Cytokines - Langer 4/6/16 Flashcards Preview

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Flashcards in Cytokines - Langer 4/6/16 Deck (25):
1

body has to coordinate the actions of a large number of organs, tissues, etc at the CELLULAR LEVEL

 

communication is key

describe multiple modes of comm used by the body on this front

1. cell-cell contact via interaction of membrane proteins 

ex. TCR-MHC interactions

2. secretion of "signal proteins" that bind membrane receptors on target cells

ex cytokines

3. secretion of other small molecules that bind membrane receptors on target cells

ex. eicosanoids, prostaglandins involved with infl response

2

general properties of cytokines

  • proteins
  • synth'd and secreted in response to external stimuli
  • often transient (controled by transc, post-transl mechs)
  • pleiotropic : one cytokine can have diff effects on many cell types
    • can depend on time of exposure, concentration of cytokine
  • redundant : diff cytokines can have same/overlapping effects
  • autocrine, paracrine, endocrine effects

3

pleiotropy of cytokines

one cytokine can have diff effects on many cell types

  • can depend on time of exposure, concentration of cytokine

ex. IL1

  • hepatocytes → synth of acute phase proteins
  • osteoclasts → bone resorption
  • neutrophils → increased adhesion to endothelium

 

one way to understand pleiotropic effects of cytokines : cytokines "answer" a question

  • same answer can have diff effects depending on the question being asked → diff cells at diff stages are asking diff Qs, so cytokines may affect them differently

4

experimental methods to discover cytokines

1. [historical] cellular assay

2. [genomic era] "in silico"

  • look for relationship to known cytokines
  • downside: you'll only find things that look structurally similar to the sequence you're using as baseline

5

general ROLES of cytokines

1. developmental : formation of immune system → stimulation of cell production, prolif, diff

2. homeostasis : maintenance → targeting cells to immune tissues for formation/organization

3. response to infection/infl

6

major classes of cytokines

cytokines

  • generally soluble proteins, >18kD
  • signal through receptors coupled to protein kinases growth, diff, fx of immune system cells
  • produce local and systemic manifestations of disease

chemokines (= chemotactic cytokine)

  • smaller (8-10 kD)
  • signal through G protein coupled receptors (GCPRs) chemotactic effects (attract infl/effector cells to site of chemokine prod), cellular activation, devptal targeting of cells to organs

7

general properties of IL/IFNs

interleukins/interferons

  • induced/produced transiently when and where needed
    • unregulated or chronic production can cause damage
  • mechanism: bind to specific cell-surface receptor proteins → intracellular signaling cascade → changes in transcription/other pathways
  • pleiotropy, i.e. cells may undergo many diff changes and/or diff cells may respond differently

8

cytokine therapeutics:

IFNalpha, IFN beta

broad spectrum antiviral

(hepB, hepC, treatment of MS)

9

cytokine therapeutics:

IL2

in vitro growth of T cells for T cell therapies

some anti-tumor apps

10

cytokine therapeutics:

GM-CSF

growth factor for neutrophils follwing bone marrow transplant

neutropenia following chemo

11

cytokine therapeutics:

IFN-gamma

chronic granulomatous disease

(poor killing of bacteria by neutrophils)

12

cytokine therapeutics:

epo

anemia

myelodysplasia

13

specfic cytokines and their roles

  • IFN1
  • IL1/TNFalpha
  • cytokines in T cell and B cell diff and maturation
  • chemokines

 

  • IFN1 : antiviral protection
  • IL1/TNFalpha : inflammation
  • cytokines in T cell and B cell diff and maturation
  • chemokines

14

Type I interferons

 

basics

gen mechanism

globular proteins with 5 alpha helices

whole family encoded in a cluster on chr9

  • 13 IFNalpha, IFNbeta, IFNepsilon, IFNomega, IFNkappa : prob evolved through duplication/divergence
  • receptor: IFNAR = IFNAR1 + IFNAR2

