Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB.

Abstract

RATIONALE:

Helper CD4(+) T cell subsets, including IL-9- and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation.

OBJECTIVES:

To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation.

METHODS:

COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.

MEASUREMENTS AND MAIN RESULTS:

Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro.

CONCLUSIONS:

COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.

• Authors: Hong Li, Matthew L Edin, J Alyce Bradbury, Joan P Graves, Laura M DeGraff, Artiom Gruzdev, Jennifer Cheng, Ryan T Dackor, Ping Ming Wang, Carl D Bortner, Stavros Garantziotis, Anton M Jetten, Darryl C Zeldin
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 187 Issue 8 Pg. 812-22 (Apr 15 2013) ISSN: 1535-4970 [Electronic] United States
• PMID: 23449692 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cytokines
• Eicosanoids
• Il17rb protein, mouse
• Receptors, Interleukin-17

Topics

• Animals
• Asthma (immunology)
• Cyclooxygenase 2 Inhibitors (immunology)
• Cytokines (analysis)
• Eicosanoids (immunology, physiology)
• Flow Cytometry
• Humans
• Immunoblotting
• Inflammation (immunology)
• Lung (immunology)
• Male
• Mice
• Microscopy, Confocal
• Models, Animal
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-17 (immunology)
• T-Lymphocyte Subsets (immunology)