Cytokines - Langer 4/6/16 Flashcards Preview

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

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


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


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


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


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


major classes of 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


general properties of IL/IFNs


  • 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


cytokine therapeutics:

IFNalpha, IFN beta

broad spectrum antiviral

(hepB, hepC, treatment of MS)


cytokine therapeutics:


in vitro growth of T cells for T cell therapies

some anti-tumor apps


cytokine therapeutics:


growth factor for neutrophils follwing bone marrow transplant

neutropenia following chemo


cytokine therapeutics:


chronic granulomatous disease

(poor killing of bacteria by neutrophils)


cytokine therapeutics:





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


Type I interferons



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)




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



T cell growth factor


IL4, IL5

B cell growth, survival, diff



activates macrophages (produced by T cells)



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


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)


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"


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



  • 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


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


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