The double effect of Dexmethasone

[Guest guest]

Dexmethasone is a glucocorticoid and therefore is used for its anti-inflammatory

properties, but it turns out that it has a double effect on some lymphocytes, by

making

them more sensitive to leukotrienes. In mice, this translates into increased

allergic

inflammation.

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Corticosteroids enhance CD8+ T cell–mediated airway hyperresponsiveness and

allergic

inflammation by upregulating leukotriene B4 receptor 1

Journal of Allergy and Clinical Immunology - April, 2008

Hiroshi Ohnishi, MD, PhDa, Nobuaki Miyahara, MD, PhDa, Azzeddine Dakhama, PhDa,

Katsuyuki Takeda, MD, PhDa, Mathis, PhDb, Bodduluri Haribabu, PhDb, Erwin

W.

Gelfand, MDa

Received 24 September 2007; received in revised form 25 January 2008; accepted

29

January 2008.

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 ovalbumin257-264–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.