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Cytokines
Weilin Chen, Ph. D.
Institute of Immunology, ZJU
[email protected]
History for the research of the cytokines
 In 1957，Interferon （IFN ） was found
 In 1969， termed lymphokine
 In1974，denominated cytokine
 cytokinology；
international cytokine society
《 Cytokine 》
 Companies for developing cytokines
 Introduction to cytokines
 Categories of CKs
 Biological function of CKs
 Cytokines related diseases
 Medical application of cytokines
Introduction to cytokines
 Cytokine (CK)
Cytokines are small proteins (8-80 KD) that
are secreted by cells and exert biological
activity through specific cell surface
receptors.
Inducing stimulus
Cytokine
gene
Cytokineproducing cell
Cytokine
Receptor
signal
Gene
activation
Overview of the induction
and function of Cytokine
Biological
effects
General properties of CKs
 Small proteins (MW: approx. 15-80 KD)
 Extremely potent, acting at pM or fM
 The production is transient and tightly
regulated
 Autocrine, paracrine or endocrine
 Non-specific and non-MHC restricted
3 MAJOR ROUTES OF CYTOKINE TRAVEL

Cytokine actions
1) Pleiotropy
Acts on more than one cell type
2) Redundancy
More than one cytokine have the same action
3) 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
4) Antagonism
Two or more cytokines work against each other
5 ) The cytokine network
Categories of CKs
CKs are classified into 6 functional categories
 Interleukin (IL)
 Interferon (IFN)
 Tumor necrosis factor (TNF)
 Colony stimulating factor (CSF)
 Chemokine
 Growth factor (GF)
Interleukin, IL
IL-2
 IL 1～38
IL-1
IL-2
IL-4, IL-5, IL-6, IL-13 (Th2 type)
IL-8 (belongs to chemokine family)
IL-10 (Tr, Ts type)
IL-11 (stimulator of platelets)
IL-12 (DC, macrophages, directs Th1)
IL-4
IL-13
AUTOCRINE IL-2
DRIVES CLONAL
EXPANSION OF
T CELLS
Ag-specific
stimulus
IL-2
T cell
IL-4
PARACRINE IL-4
DRIVES CLONAL
EXPANSION OF
B CELLS
AUTOCRINE OR PARACRINE
IL-4 OR IL-13 DRIVES
Ig CLASS SWITCHING
TO IgE
B cell
IgG1
IgE
Interferon, IFN
 IFNs are mediators of the innate immune
response and Th1/CTL responses.
 Groups
Type I IFN: IFN-α and IFN-β
The major source is leukocytes (PDC),
fibroblasts and virus infected cells.
Type II IFN: IFN-γ
IFN-γ is produced by activated T cells and
NK cells.
Production of interferon by infected cells
Anti-viral effects of interferon a/b
© New Science Press Ltd. 2004
Tumor necrosis factor, TNF
 TNF was originally identified (and was so
named) as a substance that can cause the
necrosis of tumors in vivo
 TNF-α and TNF-β
TNF-α is produced
by LPS-stimulated
mononuclear phagocytes and activated T cells.
TNF-β is also termed lymphotoxin ( LT), and is
produced mainly by activated T cells.
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Colony-stimulating factors, CSF
 Stimulates the differentiation and expansion of
bone marrow progenitor cells.
 It is assayed by its ability to stimulate the
formation of cell colonies in culture.
 Includes IL-3, CSF (G-CSF, M-CSF, GM-CSF), SCF,
EPO, TPO, etc .
GM-CSF
G-CSF
Chemokines (chemotactic cytokines)
 Chemokines are a large family of structurally
homologous CKs that stimulate movement
and regulate the migration of leukocytes
from the blood to tissues and within tissues,
and includes about 50 different members.
 Subfamilies: CXC (a), CC (b), C (), CX3C (),
based on structural characteristics (cysteine
residues).
 IL-8
CXC
 MCP-1
CC
 Lymphotactin C
 Fractalkine
CX3C
neutrophils
monocyte
lymphocyte
lymphocyte
The Chemokine Fold
C
N
G.M.Clore & A.M.Gronenborn
IL8
Growth factors, GF
 Promote the proliferation and differentiation of
cells.
 Include TGF-b、EGF、VEGF、FGF、NGF, etc.
vascular endothelial
growth factor (VEGF)
VEGF promotes Tumor Angiogenesis
Biologic functions of CKs (1)
 Anti-bacteria: IL-1, TNF, IL-6, IL-8 and IL-12
 Anti-virus: type I IFN
 Mediation and regulation of adaptive immunity:
*Stimulating the proliferation of lymphocytes:
IFN-, IL-2, IL-7, IL-4, IL-5, IL-15.
*Stimulating the development of lymphocytes: IL12, IFN- ,IL-4.
*Enhancing the activity of effector cells: IFN-, IL2.
*Inhibiting immune response: TGF-b, IL-10
Induction of
Inflammation
following
recognition of
pathogens
or mast cell
Inflammatory mediators:
Cytokines, chemokines
and lipids
TNF
© New Science Press Ltd. 2000
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© 2005 Elsevier
Biologic actions of CKs (2)
 Stimulation of hemopoiesis
SCF → stem cells
CSF → granulocytes and monocytes
IL-4 and GM-CSF →dendritic cells
EPO → erythrocytes
IL-11 and TPO →platelets
IL-7, IL-15 → formation of Tm
 Angiogenesis
IL-8, VEGF, etc.
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
Medical application of cytokines
 rIFN-a: Intron-A, Referon-A
 rIFN-b: Prokine
 rEPO: Epogen
 rG-CSF
 rGM-CSF: Acimmune
 Human TNF McAb: HumiraTM