inflammatory mediators corrigan
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KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Inflammatory mediators
Dr Chris Corrigan
Reader/Consultant
GKT School of Medicine
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Mediators of Inflammation
• Cytokines
• Chemokines
• Lipid mediators (leukotrienes, prostaglandins)
• Neuropeptides
• Endothelin and NO
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokines
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokines (1)
• Soluble (glyco)proteins produced by leucocytes and other cell types
• Chemical communicators between cells, but usually not end effector molecules
• Bind to specific receptors on the surface of target cells
• Most are growth/differentiation factors for haematopoietic cells; some have systemic effects
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokines (2)
• Pleiotropicitiy and redundancy of functional effects
• Tend to mediate localised effects (very short half-life in circulation), although some act systemically
• Receptors typically comprise two or more polypeptide chains which can be grouped into families
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokines (3)
• Act not singly but in patterns• Typically , any one cytokine will affect the
expression of other cytokines and/or their receptors
• Problem of implicating particular cytokines in disease processes:Correlation with disease severityUse of agonists and antagonists
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Regulation of cytokine expression
• Constitutive (steady state haematopoiesis, e.g. M-CSF, G-CSF, SCF, IL-6)
• Stored pre-synthesised:
In granules (e.g. GM-CSF, TGF-On membranes (e.g. TNF-)
Complexed to extracellular matrix (e.g. TGF-)• Most are not constitutively expressed but synthesised
rapidly in response to stimulation and/or other cytokines
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Other cytokine control mechanisms
• Processing (cleavage, precursors)
• Sequestration
• Soluble binding proteins (including soluble receptors)
• Naturally occurring antagonists (IL-1RA)
• Modulation of receptors
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokine receptor superfamilies
• Ig constant region-like domains (C1, C2)
• Complement control protein domains
• Fibronectin type III domains (FNIII)
• Cytokine receptor domains (CK)
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokine receptor superfamiliesSuperfamily Receptors for Common structureCytokine receptor IL-2 (), IL-4, Single spanning membrane
IL-3/5 (), IL-6, glycoporteins with CK,IL-9, IL-12, etc. FNIII and C2 Ig domains
Interferon receptor IFN-, IL-10 SSMG, FNIII domainsImmunoglobulin IL-1, IL-6, FGF, Domains containing the
M-CSF, SCF “Ig fold”Protein tyrosine EGF, PDGF, M-CSF Intracellular PTK domainskinase receptor SCF, FGFNGF receptor NGF, TNF-I/II 3-4 cysteine-rich repeats in
extracellular moleculeG-protein coupled C5a, PAF, 7 transmembrane domains7 transmembrane IL-8 and chemokines with 3 extra- and 4 intra-spanning receptor cellular loopsComplement protein IL-2(), complement Multiple repeats short
domains
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
“Pro-inflammatory” cytokines: IL-1, TNF-, IL-6
• Broad range of pro-inflammatory properties locally and systemically
• Cachexia, fever, neutrophilia, acute-phase response
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-1 (1)
• Two forms, IL-1 with only 20% homology but very similar activity
• Pro-peptides cleaved extracellularly by neutral proteases• Natural inhibitor IL-1RA• Monocyte/macrophages, keratinocytes, epithelium, T
cells, LGL, B cells, endothelium, Langerhans, dendritic, fibroblasts, neutrophils, eosinophils, smooth muscle, etc.
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-1 (2)
• Stimuli: toxins, haemaggluitinins, C5a, TNF-, antigen-specific T cell contact
• Two receptors IL-RI/II (Ig superfamily) on leucocytes, dendritic, fibroblast, neural, endothelium, etc.
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-1 (3)• Effects:
Haematopoiesis
Cytostatic to tumour cells; enhances cell-mediated tumour killing
Other cytokines: IL-6, IL-8, TNF-, etc.
