Hdm Tbl 4 - Cytokines And Interleukins

Front 1

Classic Immune Signaling

Back 1

Pathogen with a specific molecular signature binds to a TLR on a Macrophage.

Triggers phagocytosis and secretion of Interleukins.

Front 2

What occurs when a macrophage engages with a pathogen?

Back 2

The pathogen is degraded, and the macrophage begins releasing Cytokines (including Interleukins) to trigger further immune response.

Front 3

IL-1 Purpose

Back 3

Begins the show. Acts on vascular endothelium to increase permeability of further immune factors and STIMULATE IL-6 production.

Front 4

IL-6 Purpose

Back 4

Upregulated by IL-1 activity, acts on liver to spur production of acute inflammatory phase proteins (like CRP) and act on Hypothalamus to induce fever.

Front 5

IL-8 Purpose

Back 5

Acts on vascular endothelium to ATTRACT NEUTROPHILS.

Attractants like this are called CHEMOKINES.

Front 6

IL-12 Purpose

Back 6

Acts on NK cells to activate them, influences lymphocyte differentiation into further NK cells.

Front 7

TNF-Alpha - Purpose

Back 7

Tumor Necrosis Factor: acts on vascular endothelium to increase permeability and activate further factors.

A cytokine secreted by macrophages following TLR binding to pathogen.

Front 8

IL-6 3 Main Targets: Liver. What proteins are upregulated? Downregulated?

Back 8

IL-6 binding to hepatocyte receptors upregulates acute inflammatory protein productions.

CRP: Opsonin, aids macrophage targeting and marks inflammation.

Amyloid A: Degrades ECM to allow better diffusion of immune cells, recruits immune cells to inflammatory sites.

Fibrinogen: Clotting.

Iron Sequestration: Starve bacteria.

Albumin is downregulated.

Front 9

Erythrocyte Sedimentation Rate

Back 9

ESR is rate of clotting, elevated following IL-6 activity due to hepatic upregulation of fibrinogen in acute inflammatory response.

Front 10

IL-6 3 Main Targets: Bone Marrow

Back 10

IL-6 secreted by macrophages acts on Marrow receptors, triggering hematopoiesis of the Myeloid Lineage.

Spurs Megakaryocyte differentiation (for clotting) and Granulocyte differentiation (neutrophil/basophil/eosinophil) for inflammation and phagocytization/cytotoxicity.

Front 11

IL-6 3 Main Targets: Immune System

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IL-6 activity on B-Cell surface receptors stimulates antibody secretion of Plasma Cells.

Front 12

What sort of toxin is IL-6?

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IL-6 is an Endotoxin, so it can be targeted with drugs that act as antibodies.

Front 13

Tocilizumab and Sarilumab

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Drugs to treat acute inflammatory illness such as arthritis.

They TARGET IL-6 to downregulate acute inflammatory liver proteins (CRP, Amyloid, Fibrinogen) and decrease Erythrocyte Sedimentation rate and Iron Sequestration (increasing Hemoglobin).

Front 14

TNF-Alpha: Origin and Purpose

Back 14

Cytokine released upon macrophage binding to pathogen molecular singature on a Toll-Like Receptor. Also released by NK Cells and Neutrophils.

Pro-inflammatory, induces blood vessel permeability for further immune cell access.

Upregulated further IL-6 and TNF-Alpha and Platelet production.

Front 15

TNF-Alpha: Dual Purpose

Back 15

TNF binds to a receptor, TNFR, which activates enzyme complexes in cytosol. This triggers either Pro- or Anti-Survival responses.

Front 16

TNF-Alpha: Pro-survival Mechanism

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Inflammation triggers TNF-Alpha release -> binds to TNF Receptor -> in cytosol of cell, IKK Kinase releases and phosphorylates IkB to release Nf-kB, a transcription factor.

Triggers mRNA transcription of Adherens to increase vessel permeability.

Front 17

Purpose of Cortisol in Inflammatory Response?

Back 17

Inhibits Nf-kB transcription factor in TNF-Alpha Pro-survival pathway, reducing blood vessel permeability/inflammation.

