CYTOKINE

Cytokine 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.

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

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
autocrine self

Paracrine
Cytokine binds to receptors on near by cells

paracrine

Nearby

Endocrine
Cytokine binds cells in distant parts of the body

Blood circulation

endocrine

Distance

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- 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 Cytokines

Cytokines 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- (TGF-) and lymphotoxin (TNF- )

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 leukocytes Lymphokines - produced by lymphocytes Monokines - produced exclusively by monocytes Interferons - involved in antiviral responses Colony Stimulating Factors - support the growth of cells in semisolid medias Chemokines - 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- produced by leucocytes
induced by virus infected cells

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

Action of INF- and INF- :

- 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-
- 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)

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-). 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 -, which may be of relevance for the treatment of juvenile arthritis because this cytokine is found in inflamed tissues in this condition.

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.

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, and systemic 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

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.com www.3a.us.elsevierhealth.com