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Lecture 17 Cytokines

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Cell death. Induce non-responsiveness to other cytokines/cells ... Blood pressure drops, clots form, hypoglycemia ensues, patient dies ... – PowerPoint PPT presentation

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Title: Lecture 17 Cytokines


1
Lecture 17Cytokines
2
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

3
Cytokine nomenclature
  • Interleukins (1-18)
  • Interferons (a,b,g)
  • Others (common names)

4
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

5
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

6
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

7
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

8
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)

9
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

10
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

11
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

12
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?

13
Cytokines, growth factors and hormone signal
transduction pathways
14
The Jak/Stat Signaling Pathway
15
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.)

16
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

17
Chemokines
  • Recruit to sites of infection
  • MIP-1a (NK and T cells)
  • MIG, RANTES (CD4T cells)
  • IL-8 (neutrophils)
  • Eotaxin (eosinophils)

18
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

19
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

20
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
21
Down regulators
  • IL-10, IL-11, TGF-b
  • Inhibit proliferation, cytokine production
  • Produced by both innate and adaptive cells

22
Maintenance cytokines
  • GM-CSF, IL-3, IL-7, IL-9, etc.
  • Induce cell differentiation, cell growth

23
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

24
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)

25
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

26
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
27
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.

28
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

29
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.

30
Cytokine-inducing components of Gram-positive
bacteria
31
Cytokine-inducing components of Gram-negative
bacteria
32
Cytokine-induction by LPS from periodontopathogens
other than P. gingivalis
33
Cytokines produced by host cells in response to
components/products from periodontopathogens
34
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

35
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

36
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
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