Cytokines and Eicosanoids Flashcards
___________________are signaling proteins that modulate immune responses, inflammation, and hematopoietic cell proliferation and differentiation
Cytokines
Which are the proinflammatory cytokines?
interleukins 1, 6, 8, 12, and 18; interferons; and tumor necrosis factor
What are interferons?
A cell-signaling protein secreted by cells infected by viruses, bacteria, or parasites, as well as by leukocytes and fibroblasts in response to infection or neoplastic proliferation. Interferons have antiviral, antimicrobial, and antiproliferative properties. Part of the innate immune system.
Which are the anti-inflammatory cytokines?
anti-inflammatory cytokines (interleukins 4,10, 11, and 13; and transforming growth factor-beta)
What do pro inflammatory cytokines do?
Proinflammatory cytokines induce fever and inflammation in response to infection or tissue injury
Pro or anti-inflammatory: interferons
proinflammatory
________________ are proinflammatory and antiinflammatory signaling molecules derived from arachidonic acid (AA) and include prostaglandins, leukotrienes, prostacyclins, and thromboxane A2
Eicosanoids
A group of inflammatory mediators produced by leukocytes that potentiate allergic and asthmatic responses. They are metabolites of arachidonic acid and are produced by the enzyme 5-lipoxygenase
Leukotrienes
A group of signaling molecules derived from arachidonic acid with a wide variety of functions, including inflammation and cervical ripening.
Prostaglandins
A lipid-derived compound that stimulates vasodilation by inducing smooth muscle relaxation. It also inhibits platelet aggregation.
Prostacyclin
An arachidonic acid derivative and potent platelet aggregator and vasoconstrictor. Inhibition of thromboxane A2 synthesis in thrombocytes is responsible for aspirin’s antiplatelet effect.
Thromboxane A2
cytokines secreted by a leukocyte that acts on another type of leukocyte
Interleukins
cytokines secreted by lymphocytes
Lymphokines
cytokines secreted by monocytes
Monokines
cytokines that have chemotactic activities
Chemokines
A cell signaling protein that mediates macrophage activity and expression of MHC molecules. Plays an important role in innate and adaptive immunity against viral, bacterial, and protozoal infections.
IFN-γ
Interleukins secreted by macrophages
IL-1, 6, 8, 12 (and TNF-α)
Interleukins secreted by all T cells
IL-2 and 3
Most important proinflammatory interleukins (endogenous pyrogens and main mediators of sepsis)
IL-1 and 6 (and TNF-α)
Most important anti-inflammatory interleukin
IL-10
Secreted by Th2 and Treg cells
Macrophages.
Anti-inflammatory (immune suppression)
Inhibits activated macrophages, dendritic cells, and the inflammatory response
Reduces MHC class II expression and secretion of Th1 cytokines
Promoters of differentiation of T cells to Th2
IL-2 and 4
Class switching interleukins
IL-4 and 5
4: Promotes class switching to IgE and IgG
5: Promotes class switching to IgA
Acute phase reactant stimulators
IL-6 and 11
A set of biomarkers whose plasma concentration increases (positive markers) or decreases (negative markers) in response to an ongoing inflammatory process. Positive inflammatory markers include C-reactive protein (CRP), leukocytes, and the erythrocyte sedimentation rate (ESR). Negative inflammatory markers include transferrin, albumin, and antithrombin.
Acute phase reactants
Neutrophil chemotactic factor
IL-8 (chemokine)
Think “Neutrophils are a cleaning aid (8)” to remember that Interleukin-8 attracts neutrophils to clear infection sites.
The neutrophils ‘ate’ the infection
Which IL 1-6: I promote fever
IL-1
thats ONE HOT dog
Which IL 1-6: stimulates proliferation/differentiation of T cells
IL-2: “Two if by T”
Which IL 1-6: stimulates proliferation of granulocytes and stem cells in the bone marrow
IL-3:
a 3-bone steak
a T-BONE steak
Which IL 1-6:stimulates class switching to IgE
IL-4 NarnEEEEa!!
