lecture 8 cytokines
TRANSCRIPT
-
8/13/2019 Lecture 8 Cytokines
1/38
Course 8
Cytoki
nes &
Adhesion molecules
-
8/13/2019 Lecture 8 Cytokines
2/38
Denitions & Nomenclature
mono kineslympho kines
cyto kines
inter leukins = IL-nbiologic response modiers
polypeptides produced in response to microbes/Ag that regulate the immune response
-
8/13/2019 Lecture 8 Cytokines
3/38
Denitions & Nomenclature
Text
Abbas, Cellular & Molecular Immunology, 2007
-
8/13/2019 Lecture 8 Cytokines
4/38
General properties - secretion is brief & self-limited event
- actions are pleiotropic and redundant
- inuence the synthesis of other cytokines - cascades
- actions are local and systemic ( autocrine-paracrine-endocrine)
- initiate actions by binding to specic membrane receptors on target cells
- actions are regulated by external signals
- actions induce gene expression resulting in acquisition of new functions/cell proliferation
- induced cell responses are strictly regulated by feedback inhibitory mechanisms
C Y T O K I N E
S
-
8/13/2019 Lecture 8 Cytokines
5/38
Functional categories
Abbas, Cellular & Molecular Immunology, 2007
-
8/13/2019 Lecture 8 Cytokines
6/38
Cytokine receptors - Type 1 ( hemopoietin)
Abbas, Cellular & Molecular Immunology, 2007
- 2x cysteine residues
- Trp-Ser-X-Trp-Ser (WSXWS) - binds type 1 cytokines - induce Jak/STAT cell signaling
IL-r
Neuropeptide- r CSF-r
-
8/13/2019 Lecture 8 Cytokines
7/38
Cytokine receptors - Type II
Abbas, Cellular & Molecular Immunology, 2007
- 4x cysteine residues - 2 extracellular domains - no WSXWS - binds type 1 cytokines - induce Jak/STAT cell signaling
IL-r IFN-r
-
8/13/2019 Lecture 8 Cytokines
8/38
Cytokine receptors - IL-1 receptor
Abbas, Cellular & Molecular Immunology, 2007
- Toll-like/IL-1 (TIR) - Th1 - activatory IL-1
- Th2 - inhibitory IL-1- induce Jak/STAT cell signaling - requires IL-1RAP for signal tr.
IL-1
-
8/13/2019 Lecture 8 Cytokines
9/38
Cytokine receptors - TNF receptor
Abbas, Cellular & Molecular Immunology, 2007
- large family of proteins * - Cys-rich domains
- induce apoptosis - TRAF sign. pathway
TNF
* - some of which are NOT cytokines receptors
-
8/13/2019 Lecture 8 Cytokines
10/38
Cytokine receptors - TNF receptor
Abbas, Cellular & Molecular Immunology, 2007
- large family of proteins * - Cys-rich domains
- induce apoptosis - TRAF sign. pathway
TNF
* - some of which are NOT cytokines receptors
-
8/13/2019 Lecture 8 Cytokines
11/38
Cytokine receptors - serpentine receptors
Abbas, Cellular & Molecular Immunology, 2007
- 7 transmb. alpha-helical r - G-protein coupled r - induce apoptosis
* - some of which are NOT cytokines receptors
Chemokines
-
8/13/2019 Lecture 8 Cytokines
12/38
Role of cytokines
INNATE immunity ADAPTIVE immunity
MEDIATION OF
TNF; IL-1
Chemokines (CCL)
IL-12; Type 1 - IFNs
IL-10; IL-6; IL-15
IL-23; IL-27
IL-2; IL-4; IFN-gamma
TGF-beta; IL-13;
IL-17; IL-5
HEMATOPOIESIS
c-KIT ligand
Epo
IL-7; IL-3
GM-CSF
-
8/13/2019 Lecture 8 Cytokines
13/38
Role of cytokines
INNATE immunity ADAPTIVE immunity
MEDIATION OF
TNF; IL-1
Chemokines (CCL)
IL-12; Type 1 - IFNs
IL-10; IL-6; IL-15
IL-23; IL-27
IL-2; IL-4; IFN-gamma
TGF-beta; IL-13;
IL-17; IL-5
HEMATOPOIESIS
c-KIT ligand
Epo
IL-7; IL-3
GM-CSF
-
8/13/2019 Lecture 8 Cytokines
14/38
Role of cytokines
INNATE immunity ADAPTIVE immunity
MEDIATION OF
TNF; IL-1
Chemokines (CCL)
IL-12; Type 1 - IFNs
IL-10; IL-6; IL-15
IL-23; IL-27
IL-2; IL-4; IFN-gamma
TGF-beta; IL-13;
IL-17; IL-5
HEMATOPOIESIS
c-KIT ligand
Epo
IL-7; IL-3
GM-CSF
-
8/13/2019 Lecture 8 Cytokines
15/38
Role of cytokines
INNATE immunity ADAPTIVE immunity
MEDIATION OF
TNF; IL-1
Chemokines (CCL)
IL-12; Type 1 - IFNs
IL-10; IL-6; IL-15
IL-23; IL-27
IL-2; IL-4; IFN-gamma
TGF-beta; IL-13;
IL-17; IL-5
HEMATOPOIESIS
c-KIT ligand
Epo
IL-7; IL-3
GM-CSF
-
8/13/2019 Lecture 8 Cytokines
16/38
Tumor
Necrosis
Factor (TNF)
- No. 1 mediator of inamation in response to G(-) bacteria
- Responsible for the majority of systemic complications in infection- No.1 source are activated mononuclear phagocytes
- No. 1 function - recruitment of neutrophils and monocytes into sites of infection
- induces expression of selectins/integrins/chemokines in the endothelial cells
- In septic shock - prime inducer of fever (hypothalamus)
- high circulating levels - major methabolic disturbances (severe hypoglicemia)
- high circulating levels - muscle and fat cells wasting - cachexia
-
8/13/2019 Lecture 8 Cytokines
17/38
Tumor
Necrosis
Factor (TNF)
-
8/13/2019 Lecture 8 Cytokines
18/38
Interleukin 12 (IL-12)
- No. 1 mediator of early innate immune response to intracellular microbes
- stimulates the production of IFN-gamma by NK and T-cells
- together with IFN-gamma promotes differentiation of CD4Tcells into IFN(Th1) cells
- Enhances the cytotoxic function of NK and CD8 Tcells (CTLs)
-
8/13/2019 Lecture 8 Cytokines
19/38
Interleukin 12 (IL-12)
-
8/13/2019 Lecture 8 Cytokines
20/38
Chemokines - regulators of lymphocyte trafking from blood to tissue
