Chemical mediators of inflammation

Prostaglandins| Mast cells, leukocytes| Vasodilation (PGD2,PGE1,E2 & PGF2-? ), pain (PGE2), fever| Thromboxane A2| | Promotes platelet aggregation, vasoconstriction| Prostacyclin| | Inhibits platelet aggregation, vasodilation| Leukotrienes| Mast cells, leukocytes| Vasoconstriction & Increased vascular permeability (C4,D4,E4), chemotaxis (B4), leukocyte adhesion and activation (B4)| Cytokines| TNF| Macrophages, T cells| (1) Induce fever; induce WBC release from bone marrow.

(2) ^ thrombogenicity (coagulation) of endothelium, aggregation & activation of neutrophil (3) induce liver to synthesise acute phase protein (4) causes apoptosis of cells (5) catabolism of muscle & fat (cachexia)| IL-1| Macrophages, endothelial cells| (1) Chemotaxis, fever, WBC release from marrow, histamine release (2) Induce liver synthesise acute phase protein (3) Activate endothelium, adhesion molecule & permeability (coagulation & inflammation) (3) activate phagocyte, PMN & lymphocyte| IL-6|

Macrophage, endothelial, T cell| (1) Induce fever & liver to synthesise acute phase protein (2) stimulate proliferation of B cells (3) activate phagocyte & lymphocyte| IL-8| | (1) histamine release (2) activate endothelium (3) chemotaxis| IL-12| Macrophage, Dentritic cell| (1) ^ cytotoxic activity & IFN-?? production of NK cells + T killer cells. (2) Causes TH1 differentiation, Increase TH1 but not TH2 response| IFN-? | NK cells, T cells| (1) Activate macrophage & stimulate antibody response (2) Activate endothelial cells (3) inhibit haemopoiesis| CSF| | induce WBC release from bone marrow| Others|

PAF| Macrophage, endothelial cell, mast cell, platelet, PMNs| Platelet aggregation, vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst| ROS| Leukocytes| Killing of microbes, tissue damage| NO| Endothelium, macrophages| (1) regulates neurotransmitter release & blood flow (2) macrophages use it as a cytotoxic metabolite for killing microbes and tumor cells (3) cause vasodilation & endothelial smooth muscle relaxation (4) Tissue Destruction|

Chemokine| T cell, endothelial cell, activated macrophage, fibroblast, platelet, dentritic cell| Chemotaxis, leukocyte activation & integrin affinity| a. Vasoactive amines – Histamine (by mast cell) & Serotonin (by platelet) preformed and released quickly b.

Arachidonic acid (PUFA) – located on lipid membrane & is formed via cyclooxygenase & lipoxygenase pathways. Precursor to eicosanoid like prostaglandins, Leukotrienes, and Lipoxins c. Cytokines – polypeptide products of many cell types that mediate: (1) Inflammation (2) Immune responses (3) functions of cells of Mononuclear Phagocyte System (MPS) (4) antibody release & cytotoxicity (5) Local endothelial activation (expression of adhesion molecule), systemic acute-phase response; in severe infections, septic shock Major cytokine in acute inflammation > TNF and IL-1, chemokines. Major cytokine in chronic inflammation > interferon-? (IFN-? ) & IL-12 Tumor Necrosis Factor and Interleukin-1

Their secretion is stimulated by products of microbes & T cells. Functions: (1) endothelial activation (2) stimulate expression of adhesion molecules on endothelial cells, resulting in increased leukocyte binding and recruitment (3) enhance production of additional cytokines (notably chemokines) & eicosanoids. Interferons Type 1 IFN > IFN-???? IFN-? -Produced in response to viral infection -They inhibit viral replication & cell proliferation, increase NK actibity & induce MHC expression Type 2 IFN > IFN-? TGF??? inhibit MPS activation & lymphocyte growth TGF??? inhibit MPS activation & lymphocyte growth Lymphokines -Growth factor for lymphocytes (mainly interleukines 2, 3, 4, 5) Monokines

-IL-1, 6, 8, 12 & TNF-? Colony Stimulating Factor (CSF) -drive development, differentiation & expansion of myeloid cells. Cytokines| Cell releasing| Cell targeted| Function| IFN-? | MPS, dentritic cells| All| Anti-viral, increase MHC 1 expression| IFN-? | Fibroblast| All| Anti-viral, MHC, NK cell activation| IFN-? | T cells, NK cells| Macrophages, PMN| ? Activity| | | B cells| Ig class-switch, anti-proliferation, induce differentiation| | | T killer & NK cells| Activation| | | Many cells| Induce MHC 2 expression (so, conflict with type 1 IFN)| TNF-? | Macrophage| Macrophages| Activation| | | Neutrophil| Cytotoxicity| | | All cells| MHC, cytotoxicity|