Which IL 1-6: stimulates class switching to IgA
IL-5: ea5y A
Which IL 1-6: stimulates the synthesis of aKute phase reactants
IL-6: sixy cutie
six-acte phase reactants
Which IL 1-6: stimulates growth of B cells, enables class switching to IgE and IgG and triggers T cell differentiation into Th2 (helper) cells.
IL-4
There are over 20 tumor necrosis factors, of which _____________________ and ___________________are the most important.
cachectin (TNF-a) and lymphotoxin-alpha (TNF-b)
Tumor necrosis factor secreted by macrophages
TNF-a
Tumor necrosis factor secred by lymphocytes
TNF-b
Tumor necrosis factor that is pyrogenic, inhibits carcinogenesis of certain tumors, mediates septic shock, and maintains granulomas
TNF-a
How does TNF-a mediate sepsis
Mediates septic shock by activating the endothelium, which causes vascular leakage and recruitment of white blood cells
Interferon essential for the formation of granulomas
INF-gamma
Th1 lymphocytes secrete IFN-γ, which activates macrophages and is essential for the formation of granulomas.
Activated macrophages secrete TNF-α, which is essential for the maintenance of granulomas.
There are four subtypes of eicosanoids:
Prostaglandins
Prostacyclins
Leukotrienes
Thromboxane A2
What are the two major pathways for arachidonic acid breakdown
Cox 1 and 2 versus 5-lipoxygenase
Which pathway leads to the production of leukotrienes?
5-lipoxygenase arm
Which pathway leads to the production of prostaglandins, thomoxane A2, prostacyclins?
Cox 1 and 2
Zileuton inhibits what for the treatment of asthma?
5-lipoxygenase
What are the first major precurosors that arachidonic acid is broken down into?
Prostaglandin H2 and Leukotriene A4
Phospholipase A2 plays what role in arachidonic acid metabolism?
Phospholipase A2 takes FAs from the cell membrane and brakes it down into arachidonic acid
How does PGE4 production in neurons, the brain, stomach, kidney, uterus, and prostate impact their organ function?
What antagonizes PGI2?
Thromboxane
What are some of the major actions of leukotrienes?
Neutrophil chemotaxis and bronchospasm
Platelet aGgregation Inhibitor
PGI2
Prostaglandin that elevates body temperature
PGE2
Fever, headache, jaw pain, vision loss, and an elevated ESR in a patient > 50 years raises suspicion for giant cell arteritis. This patient’s symptoms are refractory to corticosteroid therapy and require treatment with another agent. This agent is likely to inhibit what?
IL-6
Monocytes differentiate into macrophages and giant cells that produce cytokines such as interleukin-6 (IL-6). IL-6 is an acute phase reactant that is highly expressed in GCA lesions and functions to sustain the inflammatory activity. IL-6 also mediates the systemic symptoms seen in GCA (e.g., fever, weight loss) and is responsible for this patient’s elevated ESR. Tocilizumab is an IL-6 receptor inhibitor shown to reduce relapses and lower the dose of glucocorticoids required to maintain disease remission.
Where do glucocorticoids act in the arachidonic acid pathway?
The first step in this pathway (membrane phospholipids → arachidonic acid) is catalyzed by phospholipase A2, which can be inhibited by glucocorticoids.
What are some POSITIVE acute phase reactants?
fibrinogen, ferritin, serum amyloid A, hepcidin, and C-reactive protein. Fibrinogen, which facilitates rouleaux formation, correlates positively with erythrocyte sedimentation rate.
What are some NEGATIVE acute phase reactants?
albumin, transferrin, and transthyretin would also be decreased by the cytokines that induce positive acute phase reactants.
__________________________is a cytokine secreted by osteoblasts that, in addition to RANKL, binds to surface receptors on precursor osteoclast cells to promote their proliferation and differentiation into mature osteoclasts. Osteoclastic tissue degradation and osteoblastic tissue formation contribute to a dynamic remodeling process that facilitates bone healing.