 

general mechanism

IFN binds to IFNAR (heterodimer) → stimulates Jak/STAT pathway → cascade which eventually hits nuclear ISRE (ifn stimulatory resp element) → stimulate ISG (ifn stimulated genes) → transc/transl of proteins that have cellular effect

  • direct antiviral effects
  • apoptosis
  • stimulation of adaptive and innate immune resp
    • MHC induction
    • NK cell activation
    • DC maturation
    • Th1 biasing
    • B-cell class switching → IgG (viruses vs allergens)

15

IFN1

 

what if the stimulus is an immune complex instead of a virus?

in a situation like lupus, immune complexes can be mistaken for virus!

→ IFN constantly being made → autoimmunity

16

IL2

T cell growth factor

17

IL4, IL5

B cell growth, survival, diff

18

IFN-gamma

activates macrophages (produced by T cells)

19

IL10

inhibits immune responses (except when activating them...)

20

cytokine receptor families

  • IL2, IL4
  • IFNalpha, IFNbeta, IL10
  • TNFalpha
  • IL1
  • chemokines

  • IL2, IL4 : Type I cytokine (hematopoeitin) receptors - dimeric
  • IFNalpha, IFNbeta, IL10 : Type II cytokine receptors - dimeric
  • TNFalpha : TNF receptor family - trimeric
  • IL1 : IL1 receptor family
  • chemokines : Gprotein coupled receptors

 

**cytokine receptor families sometimes have common subunits (ex. gamma-c)

  • mutation in that subunit gene → more than one signal affected (ex. mutation in gamma-c → X-SCID, severe combined immunodeficiency due to mutation on X chromosome)

21

inflammatory cytokines

IL1 & TNFalpha (and IL6)

"pro-inflammatory" cytokines

 

  • major producers: monocytes and macrophages, esp in response to bacteria
    • can be produced by several other cell types
  • effect dependent on level and persistence of production
    • low : local infl + stimulates body's response to damage/infection
    • high : shock, disseminated intravascular coagulation (DIC), death
    • chronic : weight loss, loss of conn tissue and bone
  • typical sepsis cascade: LPS → TNF → IL1 → IL6 in "waves"

22

role of cytokines in T cell and B cell devpt and diff

IL2 is the key growth factor for proliferation of all T cells → acts via IL2 receptor

 

diff combos of other cytokines present work together to lead to diff specific outcomes during differentiation

 

ex. Th1 cell devpt

DCs and macrophages interact with mibrobes, produce IL12  (maturation of naive T cell)

NK cells produce IFN-gamma (T cell diff)

  • combo of IL12 and IFNgamma → STAT4 and STAT1 respectively → tf Tbet → Th1 cells

23

chemokines

  • size
  • major effects
  • structural relationships based on... & naming

small proteins

signal chemotaxis and "homing", modulate cell adhesion

signal through GPCRs → activate cellular G proteins

  • over 20 known receptors, with some overlap ("promiscuity") → multiple chemokines can interact with some receptors, producing similar effects

structural family relationships based on Cys in structure

  • C chemokines - 1 Cys = CCLx
  • CC - 2 Cys = CCL
  • CXC - 2 Cys sep by 1 a.a. = CXCLx
  • CX3C - 2 Cys sep by 3 a.a. = CX3CLx
  • XCL - other a.a. patterns

24

chemokine & receptor expression

  • expression can be constitutive or inducible
  • can be modified by cell maturation, diff, cytokine action
  • cells can express characteristic chemokine receptors, but can also express multiple chemokine receptors → highly sensitive immune response

25

real life: 

chemokine receptors and HIV

dominant receptor for HIV : CD4 protein on T cells

  • sufficient for viral attachment, NOT INFECTION

need either CXCR4 (T cells) or CCR5 (macrophages, some T cells) to get infection

→ some people with mutations in CCR5 are resistant to infection

 

implication: CXCR4 and CCR5 are routes to look at for HIV therapies