| | Endothelium| Activation, adhesion molecules, permeability | | T cells| T cells| Co-signal for activation cytotoxic| TNF-? | T cell, Macrophage| Fibroblast Endothelium| adhesion molecules , inflammationOther cytokines (IL-2, IL-1, GM-CSF)| | | T cells| Major T cell growth factor (autocrine & paracrine), Activate CTL| | | B cells| Growth and differentiation factor| | | NK| Activate, ? cytotoxicity| IL-1| Macrophage, endothelial cell| NK| ? cytotoxicity| | | TH cells| Proliferation & cytokine production| | | Tissue fibroblast| Proliferation & production of ECM| | | Stimulate IL-6 production, tissue destruction| IL-2| TH| NK, monocyte| activation|

| | B cells| Activation & division| | | T cells| Division & mediator release| IL-3| T cells (multi-lineage CSF)| Immature bone marrow progenitor cells| Promote growth and differentiation Stimulate hematopoiesis| IL-4| TH2 cells| T cells| Growth factor for TH2, ^ TH2 but not TH1 response| | | B cells| IgE production, Growth factor, Activator| | | Macrophage| Inhibitory| IL-5| TH2 cells| Eosinophils| Growth and differentiation| | | B cells| Activation & production of Ig A| IL-10| Macrophage, dentritic, T cell| Macrophage & dentritic| Inhibit IL-12, v expression of costimulator & MHC 2| | | T cells| Increase TH2 but not TH1 response| | | B cells| Activation|

IL-15| Macrophage, others| NK & T cells| Proliferation | IL-18| Macrophage| NK & T cells| IFN-?? production| G-CSF| THMPS| Granulocyte lineage| growth and differentiationRestore WBC counts after marrow-toxic treatment| GM-CSF| THMPS| Granulocyte-monocyte lineage| growth and differentiationRestore WBC counts after marrow-toxic treatment| M-CSF| MPS cells| MPS lineage| growth and differentiation| d. Chemokines – chemoattractants for different subsets of leukocytes. Produced in response to infection or damage. Functions: leukocyte recruitment in inflammation and in the normal anatomic organization of cells in lymphoid and other tissues. The two major groups: CXC and CC e. Reactive Oxygen species (ROS)

* When ROS produced within lysosomes, it destroy phagocytosed microbes & necrotic cells, much like NO. * When secreted at low levels, ROS increase chemokine, cytokine, and adhesion molecule expression, thus amplifying the cascade of inflammatory mediators. * At higher levels, (1) endothelial damage, with thrombosis & increased permeability (2) protease activation & antiprotease inactivation, increasing breakdown of ECM (3) direct injury to other cell types f. Nitric Oxide — free-radical gas. g. Lysosomal Enzymes of Leukocytes – lead to tissue damage. h. Neuropeptides – substance P transmit pain signals, regulate vessel tone, and modulate vascular permeability i. Platelet activating factor (PAF) – phospholipid-derived mediator

Plasma Protein-Derived Mediators Mediator| Source| Function| Complement| Plasma (produced in liver)| Leukocyte chemotaxis and activation, opsonization, vasodilation (mast cell stimulation)| C3a| | (1) Promotes histamine release, mediates chemotaxis & opsonisation (2) Phagocyte activation & ^ activity (3) activate endothelium| C5a| | (1) Promotes histamine release & mediates chemotaxis (2) Phagocyte activation & ^ activity (3) activate endothelium & neutrophil| Kinins| | Increased vascular permeability, smooth muscle contraction, vasodilation, pain| Bradykinins| | increased vascular permeability, vasodilation, and bronchial smooth muscle contraction.

It also causes pain. | Thrombin| | binds to protease-activated receptors expressed on platelets, endothelial cells (leads to their activation and enhanced leukocyte adhesion) & other cell types. Also generates fibrinopeptides (during fibrinogen cleavage) that increase vascular permeability and are chemotactic for leukocytes. | Proteases activated during coagulation| | Endothelial activation, leukocyte recruitment| A. Complement system – protection against infection. Synthesized by liver & monocytes for innate response. Upon activation, functions: 1) opsonisation for phagocytosis and destruction 2) increase vascular permeability 3) leukocyte chemotaxis.

4) Generate pore-like membrane attack complex (MAC) to punches holes in membranes of microbes (lysis) Activation Pathway 1) Alternative pathway – indirectly by microbes 2) Classical pathway – antibodies bound to microbes B. Coagulation & Kinin Systems – Activated Hageman factor (factor XIIa) initiate 4 system involved in inflammatory response: (1) Kinin system activation leads to formation of bradykinin from its circulating precursor in plasma, HMWK. (2) clotting system, inducing the activation of thrombin, fibrinopeptides, & factor X, all with inflammatory properties (3) fibrinolytic system, producing plasmin and inactivating thrombin; (4) complement system, producing the anaphylatoxins C3a and C5a