CYTOKINES

MD AQUIB MAHMOODM.PHARM II SEM

CYTOKINECytokine is a word that comes from cyto meaning “cell” and kinin meaning ‘hormones’.

Cytokine is a term that is applied to protein or polypeptide mediators which is synthesised and released by cells of the immune system during inflammation.

Their major functions are to mediate and regulate immune response and inflammatory reactions.

Cytokines are secreted by white blood cells as well as variety of other cells (fibroblasts, endothelial cells, epithelial cells, etc.) in the body in response to inducing stimuli.

PROPERTIES

Low molecular weight polypeptides or glycoprotein(8~80 KD), and most of them are monomer.

Secretion is a self limited event .

They are potent in minute amounts.

Cytokines often influence synthesis and action of other cytokines.

Signal results in altered pattern of gene expression.

Cytokines act in three different manners

Autocrine

Cytokine binds to receptor on cell that secreted it

Paracrine

Cytokine binds to receptors on near by cells

Endocrine

Cytokine binds cells in distant parts of the body

Distance

autocrine

endocrine

Blood circulation

paracrine Nearby

self

Cytokine Actions

Pleiotropy refers to the ability of one cytokine having multiple effects on diverse cell types.For example IL-4 initially discovered as a T-cell growth factor also affects B-cell and natural killer (NK) cell growth and differentiation.

Redundancy refers to the property of multiple cytokines having the same or overlapping functional effects.

For example IL-2 and TNF-α both act as inflammatory mediators.

Synergy refers to the property of two or more cytokines having greater than additive effects

Antagonism refers to the ability of one cytokine inhibiting the action of another cytokine

Functional Categories of CytokinesCytokines classified according to their biological

actions into three groups:

1) Mediators and regulators of innate immunity

• Produced by activated microphages and NK cells in response to microbial infection

• They act mainly on endothelial cells and leukocytes to stimulate the early inflammatory

response to microbes

2) Mediators and regulators of acquired immunity - Produced mainly by T lymphocytes in response to specific recognition of foreign antigens - They include IL-2, IL-4, IL-5, IL-13, IFN, Transforming growth factor-β (TGF-β) and lymphotoxin (TNF- β)

3) Stimulators of hemoptysis.

- Produced by bone marrow, leukocytes - Stimulate growth and differentiation of leukocytes - Stem cell factor, IL-3, IL-7, GM-CSF

Cytokine Names(classification)Interleukins - produced exclusively by leukocytesLymphokines - produced by lymphocytesMonokines - produced exclusively by monocytesInterferons - involved in antiviral responsesColony Stimulating Factors - support the growth of cells in semisolid mediasChemokines - promote chemotaxis

INTERLUKINS

• Cytokines secreted by leukocytes that have the ability to act as signal molecules between different population of leukocytes

• IL-1~IL-29

Interferons (IFNs)

Interferons (IFNs): are proteins secreted in response to viral infections or other stimuli

They include:

- INF-α produced by leucocytes induced by virus infected cells

- INF-β produced by fibroblasts

- INF-γ produced by NK cells,TH1 cells, CD8 T-cells

Action of INF-α and INF-β :

- Prevent viral replication - Increase MHC-I expression on viral infected cells helping their recognition by CD8 T-cells

- Increase cytotoxic action of Nk cells

- Inhibit cell proliferation and tumor growth

Action of IFN-γ

- Activate Macrophages - Increase expression of MHC-I and II on APCs - Enhance cytotoxic actions of NK cells - Promote production of TH1 and inhibits proliferation of TH2

Tumor necrosis factor (TNF)

TNFs were originally thought of as selective antitumour agents, but are now known to have a multiplicity of actions.

TNF- is produced mainly by LPS activated monocytes and macrophages.

TNF-(lymphotoxin, LT) is produced mainly by activated Th0 and Th1.

CHEMOKINES

• Defined as chemo attractant cytokines that control the migration of leucocytes, functioning as traffic coordinators during immune and inflammatory reactions.

• More than 40 Chemokine have been identified.

• Chemokine act through G-protein-coupled receptors.

• Alteration or inappropriate expression of these is implicated in multiple sclerosis, cancer, rheumatoid arthritis and some cardiovascular diseases.

