Home ANAT 322 Monday, February 27, 2012

Monday, February 27, 2012 CC-BY-NC
Cytokines and neuroendocrine functions

Maintainer: admin

1Main idea

IL1 , a cytokine released during inflammatory response at the site of infection. IL1 would travel to the brain, through some mechanisms, induce release of prostaglandin (which brings up the body temperature and promotes fever) and, at the same time, act on PVN to ultimately induce the synthesis and release of glucocorticoid, which is immunosuppression. So in summary, it acts to bring up the fever and curb the immuno response.

2Cytokine basic info

  • commonly associated with immune system.
  • main function :
    • have pleiotropic actions (influence the same cells to do different things)
    • overlapping functions (like IL1 and IL6)
    • each cytokine recognizes and bnids to its specific receptor
    • induce acute responses like inflammation
      • there are pro inflammatory and anti-inflammatry cytokines
    • make capillaries leaky
    • cell growth/survivial/death.
  • families:
    • interleukins
    • tumour necrosis factors (TNF)
    • chemokinse (make capillaries leaky)
    • transforming growth factors (TGF)
    • interferons (released upon viral infection)
    • growth factors (FGF, EGF...)
  • size : 15-30 kDa
  • You'll have fun learning about a whole bunch of cyokines in immunology 314.

3IL1(our focus of the lecture

  • pro-inflammatory cytokines
  • receptor: IL1R1
    • ligands: IL1a and IL1b
    • need to be associated with an accessory protein (IL-1acP) to exert downstream effects
      • NK-kB, a transcription factor, becomes activated to do its job.
    • IRAK : IL-1R associated kinase
    • antagonist: Il-1ra
      • binds to Il-1R1 but fails to trigger Il-R1 and AcP association
      • blocks all action of IL-1a and IL-1b
  • decoy receptor IL-1RII
    • aka scavanger receptor.
    • soluble
    • have no signaling action but simply buffer out the excessive IL1
  • Il-1 are formed as active precursors (except pro-IL1b)

4Glucocorticoid

  • produced in adrenal gland
  • evidences that suggest adrenal gland has to do with immune system
    • thymus, site of T cells maturation, enlarges when adrenal gland is removed
    • body's response to stress includes enlargement of adrenal gland and involution of the thymus
      • body is more vulnerable to infection when stressed.
  • Yes indeed, glucocorticoid produced in adrenal gland suppresses inflammation.
    • important role in regulating immune response.
    • decreased endogenous corticosterone blood levels result in an incrased number of B cells
    • it's proposed that glucocorticoid production protects not against the source of stress but rather against "body's normal response to stress" (to prevent reactions from overshooting and destory the homeostatsis. Cool! )
  • some studies suggest that immune cells limits theri own activity by secreting molecules that stimulate the secretion of glucocorticoid
    • this is regulatory feedback mechanism
    • glucocorticoid increasing factors (GIF) is IL1
  • release of glucocoritcoid is delayed in a immune response
    • make sense, you want suppress later, not immediately.
    • the mechanism behind the delay is not well understood.

5IL1 action on glucocorticoid

  • pathway of glucocorticoid production: PVN (release CRF) --> anterior pituitary (release ACTH) --> adrenal gland (release glucocorticoid)
  • experiments on cultured adrenal cells suggested that IL1 doesn't act on adrenal gland to induce glucocoricoid release.
  • systemic administration IL1 increases plasma ACTH and GC concentratinos
    • it acts on PVN
  • in vivo studies suggested that Il1 act on the hypothalamus rather than direct activation fo the pitutiary.
    • eletrical and neurochemical activity of the hypothalamus is altered during an immune response.
    • IL-1R is expressed in the hypothalamus. (in PVN)

6IL1 action on prostaglandin

  • prostaglandin:
    • pyrogenic mediators (fever-inducing, shifts the "set point" and thereby induces fever)
  • LPS (grain - bacteria cell wall stuff) binds to TLR4 (toll-like receptor) on macrophage and induce release of IL1, IL6, TNFa
  • IL1 can then go through blood brain barrier (BBB), into the brain
    • it can also act on receptorson endothelial cell membrane
    • ilicits more IL1 production by the neurons in the brain (site of production is not limtied to injured sites)
    • IL1 then acts on neighboring neurons to increase PGE2 production, which then exerts effects on the PVN.
  • circulating IL-1 acts on endothelial cells to induce PGE2(prostaglandin) in the brain
  • evidences:
    • endothelial cells in the rat brain express IL-1R1
    • endothelial cells in culture with IL1B induces dose-dependent increase in PGE2
  • experiments:
    • either systemic infection of LPS cytokines or intracerebroventricular (ICV) injection of cytokines (w/ less concentration, into the third ventricle)
    • result: either method leads to increase in core body temperature
      • temperature is dampened when Il-1ra (the antagonist of IL1) is co-injected.
    • hypothalamus, a temperatue control center, surrounds the third ventricle, so the experiment is legit cuz the injected stuff diffuse into the hypothalamus.
    • it's also found that Il-1b gene expression in the brain, esp. PVN, increaes following systemic inflammation
      • evidence that neurons can also produce their own IL1.
      • action on PVN, which ultimately leads to increase in glucocorticoid production.

7Summary and NSAIDs

  • IL 1 produces three events:
    • IL1 production in the brain. IL1 then acts on brain
    • PGE production
      • via interaction of IL1 and neurons that produce PGE
      • or via IL1 binding on to IL-1R receptor on endothelial cells
    • act on PVN to induces glucocorticoid production
  • NSAIDS are drugs that bring down fever
    • COX2 inhibitor (COX2: critical enzyme for PGE production
    • IL1 antagonist (Il-1ra )