Front 18

TNF-Alpha: Anti-Survival Mechanism

Back 18

TNF-Alpha releases at inflammation site -> iKK kinase -> IkB phosphorylated.

However, when bound to a CANCER CELL surface rather than a healthy cell surface, Caspase and FADD are released rather than Nf-kB. Caspase and FADD cleave Nf-kB so that the pro-survival pathway does not proceed.

Induces Apoptosis and Necrosis.

Front 19

Infliximab, Etanercept, Adalimumab, Certolizumab, Golimumab

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These are drugs that target TNF-Alpha, which acts as an endotoxin. Treats auto-immune inflammatory disease like R. Arthritis and Crohn.

Front 20

Colony-Stimulating Factors

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Cytokines secreted by macrophages/NK cells/Neutrophils.

Act on Bone Marrow to upregulate Leukocyte hematopoiesis.

Utilizes Jak/STAT pathway like IL-6.

Front 21

GM-CSF: Effect in Marrow vs Effect in Inflamed Tissue

Back 21

Granulocyte-Monocyte Colony-Stimulating Factor.

In marrow, drives differentiation of Common Myeloid Precursor -> all of its terminal differentiations (Megakaryocyte, Erythrocyte, Myeloblast -> basophil/neutrophil/eosinophil/monocyte).

In inflamed area, drives IL-1, IL-6, TNF-Alpha secretions.

Front 22

G-CSF: Function

Back 22

Cytokine released during acute inflammatory response.

Drives Common Myeloid Progenitor ONLY to form Myeloblast, then Granulocytes (ONLY NEUTROPHIL AND BASOPHIL).

Front 23

Sargramostim vs Filgrastin

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Leukopenia, or low WBC, can be treated by direct application of GM-CSF and G-CSF.

Sargramostim: GM-CSF drug, increases all Common Meyloid Progenitor products.

Filgrastin: G-CSF drug, increases only Neutrophil and Basophil.

Front 24

What are Chemokines?

Back 24

Released by macrophages once initial acute response is underway (IL-1/6/TNF already released).

Attract leukocytes (granulocytes, monocytes, B/T lymphocytes, NK Cells).

Front 25

TGF-Beta and SMADs

Back 25

Halts immune response.

Bound to ECM of tissues inactively. Breakdown during acute inflammation cleaves and activates it.

Once cleaved, it interacts with TGF Beta receptors that cause SMADS protein cascade.

SMADS is a transcription factor that grows tissue back, blocks STAT action (to stop inflammatory TF production), and activates Fibrinolysis to degrade clots.

Front 26

Disseminated Intravascular Coagulation

Back 26

TNF-Alpha release that upregulates platelets can create too many clots, causing organ failure and stroke.

Front 27

TNF-Alpha and Septic Shock

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Acute inflammatory release of TNF-Alpha can cause too much blood vessel permeability, reducing blood volume and leading to dropped BP/cardiac arrest/shock.

Front 28

What can trigger overproduction of TNF-Alpha?

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Superantigens: Hyperactivation of Helper T Cells, secrete too much TNF-Alpha.

Bacterial Cell Wall components (LPS in Gram-negative and Lipoteichoic acid in Gram-positive) bind to macrophages, triggering TNF-Alpha release.

Front 29

Macrophage Cytokine: CCL2

Back 29

Recruits monocytes in response to bacteria.

Front 30

Macrophage Cytokine: IL-12

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Stimulates cell-mediated immunity, NK and CD8+ T cells in response to intracellular invaders.

Front 31

Macrophage Cytokine: IL-15

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Stimulates T-Cell/NK response, adaptive AND innate.

Front 32

Macrophage Cytokine: IL-10

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Meant to downregulate immune response. Inhibits pro-inflammatory cytokines and MHC expression (to stop T Activation).

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Non-Macrophage Cytokines: IL-2

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Secreted by T Cells. Stimulate all T cell types.

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Non-Macrophage Cytokines: IL-3

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Secreted by T-cells, supports hematopoiesis of all leukocytes.

Front 35

Non-Macrophage Cytokines: IL-4

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Secreted by Mast Cells, promotes B and T cells.

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Non-Macrophage Cytokines: IL-5

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Mast cell secreted. B and eosinophil growth.