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β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.

Publication ,  Journal Article
Nichols, HL; Saffeddine, M; Theriot, BS; Hegde, A; Polley, D; El Mays, T; Vliagoftis, H; Hollenberg, MD; Wilson, EH; Walker, JK; Defea, KA
Published in: Proceedings of the National Academy of Sciences of the United States of America
October 2012

Proteinase-Activated rreceptor-2 (PAR(2)), a G-protein-coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR(2) have been proposed for treating asthma. PAR(2) can signal through two independent pathways: a β-arrestin-dependent one that promotes leukocyte migration, and a G-protein/Ca(2+) one that is required for prostaglandin E(2) (PGE(2)) production and bronchiolar smooth muscle relaxation. We hypothesized that the proinflammatory responses to PAR(2) activation are mediated by β-arrestins, whereas the protective effects are not. Using a mouse ovalbumin model for PAR(2)-modulated airway inflammation, we observed decreased leukocyte recruitment, cytokine production, and mucin production in β-arrestin-2(-/-) mice. In contrast, PAR(2)-mediated PGE(2) production, smooth muscle relaxation, and decreased baseline airway resistance (measures of putative PAR(2) "protective" effects) were independent of β-arrestin-2. Flow cytometry and cytospins reveal that lung eosinophil and CD4 T-cell infiltration, and production of IL-4, IL-6, IL-13, and TNFα, were enhanced in wild-type but not β-arrestin-2(-/-) mice. Using the forced oscillation technique to measure airway resistance reveals that PAR(2) activation protects against airway hyperresponsiveness by an unknown mechanism, possibly involving smooth muscle relaxation. Our data suggest that the PAR(2)-enhanced inflammatory process is β-arrestin-2 dependent, whereas the protective anticonstrictor effect of bronchial epithelial PAR(2) may be β-arrestin independent.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

ISSN

1091-6490

Publication Date

October 2012

Volume

109

Issue

41

Start / End Page

16660 / 16665

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Receptor, PAR-2
  • Microscopy, Confocal
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Leukocytes
 

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Nichols, H. L., Saffeddine, M., Theriot, B. S., Hegde, A., Polley, D., El Mays, T., … Defea, K. A. (2012). β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proceedings of the National Academy of Sciences of the United States of America, 109(41), 16660–16665. https://doi.org/10.1073/pnas.1208881109
Nichols, H. L., M. Saffeddine, B. S. Theriot, A. Hegde, D. Polley, T. El Mays, H. Vliagoftis, et al. “β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.Proceedings of the National Academy of Sciences of the United States of America 109, no. 41 (October 2012): 16660–65. https://doi.org/10.1073/pnas.1208881109.
Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El Mays T, et al. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proceedings of the National Academy of Sciences of the United States of America. 2012 Oct;109(41):16660–5.
Nichols, H. L., et al. “β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 41, Oct. 2012, pp. 16660–65. Manual, doi:10.1073/pnas.1208881109.
Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El Mays T, Vliagoftis H, Hollenberg MD, Wilson EH, Walker JK, Defea KA. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proceedings of the National Academy of Sciences of the United States of America. 2012 Oct;109(41):16660–16665.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

ISSN

1091-6490

Publication Date

October 2012

Volume

109

Issue

41

Start / End Page

16660 / 16665

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Receptor, PAR-2
  • Microscopy, Confocal
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Leukocytes