vascular inflammation and HTN
• Cross sectional studies in hypertensive individuals have shown increased
plasma and vascular tissue levels of:
 CRP
 Cytokines such as TNF-α and IL-6
 Chemokines such as MCP-1 and plasminogen activator inhibitor-1 (PAI-1)
 Adhesion molecules such as P-selectin and sICAM-1.

27. Cytokine And Preeclampsia
• In 5–7% of pregnancies, women develop preeclampsia, characterized by
proteinuria, increased vascular resistance and HTN
• The role of inflammatory cytokines in preeclampsia is supported by the
observation that the plasma levels of TNF-α and IL-6 are elevated in
preeclamptic women.
• Experimental studies have also shown that chronic infusion of TNF-α or IL-6 in
late pregnant rats to increase their plasma levels a 2–3-fold results in significant
elevation in renal vascular resistance and BP.
• Also, the vascular contraction is greater in TNF-α and IL-6 infused compared
with control pregnant rats

28. Chemokines And Myocardial Ischemia
• Chemokine expression is markedly upregulated in healing myocardial infarcts
and may play an important role in regulating leukocyte infiltration and activity
in modulating infarct angiogenesis as well as fibrous tissue deposition.
• The CC-chemokine-monocyte chemo attractant protein-1/CCL2 has important
effects in infarct healing.
• CXC chemokines are also induced in healing infarcts.
• Interleukin-8/CXCL8 may mediate neutrophil recruitment and activation and
may promote neovessel formation.
• Induction of the angiostatic and antifibrotic chemokine interferon-γ-inducible
protein-10/CXCL10 may serve to prevent premature wound angiogenesis and
fibrous tissue deposition in the infarct, until the injured myocardium has been
cleared from dead cells and debris and a fibrin-rich provisional matrix is formed.
• Understanding of the role of chemokines in myocardial ischemia may result in
novel strategies in the treatment of patients with ischemic heart disease.

29. Therapy with Cytokines

30. References
• Sprague H.A. ,Khalil A. Rouf. Biochemical Pharmacology
Vol78,Issue6,2009:539
• Golds by R.A, Kindt J. Thomas, Osborne B.A. Cytokines. Kuby Immunology
Pg:302-326.
• Kuby- Immunology, 4th edition.
• www.whfreeman.com/immunology

31. THANK YOU