lecture 8 cytokines

8/13/2019 Lecture 8 Cytokines

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Course 8

Cytoki

nes &

Adhesion molecules


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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


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Denitions & Nomenclature

Text

Abbas, Cellular & Molecular Immunology, 2007


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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


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Functional categories



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Cytokine receptors - Type 1 ( hemopoietin)


- 2x cysteine residues

- Trp-Ser-X-Trp-Ser (WSXWS) - binds type 1 cytokines - induce Jak/STAT cell signaling

IL-r

Neuropeptide- r CSF-r


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Cytokine receptors - Type II


- 4x cysteine residues - 2 extracellular domains - no WSXWS - binds type 1 cytokines - induce Jak/STAT cell signaling

IL-r IFN-r


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Cytokine receptors - IL-1 receptor


- 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


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Cytokine receptors - TNF receptor


- large family of proteins * - Cys-rich domains

- induce apoptosis - TRAF sign. pathway

TNF

* - some of which are NOT cytokines receptors


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Cytokine receptors - TNF receptor


- large family of proteins * - Cys-rich domains

- induce apoptosis - TRAF sign. pathway

TNF



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Cytokine receptors - serpentine receptors


- 7 transmb. alpha-helical r - G-protein coupled r - induce apoptosis


Chemokines


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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


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Role of cytokines


MEDIATION OF

TNF; IL-1

Chemokines (CCL)


IL-10; IL-6; IL-15

IL-23; IL-27


TGF-beta; IL-13;

IL-17; IL-5

HEMATOPOIESIS

c-KIT ligand

Epo

IL-7; IL-3

GM-CSF


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Role of cytokines


MEDIATION OF

TNF; IL-1

Chemokines (CCL)


IL-10; IL-6; IL-15

IL-23; IL-27


TGF-beta; IL-13;

IL-17; IL-5

HEMATOPOIESIS

c-KIT ligand

Epo

IL-7; IL-3

GM-CSF


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Role of cytokines


MEDIATION OF

TNF; IL-1

Chemokines (CCL)


IL-10; IL-6; IL-15

IL-23; IL-27


TGF-beta; IL-13;

IL-17; IL-5

HEMATOPOIESIS

c-KIT ligand

Epo

IL-7; IL-3

GM-CSF


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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


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Tumor

Necrosis

Factor (TNF)


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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)


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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


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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


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Chemokines - most important functions

Leukocyte recruitment - infection

MOVIE

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


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MOVIE

p p p



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MOVIE

p p p

http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt


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MOVIE

p p p



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MOVIE

http://www.youtube.com/watch?v=9wkJx2elQQ0http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt


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MOVIE

http://www.youtube.com/watch?v=9wkJx2elQQ0http://artnscience.us/peripheral-lt.htmlxthttp://artnscience.us/peripheral-lt.htmlxt


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Lymphocyte trafking - adaptive immune response



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Abbas Cellular & Molecular Immunology 2007


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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


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- 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



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- 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


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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


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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


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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)



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Other cytokines in control of hematopoiesis

gy



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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

lecture 8 cytokines

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