15. Cytokines Flashcards by Claire Rosen

which cytokines is made during the innate response but drives the production of cytokines used during the adaptive immune response?

IL-12

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IFN-gamma, produced by activated Th1 cells, can act back on macrophages to activate them to do what?

become “classically activated” - more microbicidal

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cytokines and pleiotropy - what is it and what is the downside?

a single cytokine may act on many different cell types, mediates diverse biological effects

but limits use of many cyotkines therapeutically (unwanted side-effects)

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cytokines and redundancy - what is it and what is the downside?

multiple cytokines have the same functional effects (eg IL-4 causes IgE production, Th2 differentiation, and inhibiiton of macrophages)

but antagonize a single cytokine and you many not eliminate the response

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how are IL-1 and TNF an example of cytokine redundancy?

both endogenous pyrogens that act on the hypothalamus to induce a prostaglandin-mediated fever

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what three cytokines commonly lead to proliferation?

IL-2, IL-4, and IL-5

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cytokine cascades and interaction- action usually is what?

sequential - biological effect may be elicited by final cytokine in series

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cytokines and synergy

two cytokines necessary for one response - eg IFN-gamma and TNF mediate increased expression of class I MHC molecs on many cell types

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cytokines and antagonism

two cytokines may have different/opposing effects - eg IFN-gamma activates macrophages and IL-4 inhibits macrophage activation

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example of cytokine paracrine action?

virus induces IFN production which acts on adjacent cells to induce antiviral state

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example of cytokine endocrine action?

LPS on macrophages to induce TNF, IL-1, and IL-6 which induce fevere (hypothalamus = target site distant from site of production)

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example of cytokine autocrine action?

IL-2 and T cells or IFN-gamma and macrophages (may be high effective [ ] )

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cytokine mediators/regulators of innate immunity - ____ is really important. They are made mostly by ______ in response to microbial stimuli. There is _____-dependent signaling in most cases.

balance; macrophages; TLR

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what is a cytokine storm?

cytokine overproduction - as in sepsis…can lead to shock/death (systemic inflammaotry response syndrome = SIRS)

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what are the cytokines that drive hematopoiesis?

M-CSF (monocyte CSF) which is released by macrophages, endoth cells, bone marrow cells, and fibroblasts to target committed progenitors to make monocytes

G-CSF (granulocyte CSF) which is released by macrophages, fibroblasts, and endoth cells to target committed progenitors to make granulocytes

GM-CSF (granulocyte-monocyte CSF) which is released by T cells, macrophages, endoth cells, and fibroblasts to target immature and committed progenitors (and mature macrophages) to make granulocytes/monocytes or to induce macrophage activity

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what do we give to pts who are neutropenic to bump up neutrophils after chemo and radiation?

G-CSF

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cytokines in the adaptive immune system are produced primarily by ______ upon antigen recognition. They then do what?

T-lymphocytes

they regulate differentation/growth of lymphocyte subpopulations (Th1, Th2, Th17), recruit/activate/regulate specialized effector cells (eg eosinophils), and they eliminate antigens in the effector phase of the immune response

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cytokines bind with high affinity, so what does this mean?

act at low concentrations (low % receptor occupancy required to initiate signaling)

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most cytokines induce gene expression (interaction with receptors results in activation of signaling pathways that result in activation of DNA binding proteins that direct txn, eg STAT1 activation through IFN-gamma R). What are some exceptions?

chemokines induce rapid cell migration (actin mobilization)

TNF induces apoptosis without de novo protein synthesis (TNF->activ of sphingomyelinase -> ceramine -> apoptosis of endoth cells)

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all cytokine receptors are comprised of >= 1 transmembrane protein - role of extracellular domain and intracellular domain?

extra: binding of cytokine
intracell: signaling

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Type I cytokine receptors

dimerize

conserved cysteines in extracellular domains (2 conserved region per extracell domain)

bind cytokines that form 4 alpha-helices; specificity determined by amino acids that distinguish extracellular domain; additional signal transducing chains co-associate with receptor

TNF receptor family?

induce apoptosis or gene expression….receptor trimerizes

7-TM alpha-helical receptors?

chemokine receptor; GPCRs

within a receptor class, certain chains may be shared - this leads to what?

redundancy

low quantities of TNF-alpha does what?

