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


OBJECTIVE
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.
Ohnishi
Hiroshi
H
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Miyahara
Nobuaki
N
Dakhama
Azzeddine
A
Takeda
Katsuyuki
K
Mathis
Steven
S
Haribabu
Bodduluri
B
Gelfand
Erwin W
EW
D000276:Adjuvants, Immunologic / Q000502:physiology; D000485:Allergens / Q000502:physiology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004527:Egg Proteins / Q000502:physiology; D007156:Immunologic Memory / Q000187:drug effects; D018836:Inflammation Mediators / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology* / Q000502:physiology; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects; D018102:Receptors, Leukotriene B4 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000485:Allergens; D004527:Egg Proteins; D018836:Inflammation Mediators; C503704:Ltb4r1 protein, mouse; C110366:OVA-8; D010446:Peptide Fragments; D018102:Receptors, Leukotriene B4; D003907:Dexamethasone; D010047:Ovalbumin