Expression and regulation of intercellular adhesion molecule-1 on airway parasympathetic nerves

J Allergy Clin Immunol. 2007 Jun;119(6):1415-22. doi: 10.1016/j.jaci.2007.03.005. Epub 2007 Apr 5.

Abstract

Background: Eosinophils cluster along airway nerves in patients with asthma and release eosinophil major basic protein, an antagonist of inhibitory M2 muscarinic receptors on nerves. Blocking M2 function increases bronchoconstriction, leading to airway hyperreactivity. Intercellular adhesion molecule-1 (ICAM-1) mediates eosinophil adhesion to nerves.

Objective: We investigated mechanisms of ICAM-1 expression by parasympathetic nerves.

Methods: ICAM-1 expression was examined by immunocytochemistry of lung sections from ovalbumin-sensitized and challenged guinea pigs. ICAM-1 was measured in parasympathetic nerves isolated from subjects and guinea pigs and in human neuroblastoma cells by real-time RT-PCR, immunocytochemistry, and Western blot.

Results: ICAM-1 was not detected in control airway parasympatheric nerves in vivo or in cultured cells. ICAM-1 was expressed throughout antigen-challenged guinea pig lung tissue and was selectively decreased by dexamethasone only in nerves. ICAM-1 was induced in human and guinea pig parasympathetic nerves by TNF-alpha and IFN-gamma and was inhibited by dexamethasone and by an inhibitor of nuclear factor-kappaB (NF-kappaB). In neuroblastoma cell lines TNF-alpha and IFN-gamma-induced ICAM-1 was blocked by an inhibitor of NF-kappaB but not by inhibitors of mitogen-activated protein kinases. Dexamethasone did not inhibit ICAM-1 expression in neuroblastoma cells.

Conclusions: ICAM-1 induced in nerves by antigen challenge and proinflammatory cytokines is sensitive to dexamethasone. ICAM-1 expression is also sensitive to inhibitors of NF-kappaB. Neuroblastoma cells mimic many, but not all, characteristics of ICAM-1 expression in parasympathetic nerves.

Clinical implications: Dexamethasone and NF-kappaB inhibitors could prevent eosinophils from adhering to nerves by blocking ICAM-1 expression on parasympathetic nerves, thus protecting inhibitory M2 muscarinic receptors and making this pathway a potential target for asthma treatment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Expression Regulation / physiology*
  • Guinea Pigs
  • Humans
  • Inflammation Mediators / pharmacology
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / genetics*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interferon-gamma / pharmacology
  • Lung / cytology
  • Lung / innervation*
  • Lung / metabolism
  • Neurons / immunology
  • Neurons / metabolism
  • Ovalbumin / administration & dosage
  • Ovalbumin / immunology
  • Parasympathetic Nervous System / cytology
  • Parasympathetic Nervous System / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Inflammation Mediators
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Interferon-gamma
  • Ovalbumin