Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation

Hiroshi Ohnishi, Katsuyuki Takeda, Joanne Domenico, Joseph J. Lucas, Nobuaki Miyahara, Christina H. Swasey, Azzeddine Dakhama, Erwin W. Gelfand

Research output: Contribution to journalArticle

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Abstract

Background: Ligation of the leukotriene B4 (LTB4) receptor 1 on effector memory CD8+ T cells by LTB4 is important for the recruitment of CD8+ T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types. Objective: The roles of ERKs in effector CD8+ T-cell function and on CD8+ T cell-mediated AHR were determined. Methods: Effector CD8+ T cells were generated from OVA257-264 (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8+ T-cell function and on CD8+ T cell-mediated AHR and allergic inflammation were examined. Results: Pretreatment of effector CD8+ T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB4-induced Ca2+ mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8+ T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8+ T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment. Conclusion: ERK1/2-dependent pathways are essential for the effector functions of CD8+ T cells, including TH2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8+ T cell-mediated AHR.

Original languageEnglish
Pages (from-to)249-257
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume123
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Inflammation
T-Lymphocytes
Leukotriene B4
Extracellular Signal-Regulated MAP Kinases
Bronchoalveolar Lavage Fluid
Cytokines
Leukotriene B4 Receptors
Phosphorylation
Goblet Cells
Interleukin-13
Adoptive Transfer
MAP Kinase Signaling System
Interleukin-5
Metaplasia
Chemotaxis
Allergens
Ligation

Keywords

  • Allergy
  • asthma
  • effector memory T cell
  • mitogen-activated protein kinase
  • signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation. / Ohnishi, Hiroshi; Takeda, Katsuyuki; Domenico, Joanne; Lucas, Joseph J.; Miyahara, Nobuaki; Swasey, Christina H.; Dakhama, Azzeddine; Gelfand, Erwin W.

In: Journal of Allergy and Clinical Immunology, Vol. 123, No. 1, 01.2009, p. 249-257.

Research output: Contribution to journalArticle

Ohnishi, Hiroshi ; Takeda, Katsuyuki ; Domenico, Joanne ; Lucas, Joseph J. ; Miyahara, Nobuaki ; Swasey, Christina H. ; Dakhama, Azzeddine ; Gelfand, Erwin W. / Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation. In: Journal of Allergy and Clinical Immunology. 2009 ; Vol. 123, No. 1. pp. 249-257.
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AU - Ohnishi, Hiroshi

AU - Takeda, Katsuyuki

AU - Domenico, Joanne

AU - Lucas, Joseph J.

AU - Miyahara, Nobuaki

AU - Swasey, Christina H.

AU - Dakhama, Azzeddine

AU - Gelfand, Erwin W.

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AB - Background: Ligation of the leukotriene B4 (LTB4) receptor 1 on effector memory CD8+ T cells by LTB4 is important for the recruitment of CD8+ T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types. Objective: The roles of ERKs in effector CD8+ T-cell function and on CD8+ T cell-mediated AHR were determined. Methods: Effector CD8+ T cells were generated from OVA257-264 (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8+ T-cell function and on CD8+ T cell-mediated AHR and allergic inflammation were examined. Results: Pretreatment of effector CD8+ T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB4-induced Ca2+ mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8+ T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8+ T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment. Conclusion: ERK1/2-dependent pathways are essential for the effector functions of CD8+ T cells, including TH2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8+ T cell-mediated AHR.

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KW - signal transduction

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