- recruit immune cells to the site of injury/infection
- regulate the trafc of lymphocyte through lymphoid organs
Numer/location of N-Cys residue
-
8/13/2019 Lecture 8 Cytokines
21/38
Chemokines - regulators of lymphocyte trafking from blood to tissue
- recruit immune cells to the site of injury/infection
- regulate the trafc of lymphocyte through lymphoid organs
Numer/location of N-Cys residue
CC chemo CX3C chemoCXC chemoC chemo
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
22/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
http://artnscience.us/peripheral lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://www.youtube.com/watch?v=9wkJx2elQQ0http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
23/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
p p p
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://www.youtube.com/watch?v=9wkJx2elQQ0http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
24/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
p p p
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
25/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
p p p
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://www.youtube.com/watch?v=9wkJx2elQQ0http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
26/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
http://artnscience.us/peripheral-lt.htmlxt
http://www.youtube.com/watch?v=9wkJx2elQQ0http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
27/38
Chemokines - most important functions
Leukocyte recruitment - infection
MOVIE
http://artnscience.us/peripheral-lt.htmlxt
http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
28/38
Chemokines - most important functions
Lymphocyte trafking - adaptive immune response
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
29/38
Chemokines - most important functions
Lymphocyte trafking - adaptive immune response
http://artnscience.us/peripheral-lt.htmlxt
http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt -
8/13/2019 Lecture 8 Cytokines
30/38
Chemokines - most important functions
Lymphocyte trafking - adaptive immune response
Abbas Cellular & Molecular Immunology 2007
-
8/13/2019 Lecture 8 Cytokines
31/38
Interleukin 2 (IL-2) - key player (required) for survival and function of T-regulatory cells
- stimulates survival, proliferation and differentiation of Ag-activated T-cells
- promotes proliferation and differentiation of NK cells
Abbas, Cellular & Molecular Immunology, 2007
Abbas Cellular & Molecular Immunology 2007
-
8/13/2019 Lecture 8 Cytokines
32/38
Interleukin 2 (IL-2)
- key player (required) for survival and function of T-regulatory cells
- stimulates survival, proliferation and differentiation of Ag-activated T-cells
- promotes proliferation and differentiation of NK cells
Abbas, Cellular & Molecular Immunology, 2007
-
8/13/2019 Lecture 8 Cytokines
33/38
Interleukin 4 (IL-4)
- major stimulus for production of IgE Ab
- key player in the development of Th2-cells from naive CD4helper Tcells - signature cytokine
- functions as an autocrine growth factor for Th2-cells
- +IL-13 functions to activate macrophages by an alternate (non-IFNgamma) mechanism
-
8/13/2019 Lecture 8 Cytokines
34/38
Interferon gamma (IFN-gamma)
- principal macrophage-activating cytokine
- produced by CD4, CD8 and NK cells
- promotes differentiation of CD4 T cells into Th1-cells
- stimulates expression of MHC-I/II + costimulation on APCs
-
8/13/2019 Lecture 8 Cytokines
35/38
Transforming growth factor beta (TGF-beta)
- Principal action - inhibition of lymphocyte activation/proliferation
- stimulates production of IgA Ab - skews B cells to this isotype
- can induce apoptosis (SMAD or DAXX)
- +IL-13 functions to activate macrophages by an alternate (non-IFNgamma) mechanism
-
8/13/2019 Lecture 8 Cytokines
36/38
Stem cell factor (c-KIT ligand)
- interacts with c-KIT (tyrosine kinase membrane receptor) present on stem cells
- required for life (knock-out with c-KIT incompatible with life)
- c-KIT rst described 1987 (Axel Ulrich)
Abbas, Cellular & Molecular Immunology, 2007
-
8/13/2019 Lecture 8 Cytokines
37/38
Other cytokines in control of hematopoiesis
gy
Abbas, Cellular & Molecular Immunology, 2007
-
8/13/2019 Lecture 8 Cytokines
38/38
Take home message
- proteins that mediate crucial processes of innate/adaptive immunity
- produced in response to inamation - act in a autocrine/paracrine/endocrine fashion
- actions are mediated by high afnity receptors engaging Jak/STAT; TIR/IRAK; TRAF pathways
- TNF/IL-1 (acute inamation to microbes); Type 1 IFNs (antiviral citokines); IL-10 (inhibit DCs)
- IL-12 stimulate production of IFN-gamma inside macrophages
- IL-2 - Tcell growth factor; IL-4 (development of Th2 Tcells); IL-5 (eosinophil activator)
- TGF-beta (T-cell inhibitor); IL-13 (IgE production)
- c-KIT Ligand/IL-7 - key roles in hematopoiesis
- excessive production of cytokines leads to pathologic consequences
- administration of cytokine inhibitors - potential approach to modify biologic response