Cytokines Flashcards
cytokines act through cell-surface protein receptors which trigger signaling pathways typically activated through _____
protein phosphorylation, leading to activation of specific transcription factors
explain how cytokines are pleiotropic, redundant, and potent
pleiotropic: 1 cytokine can have multiple and different effects on the same cell and on many cell types (may depend on exposure time or concentration)
redundant: difference cytokines can have same or overlapping effects
potent: present in small concentrations, so receptors have very high affinity for their cytokine
cytokines vs chemokines (functions and signaling)
cytokines: small soluble proteins (can be filtered out by kidney), signal to receptors coupled to protein kinases, stimulate growth/differentiation/immunity
chemokines: smaller, signal through GPCR, chemotactic and cellular activation, cell trafficking
identify each as a characteristic of either cytokines or chemokines:
a. signal through protein kinases
b. signal through GPCR
c. stimulate growth, differentiation, defensive capacity of immune system
d. chemotactic, cellular trafficking
cytokines:
a. signal through protein kinases
c. stimulate growth, differentiation, defensive capacity
chemokines:
b. signal through GPCR
d. chemotactic, cellular trafficking
what do IL-1 and TNF-alpha do
cause inflammation
what role do IL-2 and IFN-alpha/beta/gamma have?
- T-cell growth and division
- viral defense
- cell-mediated immunity
effect of IL-8
chemotaxis
function of TGF-alpha vs TGF-beta
TGF-alpha: inflammation
TGF-beta: downregulation of immune response, regulation of embryonic development
Type I cytokine (hemopoietin) receptors (IL-2-7, IL-9) and Type II cytokine receptors (IFN-a/b, IFN-y, IL-10) signaling through _____ pathway
JAK-STAT signaling:
1. cytokine mediated receptor dimerization
2. JAK-mediated phosphorylation of receptor chains
3. recruitment of STAT to cytokine receptor
4. JAK-mediated phosphorylation/dimerization of STAT
5. STAT translocation to nucleus —> transcription
*depending on what JAK/STAT combination you have, different genes transcribed
describe JAK-STAT signaling in cytokine receptors (Type I and II cytokine receptors)
JAK-STAT signaling:
1. cytokine mediated receptor dimerization
2. JAK-mediated phosphorylation of receptor chains
3. recruitment of STAT to cytokine receptor
4. JAK-mediated phosphorylation/dimerization of STAT
5. STAT translocation to nucleus —> transcription
*depending on what JAK/STAT combination you have, different genes transcribed
match the cytokine receptor component with the cytokines it binds:
TRAF, IRAK, G proteins,
TNF-a/b, FasL, IL-1, chemokines
TNF-a/b and FasL act through TNF receptor family which utilizes TRAF
IL-1 acts through IL-1 receptor family which utilizes IRAK
chemokines act through GPCR which utilize G proteins
what is the negative consequence of cytokine receptors having conserved regions in their chains?
mutation in conserved region effects interaction with many different cytokines —> many effects
example:
- X-SCID: mutation in gamma chain, blocks T cell and NK (but normal B cells)
- Steve-Wiedemann-like Syndorme: mutations in gp130 (component of IL-6 receptor family), lethal disease
how does mutation in cytokine receptors cause X-SCID and lethal Stuve-Wiedemann-like syndrome?
- X-SCID: mutation in gamma chain, blocks T cell and NK (but normal B cells)
- Steve-Wiedemann-like Syndorme: mutations in gp130 (component of IL-6 receptor family), lethal disease
*consequence of conserved regions of cytokine receptors is that binding of many cytokines is affected and therefore many downstream effects
IFN-alpha and IFN-beta vs IFN-lambda (what family of interferons do they belong to, what is their role)
IFNa/b: Type I IFNs, act on most nucleated cells
IFN-lambda: Type III IFN, act only on epithelial cells on mucosal surfaces, respiratory tract, gut, reproductive system (targeted protection for cells often exposed to viral entry)
*both types induce antiviral state, and both types signal through Type II cytokine receptors (JAK-STAT)
interferons are sometimes used as therapeutics.
what type of IFN is used to treat HBV, HCV, and papillomavirus?
