15. Cytokines Flashcards
which cytokines is made during the innate response but drives the production of cytokines used during the adaptive immune response?
IL-12
IFN-gamma, produced by activated Th1 cells, can act back on macrophages to activate them to do what?
become “classically activated” - more microbicidal
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)
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
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
what three cytokines commonly lead to proliferation?
IL-2, IL-4, and IL-5
cytokine cascades and interaction- action usually is what?
sequential - biological effect may be elicited by final cytokine in series
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
cytokines and antagonism
two cytokines may have different/opposing effects - eg IFN-gamma activates macrophages and IL-4 inhibits macrophage activation
example of cytokine paracrine action?
virus induces IFN production which acts on adjacent cells to induce antiviral state
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)
example of cytokine autocrine action?
IL-2 and T cells or IFN-gamma and macrophages (may be high effective [ ] )
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
what is a cytokine storm?
cytokine overproduction - as in sepsis…can lead to shock/death (systemic inflammaotry response syndrome = SIRS)
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
what do we give to pts who are neutropenic to bump up neutrophils after chemo and radiation?
G-CSF
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
cytokines bind with high affinity, so what does this mean?
act at low concentrations (low % receptor occupancy required to initiate signaling)
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)
all cytokine receptors are comprised of >= 1 transmembrane protein - role of extracellular domain and intracellular domain?
extra: binding of cytokine
intracell: signaling
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