Cytokines that stimulate proliferation or differentiation of pluripotent hematopoietic stem cell and different progenitors.

Multi-CSF Granulocyte macrophage-CSF(GM-CSF)Monocyte-CSF(M-CSF)Granulocyte-CSF(G-CSF)Stem cell factor(SCF)Erythropoietin(EPO)

Colony Stimulating Factor

GM-CSF induces increase in white cell count, it is used:

To restore leukocytic count after cytotoxic chemotherapy induced neutropenia

After bon marrow transplantation

To correct AIDS-associated leukopenia

Erythropoetin - anaemia of chronic renal failure and dialysis

Fibroblast Growth Factor for wound healing, recalcitrant ulcers, non-healing fractures

Pregnancy- survival of the ‘allograft’, very high secretion of M-CSF from endometrial cells, also high levels of TGF-beta in amniotic fluid

Therapeutic Uses of Cytokines Interferon in treatment of viral diseases, cancer

Several cytokines are used to enhance T-cell activation in immunodefficincy diseases, e.g. IL-2, IFN-,TNF-

IL-2 and lymphocyte activating killer cells (LAK) in treatment of cancer.

GM-CSF induces increase in white cell count, it is used: To restore leukocytic count after cytotoxic

chemotherapy induced neutropenia

After bone marrow transplantation

To correct AIDS-associated leukopenia

Erythropoetin - anaemia of chronic renal failure and dialysis (NB kidney synthesis)

Fibroblast Growth Factor for wound healing, recalcitrant ulcers, non-healing fractures.

Pregnancy- survival of the ‘allograft’, very high secretion of M-CSF from endometrial cells, also high levels of TGF-beta in amniotic fluid.

Anti-cytokines antibodies in management of autoimmune diseases and transplant rejection: a- Anti-TNF in treatment rheumatoid arthritis b- Anti-IL2R to reduce graft rejection

Anti-TNF antibodies in treating septic shock

Anti-IL-2R in treating adult T-cell leukemia

Anti-IL-4 is under trial for treatment of allergies

ANTICYTOKINES• Greatest conceptual breakthrough in the

treatment of severe chronic inflammation.

• The drugs currently available drugs are: infliximab and adalimumab (chimeric mouse/human

monoclonal antibodies against TNF-α). etanercept (a TNF receptor fused to the Fc domain of a

human IgG molecule). anakinra (an IL-1 antagonist).

Mechanism of action• Infliximab, adalimumab and etanercept bind TNF

and inhibit its effects.

• Etanercept and anakinra function as antagonists.

• Etanercept can also bind another cytokine, lymphotoxin -α, which may be of relevance for the treatment of juvenile arthritis because this cytokine is found in inflamed tissues in this condition.

Cytokine gene transfer Gene therapy with cytokines will probably be a useful complement to conventional treatments (surgery, chemotherapy, radiotherapy) prophylactic or therapeutic effective vaccination against cancer under safe and clinically feasible conditions

severe combined immunodeficiency, renal cell carcinomas, and metastatic melanoma have recently demonstrated the feasibility and safety of using gene transduction for human gene and cancer therapy

At present patients eligible for cytokine gene transfer tumor therapy are those with cancer that has failed all standard effective treatment and for which no other effective treatment options are available.

Cytokine Storm

A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines andimmune cells, with highly elevated levels of various cytokines

Cytokine storms can occur in a number of infectious and non-infectious diseases including

graft versus host disease (GVHD), acute respiratory distress

syndrome(ARDS),sepsis,smallpox, andsystemic inflammatory response

syndrome

It is believed that cytokine storms were responsible for pandemic deaths during

1918 influenza pandemic, SARS epidemic in 2003 bird flu H5N1 2009 swine flu outbreak

REFERENCE

Goodman and Gilman, Basic Principles of Therapeautics, 12th edition, Pg 757-78

H.P.Rang and M.M.Dale, Pharmacology;7th edition pg 222-227.

Betram G Katzung;Basic and clinical Pharmacology,10th edition pg 634-639.

Wwwwebmd.comwww.3a.us.elsevierhealth.com

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