Chapter 12 Cytokines

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Chapter 12 Cytokines
Dec 21, 2006
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• Cytokines
• Any of numerous secreted, low-molecular-weight
• (usually lt 30 kDa) proteins or glycoproteins
• that regulate the intensity and duration of the
• immune response by exerting a variety of
  effects
• on lymphocytes and other effector cells.
• Role in cell-to-cell communication
• Messengers of the immune system

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Overview of the Induction and Function of
Cytokines
(can mediate biological effects at pM
concentrations)
(Kd 10-10 to 10-12 M)
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Most Cytokines Exhibit Autocrine and/or Paracrine
Action Fewer Exhibit Endocrine Action
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• Interaction of TH cells
• with macrophages,
• leading to release of
• numerous cytokines
• Although a variety of cells
• can secrete cytokines, the two
• principal producers are the
• TH cell and the macrophage.

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• How to keep the Ag-nonspecific cytokines from
• activating cells in a nonspecific fashion during
  an
• adaptive immune response ?
• Cytokine receptors are often expressed on a cell
  only after that cell has interacted with antigen.
  In this way, cytokine activation is limited to
  Ag-activated lymphocytes.
• Cytokines secreted at the junction of these
  interacting cells reach high enough local
  concentrations to affect the interacting cells,
  but not more distant cells.
• The half-life of cytokines is usually very short,
  ensuring that they act for only a limited period
  of time and thus over a short distance.

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It should be kept in mind 1. Most of the listed
functions (Table 12-1) have been identified from
analysis of the effects of recombinant cytokines,
often at non-physiologic concentrations, added
individually to in vitro system. 2. In vivo,
however, cytokines rarely, if ever, act alone. 3.
Instead, a target cell is exposed to a milieu
(??) containing a mixture of cytokines,
whose combined synergistic or antagonistic
effects can have very different
consequences. 4. Cytokines often induce the
synthesis of other cytokines, resulting in
cascades of activity.
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Cytokine Receptor Families
(a)
(b)
(c)
(d)
(e)
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Subfamilies of Cytokine Receptors Have Signaling
Subunits in Common
?c
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IL-2R Is the Most Thoroughly Studied Cytokine
Receptor
3 Forms of the IL-2 Receptor
(IL-2Ra CD25) ( TAC T-cell activation)
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JAK-STAT Signal Transduction Pathways of
Cytokine Receptors
JAK Janus kinases STAT signal tranducers and
activators of transcription
Janus Roman god of gates and doors
???
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Cytokine Antagonists IL-1Ra IL-1 receptor
antagonist Soluble cytokine receptors sIL-2R,
sIL-4R,
sIL-6R, sIL-7R,
sIFN-?R, sTNF-?R,
sLIFR
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TH1 and TH2 Responses of TH Cells TH1 response
produces a cytokine profile that
supports inflammation and
activates mainly certain T cells
and macrophages. TH2 response
activates mainly B cells and
immune responses that depend
upon Ab.

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TH1 response - delayed-type
hypersensitivity - activation of TC cells
- production of opsonization-promoting IgG Abs
(i.e., Abs that bind to the high affinity FcRs
of phagocytes and interact with
complement, such as IgG2a in mice) -
promotion of excessive inflammation and tissue
injury
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IFN-?, a cytokine of the TH1 response -
activates macrophages - stimulates macrophages
to a. increase microbicidal activity
b. up-regulate the level of class II MHC
c. secretes cytokines such as IL-12, which
induces TH1 response - induces Ab
class switching to IgG2a (mouse) or IgG1, 2,
3 (human) that supports phagocytosis and
complement fixation - inhibits the expansion of
the TH2 response
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IFN-? and TNF-? - mediate inflammation -
accounts for delayed hypersentivity IFN-? and
IL-2 - promote the differentiation of fully
cytotoxic TC cells from CD8 precursors
This pattern of cytokine production makes the
TH1 subset particularly suited to respond to
viral infections and intracellular pathogens.
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TH2 response - stimulates eosinophil
activation and differentiation - provides
help to B cells - promotes the production of
relatively large amounts of IgM, IgE, and
noncomplement-activating IgG isotypes
- supports allergic reactions
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IL-4, a cytokine of the TH2 response -
promotes Ab class switching to IgG1 (mouse)
or IgG4 (human), which does not activate C -
increases Ab class switching to IgE
(combined with IL-5, promotes eosinophil
activation) Typically, roundworm
infections induce TH2 responses and evoke
anti-roundworm IgE Ab. The Ab bound to the
worm binds to the FceR of eosinophils, thus
forming an Ag- specific bridge between the worm
and the eosinophils. The attack of the
eosinophil on the worm is triggered by cross-
linking of the FceR-bound IgE.
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Cytokine Environment Determines the Development
of TH1 and TH2 Responses
activated by intracellular pathogens and LPS
IFNg
IFNg
cross regulation
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T-Bet and GATA-3 play important roles in
cross-regulation of TH responses