Transcript Cytokine - Chemotaxis Group

Cytokines
Dr. habil. Kőhidai László
Assoc. Professor
Dept. Genetics, Cell- and Immunobiology
Semelweis University
Chemotaxis - Elective Course
2010/2011 – EM-ED
Cytokines - Definition
• ”Cytokine” (Cohen 1974):
• Molecules capable for chemical
communication between cells;
• Most of them are growth factors or
differentiation inducers;
• Regulators of embryogenesis,
haematopoesis, tissue ‘repair’, inflammatory
and immune functions. E.g. normal growth
and development, wound healing.
• Lymphokines, monokines, chemokines
Characterization of cytokines
Summary
• Proteines /
glycoproteines
• Narrow spectrum
• Work in solved form
• Network
• Low M.W.
• Multifunctionality
• Inducibility
• Synergy
• Effects elicited on low
cc.
• Progression factor
• Specific receptors
• Competency factor
Grouping - Functions
• Natural immunity and inflammation
(IFN, TNF, IL-1, IL-6, chemokines)
• Regulating of lymphocyte activity,
differenctiation
(IL-2, IL-5, IL-6)
• Maturation of immune cells
(IL-3, GM-CSF)
Characteristics
• Low M.W. 15-25kDa
• Products of leukocytes – BUT other cells can also
produce them
• Production induced by
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infectious substances and toxins (e.g. LPS)
tissue damage (thrombocyte aggregation)
immune iductions (stages of hypersensitivity)
other cytokines e.g. IL-1 (pro-inflammatory cytokines)
• Constitutive – e.g. IL-16, IL-18, EPO, M-CSF
Characteristics
•
Majority of cytokines are released by the cells before action
BUT there are
 membrane bound forms (TNF),
 pooled in i.c. vesicles i.c. (mast cells vagy thrombocyte)
 stored in extra-cellular matrixban (TGF-beta) – rapid release and
action
•
Narrow action radius
 autocrine – cytokine produced by the cell acts on the producer cell
 paracrine – cytokine acts on the neighbour cells of the producer cell
 endocrine – cytokine acts on cells far from the producer cell
IL-1 from site of injury to thalamus – regulation of temperature
IL-6 from site of injury to liver – acut phase reaction
Erythropoetin from kidney to bone marrow – RBC differentiation
Macrophage
Cytotoxicity ^
Monokine prod. ^
Adhesion mol. ^
Autocrine
IL-1
T cell
Activation ^
IL-2R ^
Lymphokines ^
Paracrine
Endocrine Prostaglandins
Pain threshold
Brain
Fever
Characteristics
• Effects on low concentrations :
10-12 – 10-9 M
! 10 IL-1 molecules are enough to induce IL-2
synthesis in T cells !
! 50 IFN gamma molecules are enough to induce
anti-viral effects !
Receptors
• Specific receptors: high affinity, inducibility,
specific intracellular signal-transduction and
second messenger pathways.
• Cytokine networks: cytokines are never produced
alone, their synthesis is controlled by the balance of
positive and negative signals.
inflammation
Immunesuppression
Defense against
infections
Autoimmunity,
rejection
Characteristics
• Synery : combined effetc of two or more cytokines is higher
than the simple summary of the individual effects
• Antagonism : cytokines can block each other
e.g. IL-4 and IFN-g.
• Multifunctionality: (pluripotent , pleiotrope)
several cytokines possess more, different
effects on the diverse target cells
• Progressive factor:
cytokines induce cell proliferation
(IL-2, IL-3, IL-5)
• Competency factor:
inducing of differentiation
(IL-1, IL-4, IL-6)
Nomenclature
Factors (names) describe the function - Historical
 colony stimulating factor CSF
 tumor necrosis factor TNF
 transforming growth factor TGF
Classification based on characteristic gene sequence
– result of joint agreement
 IL-1 – IL-24
Names describing the structure and function
 chemotactic factors - ‘chemokins’.
Regulation
• DNA-level
 genes turned on continously e.g. M-CSF, G-CSF,
SCF, IL-6, Epo génjei
 other genes of cytokines are turned off
 co-ordinated expression e.g. IL-3, IL-4, IL-5,
GM-CSF genes on 5. Chrs q
• Post-transcription level
• Post-secretion level
 short half life time in serum e.g. TNF = 15min
 soluble cytokine receptors, e.g. sTNF-R
• Target cell
 up- and down-regulation of receptors
 induction or amplification of inflammation by i.e. proinflammatory cytokines
Examples
IL-1 – produced by all cells possessing nucleus, its spectrum is
wide, it has several target cells.
In vivo effects: hypotensio, fever, loss of weight, neutropoenia
and acut phase reaction.
The chief function is elicited as a factor released from dendritic
cells.
Promotes proliferation of T lymphocytes.
IL-3 – haematopoetic growth factor, inducer of colony formation in
erythroid, megakaryocyte, neutrophil, eosinophil, basophil, mast cell
and monocyte cell lines.
Examples
IL-6 – multifunctional cytokine, produced by lymphoid and
non-lymphoid cells. Regulator of B-cell funkcions,
haematopoesis and the acut phasis reakction.
IL-8 - cytokine released in inflammation, several cells can produce it,
It works as chemoattractant in neutrophils.
Can also influence activity of basophils and some subpopulations
of lymphocytes.
Effective angiogen factor.
Examples
IL-12 – important in responses against intracellular pathogens.
Inducer of IFN gamma synthesis in T-cells and in NK cells.
Increases the NK and ADCC activity.
Inducer of proliferation and differentiation in Th1 CD4 cells.
Clinical significance
• auto-immune diseases
• infections
• immune-defficiencies
• malignant tumors