Down-regulation of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), an endogenous allosteric alpha7 nicotinic acetylcholine receptor modulator, in murine and human asthmatic conditions

Biochem Biophys Res Commun. 2010 Aug 6;398(4):713-8. doi: 10.1016/j.bbrc.2010.07.006. Epub 2010 Jul 16.

Abstract

Whereas acetylcholine (ACh) acts as a bronchoconstrictor and stimulator of mucus secretion from bronchial epithelium, it acts via alpha7 nicotinic Ach receptors (nAChRs) on macrophages in the airways to exert anti-inflammatory effects by reducing synthesis of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). Moreover, the effects of ACh are modified by secreted ly-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of alpha7 nAChR signaling. Our aim was to explore the roles played by SLURP-1 in the pathophysiology of asthma by assessing SLURP-1 expression in the OVA-sensitized murine asthma model and in cultured human bronchial epithelial cells. Using real-time PCR we found that expression of SLURP-1 mRNA is down-regulated in the lungs of asthmatic model mice, as compared to healthy mice. In addition, immunohistochemical studies confirmed the diminished expression of SLURP-1 in the bronchioles of asthmatic mice, and showed it was due to extensive metaplasia of mucus-secreting cells and the concomitant loss of ciliated epithelial cells. Expression of SLURP-1 mRNA and protein was also significantly down-regulated in human epithelial cells stimulated with the pro-inflammatory cytokine interleukin-13 (IL-13), which is related to asthmatic condition. Thus SLURP-1 appears to be down-regulated in both an animal model of asthma and human epithelial cells treated with an inflammatory cytokine related to asthma. Those findings suggest that diminished expression of SLURP-1 in asthma attenuates its negative regulation of airway inflammation, and that perhaps changes in SLURP-1 expression could serve as a marker of airway damage in asthma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism*
  • Asthma / metabolism*
  • Asthma / pathology
  • Biomarkers / metabolism
  • Bronchi / metabolism
  • Bronchi / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / metabolism
  • Receptors, Nicotinic / metabolism*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism*
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Antigens, Ly
  • Biomarkers
  • Chrna7 protein, human
  • Chrna7 protein, mouse
  • RNA, Messenger
  • Receptors, Nicotinic
  • SLURP1 protein, human
  • alpha7 Nicotinic Acetylcholine Receptor
  • Urokinase-Type Plasminogen Activator