Lecture 14: Cytokines I Flashcards
Cytokines
-small proteins
-control growth and activity of immune-system cells and blood cells =. inflammation response
-coded for by over 100 genes
Cytokine functions
-immune cell proliferation and differentiation
-cell migration
-chemoattractant/chemotaxis
-communication
-cytotoxicity
-effect nearly every biological process
Protein therapeutic cytokines
-interferon a
-interleukin 2
-erythroprotein
interferon a
-multiple sclerosis
-hep C
interleukin 2
cancer
erythropoiten
anemia
Cytokines sender cells
-produce and release cytokines
-macrophage
-B cells
-effector T cells
-Mast cells
-endothelial
-fibroblasts
Cytokine target cells
-Macrophage
-B cell
-tumor cell
-plasma cells
cell-cell communications
-autocrine (same)
-paracrine (nearby)
-distant (far)
cytokine storm
-too many cytokines
-over response
-damage tissue
-deadly
diseases involve cytokines
-autoimmune
-metabolic disease
-cancer
-sepsis
Cytokine nomenclature
-could be anything tbh
-based on function, secretion, or target
-most are IL
Interleukin
-between blood cells
Colony stimulating factor (CSF)
-hematopoietic stem cell signaling to develop blood typeshe
chemokines
-direct immune cells to places in body
tumor necrosis factor (TNF)
-regulate inflammation
Interferons
signal defense against viruses
cytokine receptor types
-based on common structural features:
-Ig superfamily
-Interferon receptors
-TNF receptors
-chemokine receptors
-TGF receptor
-hematopoietin receptors
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
