Lecture 17

Cytokines
 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
 Cytokine nomenclature

 Interleukins (1-18)
 Interferons (a,b,g)

 Others (common names)

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
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
 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
 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
 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 IFNg)
 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)
 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
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
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
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?
Cytokines, growth factors and hormone
signal transduction pathways
The Jak/Stat Signaling Pathway
Involvement of cytokines in the
immune response
 Alert to  Early mediators
infection.tumor/etc. (IFNa/b)
 Recruit cells to site  Chemokines (MIP-
 Specify type of 1a)
immune response  Early & late
 Immune effector mediators (IL-2,
phase IFNg, IL-4, IL-5)
 Immune down-  Down-regulators
regulation (IL-10, TNFg)
 Immune memory  Maintenance of
and resetting the cytokines, etc. (GM-
system CSF, IL-3, IL-7,
etc.)
 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

 Chemokines

 Recruit to sites of infection

 MIP-1a (NK and T cells)
 MIG, RANTES (CD4+T cells)
 IL-8 (neutrophils)
 Eotaxin (eosinophils)
 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
 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
 Cytokine secretion and
biological activities of TH1 and
TH2 Subsets

Type 1 Type 2
Cell-mediated Humoral
Immune response T cell response
(intracellular (parasites)
Organisms) IL-2 IL-4
IFN-g IL-5
TNF
 Down regulators

 IL-10, IL-11, TGF-b

 Inhibit proliferation, cytokine
production
 Produced by both innate and adaptive
cells
 Maintenance cytokines

 GM-CSF, IL-3, IL-7, IL-9, etc.

 Induce cell differentiation, cell growth
 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
 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)
 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 APC’s, 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
 Components of the immune
system
ab ab Help
g B cell
T cell T cell
T cell
CD8 CD4

Inflammatory
Cytotoxic cytokines
? Antibody
T cells

Intra- and Extracellular Inflammatory

Mechanisms to Destroy or Inactivate Pathogens

Macro- Interferon & Complement

Granulo-
phages Non-lymphoid
cytes
Cytokines
Adapted from Marrack and Kappler, 1994
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.
 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
 Cytokine-inducing components of
Periodontopathogens
 Taken from Wilson, M., Reddi, K., Henderson, B. 1996.
Cytokine-inducing components of periodontopathogenic
bacteria. J. Periodont. Res. 31:393-407.
 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.
Cytokine-inducing components of
Gram-positive bacteria
Cytokine-inducing components of
Gram-negative bacteria
 Cytokine-induction by LPS from
periodontopathogens other than P. gingivalis
 Cytokines produced by host cells in response to
components/products from periodontopathogens
 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
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
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