MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: a new perspective for the treatment

Pharmacol Res. 2013 May:71:9-18. doi: 10.1016/j.phrs.2013.02.004. Epub 2013 Feb 18.

Abstract

Airway hyperreactivity (AHR) is a major feature of asthmatic and inflammatory airways. Cigarette smoke exposure, and bacterial and viral infections are well-known environmental risk factors for AHR, but knowledge about the underlying molecular mechanisms on how these risk factors lead to the development of AHR is limited. Activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) and their related signal pathways including protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and protein kinase A (PKA) signaling pathways may result in airway kinin receptor upregulation, which is suggested to play an important role in the development of AHR. Environmental risk factors trigger the production of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukins (ILs) that activate intracellular MAPK- and NF-κB-dependent inflammatory pathways, which subsequently lead to AHR via kinin receptor upregulation. Blockage of intracellular MAPK/NF-κB signaling prevents kinin B₁ and B₂ receptor expression in the airways, resulting in a decrease in the response to bradykinin (kinin B₂ receptor agonist) and des-Arg⁹-bradykinin (kinin B₁ receptor agonist). This suggests that MAPK- and NF-κB-dependent kinin receptor upregulation can provide a novel option for treatment of AHR in asthmatic as well as in other inflammatory airway diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / genetics
  • Asthma / immunology*
  • Humans
  • Inflammation Mediators / immunology*
  • Kinins / immunology
  • Mitogen-Activated Protein Kinases / immunology*
  • Molecular Targeted Therapy
  • NF-kappa B / immunology*
  • NF-kappaB-Inducing Kinase
  • Protein Serine-Threonine Kinases / immunology*
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / immunology*
  • Receptor, Bradykinin B2 / genetics
  • Receptor, Bradykinin B2 / immunology*
  • Signal Transduction
  • Up-Regulation

Substances

  • Inflammation Mediators
  • Kinins
  • NF-kappa B
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases