Lecture 17 Cytokines

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Lecture 17Cytokines
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What are cytokines?

• A collection of polypeptides used for
  communications between cells
• Play role similar to hormones (messengers of the
  endocrine system)
• Hormones usually act at a distance
• Cytokines act locally
• Differ from growth factors that are produced
  constitutively, while cytokine production is
  carefully regulated
• Play an important role in both innate and
  adaptive immunity

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Cytokine nomenclature

• Interleukins (1-18)
• Interferons (a,b,g)
• Others (common names)

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Cytokine -mediated effects

• Cell growth
• Cell differentiation
• Cell death
• Induce non-responsiveness to other
  cytokines/cells
• Induce responsiveness to other cytokines/cells
• Induce secretion of other cytokines

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How do cytokines tell cells what to do?

• Produced by cells as part of normal cellular
  activity and/or the result of environmental
  trigger
• Bind to receptors on cells
• Trigger signal transduction pathways
• Initiate synthesis of new proteins

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Properties of cytokines

• Proteins
• Low molecular weight
• Bind to receptor on either cell which produced it
  or another cell
• Receptor binding triggers a signal
• Signal results in altered pattern of gene
  expression

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Cytokines can 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

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Cytokine Actions

• Pleiotropy
• Act on more than one cell type (INFa/b)
• Redundancy
• More than one cytokine can do the same thing
  (IFNa/b and IFN?)
• Synergy
• Two or more cytokines cooperate to produce an
  effect that is different or greater than the
  combined effect of the two cytokines when
  functioning separately (IL-12 and IL-8)
• Antagonism
• Two or more cytokines work against each other
  (IL-4 and IL-12)

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How can non-specific cytokines act specifically?

• Only cells expressing receptors for specific
  cytokines can be activated by them
• Many cytokines have very short half-lives
• Only cells in close proximity will be activated
• High concentrations of cytokines are needed for
  activation
• Only cells in close proximity will be activated
• May require cell-to cell contact

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Five cytokine receptor families

• Immunoglobulin superfamily receptors
• Class I cytokine receptor family (hematopoietin
  receptors)
• Binds most of the cytokines in the immune and
  hematopoietin systems
• Class II cytokine receptor family
• TNF receptor family
• Chemokine receptor family

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Cytokines regulate the immune response

• Cells with the appropriate receptors become
  activated
• To differentiate
• To express receptors which will make them
  receptive to other cytokines
• To secrete other cytokines

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Signal Transduction by cytokine receptors

• Cytokine receptors on different cell types
  trigger different events
• How do you get the message from the outside of
  the cell to the machinery inside?

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Cytokines, growth factors and hormone signal
transduction pathways
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The Jak/Stat Signaling Pathway
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Involvement of cytokines in the immune response

• Alert to infection.tumor/etc.
• Recruit cells to site
• Specify type of immune response
• Immune effector phase
• Immune down-regulation
• Immune memory and resetting the system

• Early mediators (IFNa/b)
• Chemokines (MIP-1a)
• Early late mediators (IL-2, IFNg, IL-4, IL-5)
• Down-regulators (IL-10, TNFg)
• Maintenance of cytokines, etc. (GM-CSF, IL-3,
  IL-7, etc.)

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Early mediators

• Interferons a/b
• Induced by dsRNA, etc.
• Induced by CD40/CD40L pathway
• IFNs can induce more of themselves
• Directly interferes with viral replication
• Activation of T and NK cells

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Chemokines

• Recruit to sites of infection
• MIP-1a (NK and T cells)
• MIG, RANTES (CD4T cells)
• IL-8 (neutrophils)
• Eotaxin (eosinophils)

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Early mediators

• IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10
• Proinflammatory mediators
• Produced by cell associated with innate immunity
  (macrophages, NK, etc.)
• Mediate direct effects
• Promote inflammation
• Shape downstream responses

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Late mediators

• IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10
• Produced by cells of the adaptive immune response
  (T and B cells)
• Direct effects
• More immunoregulatory functions

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Cytokine secretion and biological activities of
TH1 and TH2 Subsets
Type 1
Type 2
Cell-mediated Immune response (intracellular Organ
isms)
Humoral response (parasites)
T cell
IL-2 IFN-g TNF
IL-4 IL-5
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Down regulators

