Cytokines, Mediators and Homeostasis

Adrenomedullin plays a significant role in the regulation of many cytokines and mediators, and is a key mediator in maintaining vascular tone and a constant blood supply to individual organs and tissues. This makes adrenomedullin crucial in homeostasis and in many disease conditions.

 

Mechanism of action and functions of Adrenomedullin

Down: Adrenomedullin is down-regulated by IFN-γ; TGF-β; Down: Adrenomedullin down-regulates TNF-α; IL-6; IL-1β; IL-12; IFN-γ; MIP-2; RANTES; Serum amyloid A; Up: Adrenomedullin is up-regulated by LPS; TNF-α; IL-6; Hypoxia; Shear stress; IL-1β; Nitric oxide; Up: Adrenomedullin up-regulates IL-10

Adrenomedullin, present mainly in endothelial and vascular smooth muscle cells19, can act as both a hormone and cytokine (often termed a “hormokine”20) in an autocrine and paracrine manner21. Its potent vasodilatory and hypotensive response is elicited through an initial increase in cyclic adenosine monophosphate levels, and a subsequent production of nitric oxide1, 22, 23.

The importance of adrenomedullin in homeostasis is illustrated by its central role in the up- and down-regulation of cytokines and other mediators, as well as its own stimulatory and inhibitory24, 25 effect on cytokine production. Indeed, Interleukin (IL)-1β and tumour necrosis factor (TNF) are two of the most potent stimulators for adrenomedullin production26 and adrenomedullin itself is up-regulated by hypoxia, bacterial products and shear stress20.

The ubiquitous and important functional role of adrenomedullin results in its clinical use in many diverse indications. For example, its precursor molecule, MR-proADM, has been shown to be a powerful risk assessment marker in sepsis and lower respiratory tract infections8, 17, 27, 28, with the ability to predict 30-day mortality regardless of the underlying diagnosis29, and in the non-specific complaints of elderly patients30. Its plasma concentrations have been shown to be elevated in myocardial infarction, and to correlate with the severity of acute and chronic heart failure31-34, as well as being elevated in various types of glomerulonephritis and progressively increased in patients with chronic renal failure35, 36.

 

Adrenomedullin: a key mediatorAdrenomedullin: a key mediator

  • Up-regulated by LPS and pro-inflammatory cytokines (including TNF-α and IL-1β)26, 37-39
  • Potent anti-microbial, through membrane channel formation and lysis, and anti-apoptotic actions40-43
  • Enhanced or modified activity via interaction with complement factor H5, 21, 44, 45
  • Significant role in cellular growth, development, chemotaxis and migration46-51

 

 

Adrenomedullin: vasodilation is keyAdrenomedullin: vasodilation is key

  • Key mediator of vascular tone regulation resulting in an intense, prolonged vasorelaxation and hypotension1, 2, 17, 52-54
  • Widespread production helps maintain blood supply to individual organs1, 2, 23
  • Localized cellular production and release to meet specific perfusion requirements of individual organs21, 55
  • Significant role in hemorrhagic and endotoxic shock56-58, pulmonary hypertension13, hypertrophy59, 60, hypoxia61-66, oxidative stress67, ischaemic myocardial injury27, 68-70 and ischaemic injury and organ failure7, 71

 

Adrenomedullin: key role in organ protectionAdrenomedullin: key role in organ protection

  • Use as marker for the early prediction of organ dysfunction and outcome72
  • Protects against endothelial permeability and consequent organ damage73-75
  • Protective effects in organs in response to bacterial induced shock76, 77
  • Stabilization of microcirculation in inflammation - a hallmark of organ failure78
  • Restoration of endothelial stability in infected organs due to prevention of undesired inflammatory decompartmentalization79

 

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