IFN-alpha
how can abnormal activity of interferons cause Lupus (SLE/ Systemic Scleroderma) and other autoimmune diseases?
cytokines are very potent - expression must be tightly controlled or else they can cause damage
in Lupus/SLE, there is long-term low-level production of Type I IFNs (IFNa/b)
which interleukin is a chemokine
IL-8: functions in chemotaxis
name the functions of each of these cytokines:
a. IL-2
b. IL-4 and IL-5
c. IFN-y
d. IL-10
a. IL-2: T cell growth factor
b. IL4/5: produced by Th cells, cause B cell growth/ differentiation
c. IFN-y: produced by Th cells, activates macrophages
d. IL-10: inhibits immune responses
which interleukin inhibits immune responses
IL-10
what are the inflammatory cytokines, and major producers of them?
IL-1, IL-6, TNF-alpha
produced by many cells, but mostly monocytes/macrophages
low level produces local inflammation
high level causes shock, disseminated intravascular blood coagulation (DIC)
chronic causes cachexia (weight loss), loss of tissue
what is the effect of low levels, high levels, and chronic levels of IL-1, IL-6, and/or TNF-alpha?
inflammatory cytokines
low level produces local inflammation
high level causes shock, disseminated intravascular blood coagulation (DIC)
chronic causes cachexia (weight loss), loss of tissue
given that inflammatory cytokines (IL-1, IL-6, TNF-alpha) produce the signs and symptoms of infection, predict the effect on the following organ/systems:
a. CNS
b. muscle
c. fat
d. bone
e. circulation
f. bone marrow
a. CNS —> fever, anorexia, malaise
b. muscle —> pain/soreness, proteolysis
c. fat —> lipolysis
d. bone —> resorption
e. circulation —> dilation lowers blood pressure
f. bone marrow —> higher WBC count (neutrophil proliferation)
cytokine storms
when inflammation gets out of control, dysregulation of inflammatory cytokines (IL-1, IL-6, TNF-a)
what cytokine is the “T cell growth factor”
IL-2
contrast effect of IL-4/5 and IFN-y on B cell differentiation
IL-4 (from Th2) —> B cell differentiates to IgE-producing plasma cells (activate mast cells and eosinophils)
IL-5 (from Th2) —> B cell differentiates to IgA-producing plasma cells (activate eosinophils)
IFN-y (from Th1) —> B cell differentiates to IgG-producing plasma cells (activate macrophages)
in HIV infection, CD4 on T cells is sufficient for viral attachment to cells, but not for infection
what additional factors are needed
either of 2 chemokines - CXCR4 (on T cells) or CCR5 (macrophages, some T cells)
some individuals have mutations in CCR5 that can confer HIV resistance
which of these induces production of acute phase proteins from the liver?
a. TNF-alpha
b. IL-17A
c. IL-6
d. IL-2
e. IFN-y
c. IL-6 (Th2, macrophage, B cells) —> inflammation, production of acute phase inflammation proteins from liver
A mutation in the gamma receptor chain of which of these will cause X-SCID?
a. IL-4
b. TGF-beta
c. IL-6
d. IL-11
a. IL-4 - Type I (hemopoetin) receptor (Jak/STAT), gamma chain family —> mutation causes X-SCID (no T/NK, normal B cells)
also gamma family: IL-2, IL-15
A mutation in the g130 receptor subunit of which of these causes lethal Stuve-Wiedemann-like syndrome?
a. GM-CSF
b. TNF-alpha
c. IL-12
d. IL-6
d. IL-6 - mutation in gp130 receptor subunit —> lethal
also have gp130 subunit (so same effect can occur): IL-11, IL-27