local inflammation (eg leukocyte activation, endothelial cell express adhesion molecules and release of IL-1 and chemokines to drive recruitment of more white cells through diapedesis)

moderate quantities of TNF-alpha do what?

systemic effects (signal to the hypothalamus to cause a fever, signal to liver to release acute phase proteins, signal to bone marrow to produce more lymphocytes)

what do high quantities of TNF-alpha do?

septic shock (low CO, low resistnace -> thrombi -> DIC, is a glucocorticoid antagonizing factor that blocks gluconeogenesis -> hypoglycemia)

TNF-alpha is the primary mediator in the inflammatory response to what type of infection?

gram(-)

primary source of TNF-alpha?

macrophages thanks to LPS induction

what are the two receptors for TNF?

TNFRI and TNFRII (TNFRI mediates most of the biological effects like NF-kB translocation and apoptosis)

antagonism of TNF-alpha has been very successful in which disease?

rheumatoid arthritis - eg Etanercept/Enbrel = soluble TNF receptor-immunoglobulin Fc fusion protein dimer that competes with cell-assocaited receptor or free TNF or Ifliximab/Remicade//adalimumab/humira are Mab to TNF

potential side effects of anti-TNF Rx?

exacerbation of latent TB

What two cytokines are involved in RA?

IL-1 and TNF-alpha (produced by macrophages and fibroblasts in the synovial fluid - IL-1R are found on cells with various functions and when stimulated they release secondary cytokines to mediate inflammation, tissue remodeling, and cartilage destruction)

IL1 & TNF-a in RA? just | IL1? just TNF-a?

both: ^COX2, ^PGE2, ^adhesion molecs, ^IL6, ^chemokines, ^collagenases IL1: ^TNF-a, ^osteoclast activ, ^angiogenic factors TNF-a:^IL1, ^apoptosis

why does enbrel have an IgG1 FcR?

increases half life

The binding of IL-1 to high affinity IL-1R (type I) does what?

draws in the IL-1R accessory proteins, the adaptor protein MyD88 is recruited, NF-kB mediated signaling commenses through recruitment of downstream kinases

IL-1Ra does what?

natural antagonist that provides negative feedback in response to inflammatory stimuli - prevents binding to IL-R1 (competes with IL-1)

IL-1RA or anti-IL1 antiboies are being used clinically to treat what?

Type II diabetes, gout, muckle-wells

what drug is an IL-1Ra used to block inflammation in RA by binding to IL-1R1 but doesn't signal?

anakinra/kineret

IL-1B and gout

inflammasome signaling (NALP3 = NLRP3) leads to processing of pro-IL1B to active IL-1B....uric acid crystals in joints activates NLRP3 and drives production of IL-1B to cause gout...rilonacpet (arcalyst) used in gout to trap IL-1 fusion protein muckle wells is a mutation in NLRP3

IL-12 is a ____ protein and the primary mediator of what response?

heterodimeric protein, primary mediator of innate response to intracellular microbes

IL-12 is a key inducer of cell-mediated immunity through its ability to induce what?

IFN-gamma

primary stimuli to make macrophages secrete IL-12?

LPS, intracellular bacteria

major function of IL-12?

stimulates production of IFN-gamma by NK and T cells - results in synergistic production of TNF in response to LPS - stimulates differentiation of CD4+ cells to become IFN-gamma producers (Th1 response) - enhances CTL and NK cell activity (through production of IFN-gamma)

therapeutic approaches to IL-12?

recombinant IL-12 in trials to boost cell-mediated immunity in pts w/immunodefic or cancer anti-IL-12 therapy to block pathology associated with crohn's disease

IL-17 is implicated in which diseases?

RA, lupus, asthma, allograft rejection, MS, CF, involved in crohn's antagonizing IL-17 seen as an approach to arthritis and psoriasis

for a low PMN count, what would you perhaps give a patient?

G-CSF

IFN-a/B does what to viral replication?

inhibits

effects of IFN-a/B on immune response

- increases Class I MHC expression on infected cells (increases CTL recognition) - inhibits proliferation of many cell types, including lymphocytes - activates macrophages (increases IL-10 and FcR, decreases IL-12) - contributes to larger repertoire of inflammatory genes induced by TLR4 agonists

IFN-a/B is used clinically to treat what disease?

Hep B and C recently for SARS outbreak in toronto hairy cell leukemia MS - unknown mechanism