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Chapter 12
Cytokines
Dec 21, 2006
Cytokines:
- Any of numerous secreted, low-molecular-weight
(usually < 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
Overview of
the Induction
and Function
of Cytokines
(can mediate
biological effects
at pM concentrations)
(Kd ~ 10-10 to 10-12 M)
Most Cytokines Exhibit Autocrine and/or Paracrine
Action; Fewer Exhibit Endocrine Action
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.
How to keep the Ag-nonspecific cytokines from
activating cells in a nonspecific fashion during an
adaptive immune response ?
1. 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.
2. Cytokines secreted at the junction of these interacting cells
reach high enough local concentrations to affect the
interacting cells, but not more distant cells.
3. 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.
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 (環境)
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.
Cytokine Receptor Families
(a)
(c)
(b)
(d)
(e)
Subfamilies of Cytokine Receptors Have
Signaling Subunits in Common
c
IL-2R Is the Most Thoroughly
Studied Cytokine Receptor
3 Forms of the
IL-2 Receptor
(IL-2Ra = CD25)
( = TAC: T-cell activation)
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 兩面神
Cytokine Antagonists:
IL-1Ra: IL-1 receptor antagonist
Soluble cytokine receptors: sIL-2R, sIL-4R,
sIL-6R, sIL-7R,
sIFN-R, sTNF-R,
sLIFR
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.
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
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
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.
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
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 Agspecific bridge between the worm and the eosinophils. The
attack of the eosinophil on the worm is triggered by crosslinking of the FceR-bound IgE.
Cytokine Environment Determines the
Development of TH1 and TH2 Responses
activated by
intracellular
pathogens and
LPS
IFN
IFN
cross regulation
T-Bet and GATA-3 play important roles
in cross-regulation of TH responses