Lecture 14: Cytokines I Flashcards by Brooke Thornburg

Cytokines

-small proteins
-control growth and activity of immune-system cells and blood cells =. inflammation response
-coded for by over 100 genes

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Cytokine functions

-immune cell proliferation and differentiation
-cell migration
-chemoattractant/chemotaxis
-communication
-cytotoxicity
-effect nearly every biological process

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Protein therapeutic cytokines

-interferon a
-interleukin 2
-erythroprotein

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interferon a

-multiple sclerosis
-hep C

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interleukin 2

cancer

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erythropoiten

anemia

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Cytokines sender cells

-produce and release cytokines
-macrophage
-B cells
-effector T cells
-Mast cells
-endothelial
-fibroblasts

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Cytokine target cells

-Macrophage
-B cell
-tumor cell
-plasma cells

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cell-cell communications

-autocrine (same)
-paracrine (nearby)
-distant (far)

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cytokine storm

-too many cytokines
-over response
-damage tissue
-deadly

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diseases involve cytokines

-autoimmune
-metabolic disease
-cancer
-sepsis

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Cytokine nomenclature

-could be anything tbh
-based on function, secretion, or target
-most are IL

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Interleukin

-between blood cells

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Colony stimulating factor (CSF)

-hematopoietic stem cell signaling to develop blood typeshe

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chemokines

-direct immune cells to places in body

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tumor necrosis factor (TNF)

-regulate inflammation

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Interferons

signal defense against viruses

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cytokine receptor types

-based on common structural features:
-Ig superfamily
-Interferon receptors
-TNF receptors
-chemokine receptors
-TGF receptor
-hematopoietin receptors

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pleiotropic

-same cytokine can have diff target cells with different biological outcomes

cytokine cellular effects

-pleiotropic
-redundant
-cascade effect

redundancy

-different cytokines produce similar effects

cascade effect

-cytokines stimulate production of other cytokines

Interleukins (IL-2, IL-6, etc)

-secreted by one leukocyte and acting on other leukocytes in inflammatory response
-between blood cells
-regulate growth/differentiation of hematopoietic cells
-some have 4 helix bundle structure

Chemokines

-cell migration during development, immune response, cancer
-some ILs are chemokines (CXCL8) produced by macrophages (IL-8)
-monomeric or homodimeric
-receptors are GPCRs

Tumor necrosis Factor (TNF)

-released by macrophages during acute inflammation -lead to necrosis and apoptosis -transmembrane form (mTNFa) and soluble form (sTNFa) -ribbon structure: beta sheet bell shape

mTNF-a

-on monocytes and macrophages -binds to 2 TNF receptors on tissue cells (juxtacrine)

sTNF-a

-results from cleavage -binds selectively to one TNF receptor

interferons (IFN)

-regulate signaling among infected cells -interfere with viral replication -activate macrophages and NK cells -upregulate antigen presentation -fever symptoms -3 types based on receptors they bind (I-III) -helical structure

Cytokines are involved in anti-inflammatory pathways and are therefore

a possible approach for treatent of pain from inflammation such as peripheral nerve injury

Cytokine receptors

-some with multiple chains -activated upon binding -associated with immune disease -overly expressed on tumor cells

Types of cytokine receptors

-Ig family -hemopoietic growth factor -interferon -tumor necrosis factor -GPCR -IL-17 receptor family

Ig family of receptors

-lots of cells -Ig domain -IL-1 and IL-18 receptors

Hemopoitec growth factor (type 1) family

-certain conserved motifs in extracellular domain -IL-2 receptor and IL-6 receptor

SCID

-IL-2 difficiency

Interferon (type 2) family

members are receptors for IFN B and y

Tumor necrosis factor (type 3) family

-cysteine-rich extracellular binding domain -binds TNF and some NON-cytokine ligands

GPCR family

bind chemokines

IL-17R family

-little homology with any other family -induce proinflammatory responses and allergic reactions -may treat rheumatoid arthritis, psoriasis, inflammatory bowel disease -signaling pathways not well defined -IL-17RA, B,C,D,E

Chemokines

-subset of cytokines -direct migration of leukocytes to infection -46 proteins -23 GPCRs -chemoattractant

chemokine function

-immune surveillance -promote angiogenesis and tissue differentiation -proinflammatory (release stimulated by other cytokines)

Chemokine receptor structure

-GPCR with 7TMs -solid surface/ receptor ribbon that chemokine fits in -extensive binding surface comprising GPCR external loops and extending into transmembrane helical region

vMIP

-viral chemokine antagonist from herpes -thought to bind like CXCL12

cytokine receptor cross-reactivity

-with multiple diff cytokines -receptors have multiple different cytokine ligands

Type I cytokine receptors

-extracelllular domains -receptor: 2 chains, IFNAR1 and IFNAR2 -in complex with cytokine IFNa -multiple interactions of dif protein chains might be why cross reactivity

Type 1 cytokine receptor intracellular domains

-atypical -long disordered region: lots of residues with no strucutral order or kinase activity -intracellular signals transduced by binding effector proteins