CYTOKINES

CYTOKINES

• small soluble proteins that regulate the immune

system, orchestrating both innate immunity and the
adaptive response to infection

• Chemical messengers that influence the activities of

other cells.

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 ACTIONS OF CYTOKINES

• Autocrine – affecting the same cell that

secreted it

• Paracrine – affecting a target cell in close

proximity

• Endocrine - systemic

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 FEATURES OF CYTOKINES

• Pleotropism
single cytokine has many different actions
• Redundancy
different cytokines often have very similar effects
• Synergy
cooperative effect of multiple cytokines
• Antagonist
inhibition of one cytokine effects by another
cytokine
• Act in networks
stimulate the release of other cytokines
• Act as growth factors for hematopoietic cells
modulate the number and composition of cells

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 ROLES OF CYTOKINES

• Innate immunity

• Adaptive immunity

• Growth and differentiation of immature leukocytes

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CYTOKINE CATEGORIES/FAMILIES

• Tumor Necrosis Factor

• Chemokines

• Interleukins

• Interferons

• Hematopoietic Factors

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 TUMOR NECROSIS FACTOR

• Principal mediator of the acute inflammatory

response to gram-negative bacteria and other
infectious microbes

• Stimulates gene transcription or induces apoptosis

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 TUMOR NECROSIS FACTOR

• TNF α and TNF β share similar activities

• Stimulate the recruitment of neutrophils and monocytes to sites of
infection
• Activate these cells to eradicate microbes

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 CHEMOKINES

• Stimulate trans-endothelial leukocyte movement

from the blood to the tissue site of infection and
regulate the migration of PMNs and mononuclear
leukocytes within tissues

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 INTERLEUKINS

• Modulate inflammation and immunity by regulating

growth, mobility and differentiation of lymphoid
cells

• Each interleukin functions through a separate

receptor system and a distinct molecule by gene
cloning and sequencing

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 INTERFERONS

• Discovered in virally infected cultured cells

• Enhances expression of specific genes, inhibiting

cell proliferation, and augmenting immune effector
cells

• Antiviral agents, immunomodulators, antineoplastic

agents

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 HEMATOPOIETIC FACTORS

• Stem cell Factor

• it acts on immature stem cells, needed to make Bone
Marrow stem cells responsive to other CSFs
• Colony-stimulating Factors
• Stimulate hematopoietic progenitor cells to form colonies
(G-CSF, GM-CSF)
• Transforming Growth Factors
• Products of virally transformed cells
• Induce phenotypic transformation in non-neoplastic cells

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CYTOKINES IN INNATE IMMUNITY

• Non-immune (Type 1) Interferons

• IFN-α, IFN-β
• Tumor Necrosis factor
• Interleukins
• IL-1, IL-6, IL-8, IL-10 , IL-12, IL-15
• Chemokines
• C-X-C, C-C, C subgroup

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 TYPE 1 INTERFERONS

• IFN-α
• Produced by mononuclear phagocytes
• IFN-β
• Produced by fibroblasts

* Viral infection may produce these molecules

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 TYPE 1 INTERFERONS

• Induce expression of proteins that inhibit viral

replication

• Inhibits cell proliferation

• They bind to same receptor

• They increase the ability of NK cells to kill virally

infected c ells

• Enhance expression of MHC class I molecules

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 TUMOR NECROSIS FACTOR

• Triggered by the lipopolysaccharide from gram-

negative bacteria

• Bound by a specific LPS-binding protein that binds

to a receptor on mononuclear phagocytes CD14
• IL-1, IL-6

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 TUMOR NECROSIS FACTOR

• In low concentration it acts on leukocytes and

endothelium to induce acute inflammation

• At moderate concentrations it mediates the

systemic effects of inflammation
• IL-1, IL-6, IL-8

• High concentrations leads to metabolic alterations

and shock

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 INTERLEUKIN-1

• Produced by macrophages and monocytes in

response to bacterial LPS and TNF

• Pro-inflammatory cytokine

• Induces IL-2 and IL-2 receptor(CD25) in T-cells,

proliferation and differentiation of B-cells

• Enhancement of cytotoxicity of NK cells

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 INTERLEUKIN-1

• Two types (α,β)