Macrophage colony-stimulating factor (M-CSF)
Macrophage colony-stimulating factor
Monocyte colony-stimulating factor, M-CSF
A type of cytokine/growth factor that causes hematopoietic stem cells to differentiate into macrophages. Involved in differentiation, proliferation, activation, and maturation of macrophages and monocytic lineage. Also has a role in bone remodeling by activating precursor osteoclasts to undergo further differentiation.
In conjunction with recurrent asthma exacerbations despite adequate treatment, perihilar opacities and bronchial wall thickening on x-ray of the chest, elevated IgE levels, and marked eosinophilia, this should raise concern for allergic bronchopulmonary aspergillosis. What IL would you expect to be elevated in this patient?
IL-4
In a patient with sarcoid, secretion of what by macrophages supports the formation of granulomas?
TNF-a
(INF-y for activation then TNF-a for maintenence)
TNF-α secretion by macrophages is part of the pathogenesis of sarcoidosis and supports granuloma formation, which are shown in the photomicrograph of this patient’s biopsy specimen. In sarcoidosis, dysfunctional CD4+ T cells are activated by an unknown factor and secrete Th1 cytokines such as IFN-γ, which promote macrophage activation and aggregation of macrophages into giant cells to form a granuloma. Activated macrophages, in turn, secrete TNF-α, which promotes maintenance of the granuloma. Because TNF-α is instrumental for granulomas, it is important to test for latent tuberculosis (TB; another granulomatous disease) before prescribing TNF-α inhibitors, which can cause disassembly of TB-sequestering granulomas, resulting in systemic TB.
Interferon gamma, TNFa, and IL-s are important cytokines for the formation of granulomas. In what diseases do we see granuloma formation?
hypersensitivity pneumonitis, sarcoid, GCA, tuberculosis, CGD, non-hodkins, histoplasmosis, granulomatosis with polyangitis
These promote the expression of MHC class I proteins on the surface of virus-infected cells. They induce the activation of various enzymes that promote the antiviral state of the cell, including ribonuclease L.
interferon α and interferon β
The differentiation of naive T cells into TH1 cells is mainly promoted by
The differentiation of naive T cells into TH1 cells is mainly promoted by IL-12, which is secreted by macrophages.
Macrophage phagocytic function is enhanced by
INF-gamma
A transmembrane protein expressed on antigen-presenting cells (e.g., macrophages, dendritic cells, B cells). Composed of alpha and beta chains associated with an invariant chain. Bind exogenously-synthesized antigens to present to CD4+ T cells.
MHCII
A transmembrane protein expressed by all nucleated cells and platelets. Composed of a long and short chain associated beta-2 microglobulin. Binds endogenously synthesized antigens (e.g., viral and cytosolic proteins) to present to CD8+ T cells.
MHCI
Major difference between MHCI and II
MHCI presents self to CDB(cytotoxic t cells) waves a white flag
MHCII presents broken down foreign antigens and presents to helper T CD4
MHCI is important because if its infected by a virus, it will wave a red flag to be destroyed. MHCII is important because it presents material for the body to begin recognizing as foreign by CD4.
MHC class I (MHC-I) and MHC class II (MHC-II) are both parts of the major histocompatibility complex (MHC). They present peptides to T cells to help the immune system identify and respond to pathogens.
Location
MHC-I: Found on the surface of most nucleated cells in the body
MHC-II: Found on antigen-presenting cells, such as macrophages, dendritic cells, and B cells
MHC Class I molecules present peptides derived from inside a cell (endogenous antigens) to cytotoxic T cells (CD8+) on the surface of all nucleated cells, essentially alerting the immune system to potential viral infections, while MHC Class II molecules present peptides from extracellular sources (exogenous antigens) to helper T cells (CD4+) on the surface of antigen-presenting cells like macrophages and dendritic cells, initiating an immune response against pathogens taken up by these cells