Fever, acute phase response
T cell proliferation following antigen-specific activation
Development of pre-B cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
TNF- and IL-6
TNF- IL-6Source Many ManyStructure Pro-peptide; trimerises Single peptideTumour suppression +++ +Acute phase response +++ ++Receptor TNFRI/II (CD120a/b) Heterodimer
-chain CD126-chain CD130
Receptor distribution Widspread WidespreadEndothelium T cells, B cells,T cells, APC plasma cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-2 and IL-15IL-2 IL-15
Source Activated T cells Multiple (T cell,(B cells) placenta, muscle,
epithelium, monocytes)Actions T cell autocrine/paracrine growth factor
B cell differentiation and Ig secretionMonocytes: IL-1 secretion, cytotoxicity, phagocytosisNK cells, LAK cells
Receptor subunits chains of IL-2R
Receptor subunits other names CD25, Tac, p55 CD122, p75Kd (nM) 10 1000 nonesignal transduction no yes yes
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-4 and IL-13
IL-4 IL-13Source “Th2-type” CD4 T cells “Th1/0/2”-type T cells
Some CD8 T cells Some CD8 T cellsThymocytes, eosinophils, mast cells, basophils
Actions B cells: class II MHC, CD40, CD23, Ig synthesisIgE class switching (not in the mouse!)Growth and proliferation No effect on T cellsof T cells“Th2-type” T cellsMonocytes: complex effects: MHC class II, antigenpresentation, cytokine release
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-10
• Homologous to BCRF1 (EBV genome)• T cells, B cells, monocyte/macrophages• Inhibits cytokine synthesis by “Th1-like” T cells
and NK cells, and antigen presentation and cytokine (TNF-, IL-6, IL-8) production by macrophages
• Enhances activation and maturation of B cells (Ig synthesis), thymocytes, mast cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-3, IL-5 and GM-CSF• Common signal-transducing -chain in heterodimeric
receptors• Clustered on chromosome 5 (with IL-4, M-CSF)• Activated T cells, mast cells, eosinophils• IL-5 is uniquely eosinophil-specific• IL-3: pluripotential stem cells,
granulocyte/macrophage/erythroid/platelet precursors• GM-CSF: mature granulocytes and monocytes
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-12
• Heterodimer 35/40 kDa
• Induces IFN- synthesis, NK and LAK activity independently of IL-2 (CMI)
• Induces “Th1-type”, but inhibits “Th2-type” T cell responses
• Inhibits IgE synthesis by B cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interferon-• T cells and NK cells• Antiparallel homodimer• Receptor: single transmembrane protein with accessory protein.
Expressed on T/B cells, APC, granulocytes, epithelial cells, endothelial cells, tumour cells
• Inhibits viral replication• Activates macrophages: tumoricidal, microbicidal, IL-1, IL-6,
TNF-• Class II MHC expression• Prototype “Th1-type” cytokine
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Th1 Th2
IL-2IFN-
IL-4IL-5
TNF-
IL-6
IL-3IL-10GM-CSF
IL-13IL-9?
Cytolysis
Help for IgE synthesisHelp for IgG/A/M synthesis
Th0
TNF-Cytokines
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IFN- IL-4IL-13
Th1
Th2
-
-Th0
IL-12IFN-
M +
IFN-
NK
IL-4IL-13
-
Mast
+
IL-4
+
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-18 Actions
Growth of T cells and NK cells with production of IFN-, TNF-
Synergises with IL-12 to induce IL-18R on T cells and activated B cells causing IFN- release and inhibition of IgE synthesis
Sources
Monocyte/macrophages, intestinal epithelial cells, osteoblasts
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-18 (2)pro-IL-18
18 kDa
caspase 1(IL-1 CE)
Structure: similar to IL-1Receptor: IL-1R related protein
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cytokines and Th1/2 T cell development
Pro-Th1 cytokines Pro-Th2 cytokines
IFN- IL-4IL-12IL-18IFN-
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-16 (1)
Actions
CD4 ligand, causing activation and chemotaxis of CD4 bearing cells (CD4 T cells, monocytes, eosinophils) (“lymphocyte chemotactic factor”)
