Corticosteroids enhance CD8+ T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1.

Abstract

BACKGROUND:

Leukotriene B4 (LTB4) is a potent inflammatory lipid mediator that binds to LTB4 receptor 1 (BLT1). Ligation of BLT1 by LTB4 plays an important role in the recruitment of effector memory CD8+ T cells into the airways of sensitized and challenged mice.

OBJECTIVES:

The effects of the corticosteroid dexamethasone (DEX) on BLT1-expressing effector memory CD8+ T cells and effector memory CD8+ T cell-mediated airway hyperresponsiveness (AHR) and allergic inflammation were determined.

METHODS:

Effector memory CD8+ T cells were generated from ovalbumin(257-264)-primed mononuclear cells from OT-1 mice in the presence of IL-2. In some cultures DEX was added. The effects of DEX on BLT1 expression, LTB4-induced Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, chemotaxis, and effector memory CD8+ T cell-mediated AHR were examined.

RESULTS:

DEX-treated effector memory CD8+ T cells showed significant increases in surface expression of BLT1, LTB4-induced intracellular Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, and chemotaxis. Upregulation of BLT1 by DEX was accompanied by increased IL-2 receptor expression. Adoptive transfer of DEX-treated effector memory CD8+ T cells into ovalbumin-sensitized and ovalbumin-challenged CD8-/- mice resulted in significant increases in AHR, allergic inflammation, goblet cell metaplasia, and numbers of both CD8+ and CD4+ T cells in the bronchoalveolar lavage fluid and lungs.

CONCLUSIONS:

Corticosteroids upregulate BLT1 on effector memory CD8+ T cells and related signaling pathways and potentiate allergic airway inflammation and AHR induced by these cells.

• Authors: Hiroshi Ohnishi, Nobuaki Miyahara, Azzeddine Dakhama, Katsuyuki Takeda, Steven Mathis, Bodduluri Haribabu, Erwin W Gelfand
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 121 Issue 4 Pg. 864-71.e4 (Apr 2008) ISSN: 1097-6825 [Electronic] United States
• PMID: 18395551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Allergens
• Egg Proteins
• Inflammation Mediators
• Ltb4r1 protein, mouse
• OVA-8
• Peptide Fragments
• Receptors, Leukotriene B4
• Dexamethasone
• Ovalbumin

Topics

• Adjuvants, Immunologic (physiology)
• Allergens (physiology)
• Animals
• Bronchial Hyperreactivity (immunology, pathology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Calcium Signaling (drug effects, immunology)
• Cell Differentiation (drug effects, immunology)
• Cells, Cultured
• Dexamethasone (pharmacology)
• Egg Proteins (physiology)
• Immunologic Memory (drug effects)
• Inflammation Mediators (physiology)
• MAP Kinase Signaling System (genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Ovalbumin (immunology, physiology)
• Peptide Fragments
• Phosphorylation (drug effects)
• Receptors, Leukotriene B4 (biosynthesis, deficiency, genetics, physiology)
• Up-Regulation (immunology)