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inflammation is a reaction to injury or infection
EFFECTORS
SIGNALS
SENSORS PLASMA
BLOOD VESSELSINFLAMMATORYLEUKOCYTES
INJURYOR INFECTION
EPITHELIAL CELLSMACROPHAGESMAST CELLS
CYTOKINES, PROSTAGLANDINS, ETC.
mechanisms of feverMICROBES + MACROPHAGES
IL-1, TNFIL-6
PGPGEEPGPGEE
• SYMPATHETIC NERVES• VASOCONSTRICTION IN THE SKIN• DECREASED HEAT LOSS
NEUTROPHIL MOVEMENTS IN VENULES NEAR INFLAMED SITES
WHAT ATTRACTS LEUKOCYTES TO SITES OF INFLAMMATION?
IL-8 (NEUTROPHILS)MCP-1
(MONOCYTES)OTHER
CHEMOKINES
History for the research of the cytokines
In1974 ， denominated cytokine
cytokinology ；
international cytokine society
《 Cytokine 》
Companies for developing cytokines
In 1957 ， Interferon （ IFN ） was found
In 1969 ， termed lymphokine
Introduction to cytokinesCategories of CKs Biological function of CKsCytokines related diseasesMedical 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.
Cytokine gene
Inducing stimulus
Cytokine-producing cell
Cytokine
Gene activation
Receptor
signal
Biological effects
Overview of the induction and function of Cytokine
General properties of CKsSmall 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 actions1) Pleiotropy Acts on more than one cell type2) 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 CKsCKs are classified into 6 functional
categoriesInterleukin (IL)Interferon (IFN)Tumor necrosis factor (TNF)Colony stimulating factor (CSF)ChemokineGrowth factor (GF)
Interleukin, ILIL 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-2
IL-4
IL-13
AUTOCRINE IL-2DRIVES CLONALEXPANSION OFT CELLS
PARACRINE IL-4DRIVES CLONALEXPANSION OFB CELLS
B cell
Ag-specific
stimulusT cell
IL-2
IL-4
AUTOCRINE OR PARACRINEIL-4 OR IL-13 DRIVES Ig CLASS SWITCHING TO IgE
IgG1 IgE
Interferon, IFNIFNs 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.
© New Science Press Ltd. 2004
Tumor necrosis factor, TNFTNF 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.
【商 品 名】纳科思【通 用 名】注射用重组改构人肿瘤坏死因子【规 格】冻干粉针剂 500 万 IU/ 瓶【适 应 症】非小细胞肺癌【批准文号】国药准字 20030065
纳科思联合化疗药物治疗肺癌、头颈部癌、消化道癌、泌尿系统恶性肿瘤的疗效显著优于单纯化疗。
该产品是上海赛达生物药业股份有限公司与中国人民解放军第四军医大学合作研究开发的新产品， 2003 年 8月正式上市，是全球第一个上市的全身用药的肿瘤坏死因子产品。
Colony-stimulating factors, CSFStimulates 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 .
G-CSFGM-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 (), CC (), C (), CX3C (), based on structural characteristics (cysteine residues).
IL-8 CXC neutrophils MCP-1 CC monocyte Lymphotactin C lymphocyte Fractalkine CX3C lymphocyte
The Chemokine Fold
G.M.Clore & A.M.GronenbornIL8
C
N
Growth factors, GFPromote the proliferation and
differentiation of cells.Include TGF-
、 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 IFNMediation 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: IL-12, IFN- ,IL-4.
*Enhancing the activity of effector cells: IFN-, IL-2 .
*Inhibiting immune response: TGF-, IL-10
TNF
© New Science Press Ltd. 2000
or mast cell
Inflammatory mediators:Cytokines, chemokines and lipids
Downloaded from: StudentConsult (on 1 June 2006 03:50 PM)
© 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 diseasesBacterial septic shock
Blood pressure drops, clots form, hypoglycemia ensues, patient dies
LPS triggers results in TNF releaseTNF induces IL-1 which induces IL-6 and IL-8
Bacterial toxic shock and related diseasesSuperantigens 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 cancersSome cancer cells secrete cytokines
Medical application of cytokines
rIFN-: Intron-A, Referon-ArIFN-: ProkinerEPO: EpogenrG-CSFrGM-CSF: AcimmuneHuman TNF McAb: HumiraTM