Resistance to HIV-1 replication (2,4,9 kb transcripts), but not cellular penetration
Sources
Epithelium, T cells, mast cells, macrophages, eosinophils
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-16 (2)
20 kDa 30 kDapro-IL-16
caspase 3
121
HIV-1
tetramers
CD4 ligand
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-16 and allergic inflammation
mast cell
IL-5, GM-CSFRantes, MIP-1eotaxin
IL-16
histamineIL-5LTB4
+
eosinophil
CD4
CD4 T cell
CD4
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-17
• T cell regulation of haematopoiesis
• Enables fibroblasts to sustain CD34+ precursor cells and direct maturation towards neutrophils ? Via IL-6, IL-8, G-CSF
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
IL-10 family: -helices
• IL-19: monocytes, B cells
• IL-20: monocytes (keratinocytes)
• IL-22/TIF: NK, CD4+ Th1 cells
• IL-24/mda-7: T cells, melanocytes, monocytes, NK cells, B cells
• IL-26/AK155: CD4 T memory cells, NK cells
• Receptors: class II (CRF2): and chains
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-21
• 4 -helix cytokine most closely related to IL-15
• Secreted by CD4 T cells in response to antigen stimulation
• Differentiation of NK cells (CD16, IFN-)
• Blocks further recruitment of activated NK cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Interleukin-23
• 2 subunits p19 and p40• p19 4 -helix cytokine
related to p35 subunit of IL-12
• p40 is subunit of IL-12• Engages IL-12R2• Memory cell proliferation
and IFN- production• Dendritic cells
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokines
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokines
• Small MW (8-10 kDa) peptides: mediators of acute inflammatory responses
• Chemotactic cytokines• Chemoattraction, activation, diapedesis of
granulocytes (also T cells/monocytes)• Angiogenic• Bind to heparin and stromal proteoglycans• IgE-independent basophil degranulation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokine familiesCXCL 1-15Two cysteines separated by one amino acidChromosome 4q12-q21, 1024-84% homologyN-terminal Glu-Leu-Arg (ELR) (neutrophil active) or non-ELR(not neutrophil active)CCL 1-28Two adjacent cysteinesChromosome 1725-71% homologyCL 1/2One cysteineChromosome 1CX3CL 1
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokine receptors
• Seven transmembrane spanning G-protein coupled receptor superfamily
• 6 CXCR chemokine, 10 CCR chemokine receptors cloned, more to come
• CXCR 4, CCR 5, CCR 3 mediate entry of HIV into T cells/monocytes
• Most chemokines bind to several receptors
• CCR 3: confined to eosinophils and Th2-type T cells: binds to eotaxin, RANTES, MCP-2/3/4
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokine receptors• G-protein coupled, 7
transmembrane spanning• Chemokine selectivity
and range of expression on leukocytes overlap extensively
• Some constitutive, some inducible, some susceptible to down-regulation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
CXCL chemokines
• Neutrophil chemotaxis (IL-8 most potent)
• T cell chemotaxis (e.g. IL-8 CD8+ T cells)
• Neutrophil activation
• Suppress (IL-8, GRO-, PF4) or stimulate (SDF-1) myeloid colony formation
• Stimulate (ELR subgroup) or suppress (non-ELR subgroup) angiogenesis
• Fibroblast collagen synthesis (CTAP III)
• Post-translational modification, e.g. PBP and NAP-2
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Some CXCL chemokines
CXCL 1-3 GRO CXCR 2
CXCL 4 PF 4
CXCL 5 ENA-78 CXCR 2
CXCL 7 NAP-2 CXCR 2
CXCL 8 IL-8 CXCR 1/2
CXCL 9 MIG CXCR 3
CXCL 10 IP-10 CXCR 3
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
CCL chemokines
• Monocyte/lymphocyte chemotaxis/activation: MIP-1(CD4+), RANTES (CD4/CD45RO+)
• Eosinophil chemotaxis/activation: eotaxin, eotaxin 2 (eosinophils only), RANTES, MCP-3, MCP-4, (MCP-2, MIP-1)
• Histamine releasing activity: MCP-1, MCP-3, MIP-1, RANTES, MCP-2
• HIV anti-viral effects: RANTES, MIP-1, MIP-1• Post-translational modification, e.g. CD26 and RANTES, eotaxin