• α type – possesses activity without further
processing
• β type – require cleavage before its functional

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 INTERLEUKIN-3

• Secreted by t-helper cells

• Stimulates degranulation of mast cells

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 INTERLEUKIN-6

• Appears after IL-1 has been triggered

• Primary mediator of acute phase response

• Signal for enhanced fibrinogen synthesis

• Growth factor to activated B-cell and plasma cell

• Synergist with IL-3 to promote growth of

hematopoietic progenitor cells and activation and
generation of T-cytotoxic cells

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 INTERLEUKIN-8

• Secreted by macrophages and endothelial cells

• Chemotactic for neutrophils

• Promotes vascular endothelium adherence and

extravasation; inflammatory response

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 INTERLEUKIN-10

• Inhibits production of pro-inflammatory cytokines by

mononuclear phagocytes

• Inhibits the accessory functions of mononuclear

phagocytes for T-cell activation

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 INTERLEUKIN-12

• Triggers secretion of IFN-γ by T-cells and NK cells

• Promotes differentiation of T-helper1 to secrete IFN-γ

• Enhances the cytotoxic function of NK cells and CD8+ T cells

• Acts with IL-2 to promote growth of CTL’s

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 INTERLEUKIN-15

• Release occurs in response to viral, LPS, or other

pathogens

• Supports the development of NK cells

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 CHEMOKINES

• CC chemokine
• Attract mononuclear cells to sites of chronic inflammation
(MCP-1)
• CXC chemokine
• Attracts PMNs to sites of inflammation, activates monocytes
and may direct the recruitment of these cells to vascular
lesions (CXCL8)
• CX3 chemokine
• Forms a cell-adhesion receptor capable of arresting cells
under physiologic flow conditions

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CYTOKINES IN SPECIFIC IMMUNITY

• Th1 cytokines
• IL-2, IFN-γ

• Th2 cytokines
• IL-4, IL-5, IL-10

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 IFN-Γ

• stimulates antigen presentation by MHC I and MHC II

molecules

• Strong stimulator of macrophages and boosts their

tumoricidal activity

• Promotes type IV hypersensitivity

• Down regulates IgE synthesis (moderates type1 allergic

response.

• It blocks Il-4

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 INTERLEUKIN-2

• T-cell growth factor

• drives the growth and differentiation of both T and B

cells and induces lytic activity in NK cells

• Acts in synergy with IL-12 to promote growth of T-

cytotoxic cells

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 INTERLEUKIN-4

• Triggers activation, proliferation and differentiation

of B-cells

• Responsible in allergic reactions, parasitic infections

and autoimmune diseases

• Increases expression of MHC-II on resting B cells

• Also induces T-cell proliferation

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 TUMOR NECROSIS FACTOR Β

• Formerly called as lymphotoxin

• Binds to a specific receptor and triggers apoptosis

of the target cell

• Short-lived and localized

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 CYTOKINE ANTAGONISTS

• Antagonists Exist In 2 Forms

• Receptor Antagonists (Bind Receptor, No Activation)
• Bind Cytokine (Prevent Cytokine From Binding
Receptor)
• Well Studied Example: IL1Ra
• In Many Cases Antagonist Is A Soluble Receptor
• Derived From Proteolytic Cleavage Of Extracellular
Domain Of Particular Receptor
• IL-2, IL-4, IFN, IFN
• Viruses Produce Cytokine Mimics Or Cytokine
Binding Proteins
• Ex. Poxviruses Produce IL-1-Binding Protein And TNF-
binding-protein
• These Agents Offer Viruses An Advantage

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