• IL-10, IL-11, TGF-b
• Inhibit proliferation, cytokine production
• Produced by both innate and adaptive cells

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Maintenance cytokines

• GM-CSF, IL-3, IL-7, IL-9, etc.
• Induce cell differentiation, cell growth

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Cytokine cross-regulation

• In a a given immune response, either TH1 or TH2
  response dominates
• Cytokines of one response tend to down-regulate
  the other type of response
• Example TH1 cells secrete IFN-g, which inhibits
  proliferation of TH2 subset

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Role of TH1/TH2 balance in determining disease
outcomes

• Balance of two subset determines response to
  disease
• Leprosy
• Tuberculoid (TH1, CMI response, patient lives)
• Lepromatous (TH2, humoral response, patient dies)

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Cytokine-related diseases

• Bacterial septic shock
• Blood pressure drops, clots form, hypoglycemia
  ensues, patient dies
• LPS triggers results in TNF release
• TNF induces IL-1 which induces IL-6 and IL-8
• Bacterial toxic shock and related diseases
• Superantigens trigger large numbers of T cells
  which release massive amounts of cytokines (Super
  antigens are bacterial toxins that bridge CD4 T
  cell receptors and the MHC class II molecules on
  APCs, bypassing the need for antigen)
• Lymphoid and myeloid cancers
• Some cancer cells secrete cytokines
• Chagas disease
• Trypanosoma cruzi infection results in sever
  immune suppression
• Depression of IL-2 receptor production

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Components of the immune system
Help
?? T cell CD4
?? T cell CD8
?? T cell
B cell
Inflammatory cytokines
Cytotoxic T cells
?
Antibody
Interferon Non-lymphoid Cytokines
Macro- phages
Complement
Granulo- cytes
Adapted from Marrack and Kappler, 1994
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Infectious agents that target cytokines

• Epstein-Barr virus foster the generation of T
  helper cells that do not produce IL-2.
• EBV produces an analog of IL-10 that favors TH2
  cells, rather than TH1.
• Parasites such as tape worms induce high levels
  of IgE, an immunoglobulin induced by TH2 cells.
• Since TH1 cells mediate inflammation, this may be
  a protective ploy to avoid destructive
  inflammatory processes.

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Immunosuppressive effects of oral bacteria on
immune function

• Impairment of B and T cell function (P.
  intermedia, P. asaccharolytica, P. endodontalis,
  P. melaninogenica)
• Production of specific toxins that kill monocytes
  (A. actinomycetemcomitans)
• Provoke the release of peroxide, prostaglandins
  and other mediators capable of inhibiting
  lymphocyte function (T. denticola)
• Modulate expression of cytokines

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Cytokine-inducing components of
Periodontopathogens

• Taken from Wilson, M., Reddi, K., Henderson, B.
  1996. Cytokine-inducing components of
  periodontopathogenic bacteria. J. Periodont.
  Res. 31393-407.
• Pro-inflammatory cytokines such as interleukin
  (IL)-1, IL-6, IL-8 and tumor necrosis factor
  (TNF) are believed to be the major pathological
  mediators of inflammatory diseases ranging from
  arthritis to periodontal diseases.
• It is believed that components of microorganisms
  have the capacity to induce cytokine synthesis in
  host cells.

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Cytokine-inducing components of Gram-positive
bacteria
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Cytokine-inducing components of Gram-negative
bacteria
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Cytokine-induction by LPS from periodontopathogens
other than P. gingivalis
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Cytokines produced by host cells in response to
components/products from periodontopathogens
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Interferon Action

• Viral replication stimulates the infected host
  cell to produce interferon.
• Interferon induces uninfected cells to
• produce antiviral proteins that prevent
  translation of viral mRNA
• degrade viral nucleic acid
• Viral replication is blocked in uninfected cells

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Therapeutic uses of cytokines

• Modulation of TH activation
• Interfere with receptor function
• Interfere with cytokine
• Make it unable to bind to receptor
• Make it unable to act

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Examples of therapeutic uses

• Soluble T-cell receptor
• Anti-IL-2R
• Interleukin analogs which bind receptor, but do
  not trigger activation (ties up receptor)
• Toxins conjugated to cytokines which kill
  activated T-cells
• Administration of cytokines to enhance immunity
  (side effects/ short half lives)
• Allergies