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Some CCL chemokinesCCL 1 I-309 CCR 8
CCL 2 MCP-1 CCR 2
CCL 3/4 MIP-1 CCR 1/5
CCL 5 RANTES CCR 1/3/5
CCL 7 MCP-3 CCR 1/2/3
CCL 11 Eotaxin CCR 3/5
CCL 13 MCP-4 CCR 2/3
CCL 17 TARC CCR 4
CCL 24/26 Eotaxin 2/3 CCR 3
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Chemokine receptor expression by T cells
Th1• CXCR 3
Th2• CCR 3• CCR 4• CCR 8
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cooperation between eotaxin and IL-5 in eosinophil accumulation
Bone marrow
eotaxin IL-5
eosinophils& precursors
eosinophils
Tissues Eotaxin mediatedbut IL-5 dependent
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Eotaxin, eosinophils and “Th2-type” T cells
Th2 T cell Eosinophil
CCR3 CCR3
eotaxin
eotaxin
IL-5GM-CSF
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Sources of eotaxin
• Epithelial cells• Endothelial cells• T cells• Eosinophils• Fibroblasts
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Lipid mediators (leukotrienes, prostaglandins)
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Leukotrienes and prostanoids
• Ubiquitous oxygenated fatty acids
• Physiological functions: temperature regulation, coagulation, parturition, blood pressure
• Newly formed mediators
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
5(S)-HETE ProstaglandinsThromboxanes
LTB4
Nuclear membrane phospholipids
5(S)-HPETE
LTA4
LTC4
LTD4
Arachidonic acid
LTE4
Phospholipase A2
5-lipoxygenase
5-lipoxygenase
LTA4 hydrolase
-glutamyl transpeptidase
LTC4 synthase
Dipeptidases
Cyclooxygenase
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Cellular sources of leukotrienes
Predominantly LTB4 Predominantly LTC4/D4/E4
Monocytes Monocytes EosinophilsMacrophages Macrophages Mast cellsNeutrophils Basophils(B cells)
Reflects restricted expression of 5-lipoxygenaseLTC4 synthase and LTA4 hydrolase are widely expressed
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Biological activities of leukotrienes
LTB4 LTC4/D4/E4
Increase leucocyte adhesion to endotheliumIncrease microvascular permeability
Neutrophil (eosinophil) chemotaxis VasoconstrictionNeutrophil lysosomal release Smooth muscle contractionand superoxide generation Increase mucus secretionBronchoconstriction (via TXA2)CD8 T cell cytotoxicityIgG productionAugment IL-2, IFN- production
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Leukotriene degradation
LTB4
• 20- hydroxylation• Further oxidation to aldehyde and acid
LTC4
• Conversion to LTD4/E4
• Extracellular metabolism (H2O2) (sulphoxides)
-oxidation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Leukotriene receptors
LTB4
• LTB4 (B-LT) receptor
LTC4 /D4/E4
• CysLT1: inflammatory cells, smooth muscle
• CysLT2: inflammatory cells, vascular smooth muscle
• Others?
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Leukotrienes in disease
• Bronchial asthma and allergic rhinitis
• Fibrosing lung disease
• Infant/adult respiratory distress syndrome
• Rheumatoid arthritis
• Psoriasis
• Inflammatory bowel disease
• Myocardial infarction
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Leukotriene inhibitors
LTD4 receptor antagonists
• Zafirlukast
• Pranlukast
• Montelukast
5-lipoxygenase inhibitors
• Zileuton
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
ProstanoidsArachidonic acid
15-keto-PGE2
PGG2
PGH2
PGE2
PGH synthase (cyclooxygenase)15-keto-PGF2
PGF2
6-keto-PGF1
PGI2
(prostacyclin)
TXB2
TXA2
(thromboxane)
9,11PGF2
PGD2
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Biosynthesis and cellular sources
PGH synthase 2 (COX) isoforms: COX-1 (ubiquitous, constitutive)COX-2 (inducible in inflammation)
Major products characteristic of different cells:
Mast cells PGD2 Platelets TXA2
Endothelium PGI2 Smooth muscle PGI2
Epithelium PGE2 Macrophages PGF2, PGE2, TXA2
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Prostanoid receptors
PGD2 DPPGE2 EP-1(smooth muscle contraction)/2(relaxation)/3/4PGF2 FPPGI2 IPTXA2 TP-1/2 (more?)
G-protein linked 7 transmembrane domain proteinsConsiderable cross-reactivity between receptors
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Prostanoids: pro-inflammatory actions
• Pain
• Swelling
• Vascular engorgement
• Smooth muscle contraction/relaxation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Neuropeptides
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Tachykinins
• Substance P (SP), neurokinin A/B
• Neuropeptide K (NPK), NP-• Found in neurons in the CNS only (NKB), or in
the CNS and peripheral nerves (SP, NKA)
• Somatic sensory (C-fibre) nerves
• Sensitive to capsaicin
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Tachykinins: receptors and metabolism
ReceptorsNK1 NK2 NK3
Affinity SP>NKA=NKB NKA>NKB>>SP NKB>NKA>>SPDistribution Wide Wide Brain & spinal cord
Metabolism
Angiotensin converting enzyme (ACE): endotheliumNeutral endopeptidase (NEP): epithelium
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Tachykinins: inflammatory efects
• Non-adrenergic, non-cholinergic (NANC) effects of peripheral nerve stimulation
• Direct or via axon reflexes: “neurogenic inflammation”
• Smooth muscle contraction, plasma leakage, mucus secretion, vasodilatation
• Mast cell degranulation (SP)• Priming and adherence of granulocytes
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Calcitonin gene-related peptide (CGRP)
-CGRP (separate gene) -CGRP (alternative splicing of calcitonin gene)
• Widely distributed in peripheral neurones
• Metabolised by mast cell tryptase and chymase (also NEP)
• High-affinity binding sites in vascular smooth muscle
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
CGRP: pro-inflammatory effects
• Relaxation of smooth muscle, particularly large and small blood vessels, mediated via NO release
• Enhances, but does not cause vascular leakage
• Increases neutrophil adherence, inhibits T cell proliferation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Other neuropeptides
• Vasoactive intestinal peptide (VIP)
• VIP-related peptides (PHM, PHV, helodermin, helospectins)
• Neuropeptide tyrosine
• Opioids
• Gastrin-releasing peptide
• Galanin
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Other possible effects of neuropeptides
• Pain and hyperalgesia
• Smooth muscle contraction
• Vascular leakage
• Arthritis: pain, fibroblast and synoviocyte proliferation
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Endothelin (ET) and nitrous oxide (NO)
ET (vasoconstriction) NO (vasodilatation)
Vascular endothelium and endocardiumEpithelial cells
Peripheral NANC nervesCNSPlacentaInflammatory leucocytes
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Endothelin (ET) and nitrous oxide (NO): synthesis
ET NO
pro-ET
ET1-3
L-arginine
L-citrulline + NO
NG-hydroxy-L-argininebig ET
NADPH NADPO2 H2O
NADPH NADPO2 H2O
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
NO synthase: isoforms
Isoform Expression Distribution
nNOSconstitutive CNS, peripheral NANC nerves, epitheliumeNOS constitutive endothelium, placenta (membrane anchored)iNOS inducible many cells
IL-1, TNF-, IFN-, LPS stimulatoryTGF-, corticosteroids inhibitory
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
ET and NO: signalling
ET7 transmembrane domain receptor coupled to G-proteinActivates PLC and PKC, AP-1, gene expression
NOActs by local diffusionBinds to haem moiety of guanylyl cyclase, elevating cGMPNon-specific cytotoxic/cytostatic effects: forms peroxynitrate whichbinds to Fe2+
KING’SCollege
LONDONFounded 1829Respiratory Medicine & Allergy
Mediators of Inflammation
• Cytokines
• Chemokines
• Lipid mediators (leukotrienes, prostaglandins)
• Neuropeptides
• Endothelin and NO
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