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

Ohnishi, Hiroshi; Miyahara, Nobuaki; Dakhama, Azzeddine; Takeda, Katsuyuki; Mathis, Steven; Haribabu, Bodduluri; Gelfand, Erwin W.

doi:10.1016/j.jaci.2008.01.035

Cited by 47 publications

(62 citation statements)

References 50 publications

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“…We showed previously that CD8-deficient mice develop a low level of AHR and eosinophilic inflammation compared with WT mice following sensitization and challenge but that adoptive transfer of primed CD8 + T cells differentiated in IL-2 can restore AHR, eosinophilia, and goblet cell metaplasia, suggesting in vivo conversion (26)(27)(28). This was confirmed following recovery of transferred CD8 + T cells from the lung and demonstrating their ability to produce IL-13 (9,15).…”

Section: Adoptive Transfer Of Amg-treated Cd8mentioning

confidence: 52%

“…Both human (5) and mouse (27) CD8 + T cells demonstrate an insensitivity to corticosteroids not seen in CD4 + T cells, supporting the notion that CD8 + T cells are at the root of the failure of asthmatics to respond to corticosteroids and may be responsible for persistent AHR and airway inflammation (6). In asthmatics, numbers of CD8 + T cells in the airways have correlated with lower airway function (7).…”

Section: Cd4mentioning

confidence: 80%

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Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Allergic asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic airway inflammation and airway hyperresponsiveness. Numbers of CD8 + IL-13 + T cells are increased in asthmatics and during the development of experimental asthma in mice. In an atopic environment rich in IL-4, these CD8 + T cells mediate asthmatic responses, but the mechanisms regulating the conversion of CD8 + effector T cells from IFN-γ– to pathogenic IL-13–producing effector cells that contribute to an asthma phenotype have not been defined. Here, we show that cholesterol side-chain cleavage P450 enzyme, Cyp11a1, is a key regulator of CD8 + T-cell conversion. Expression of the gene, protein, and enzymatic activity of Cyp11a1 were markedly increased in CD8 + T cells differentiated in the presence of IL-2 plus IL-4 compared with cells differentiated in IL-2 alone. Inhibition of Cyp11a1 enzymatic activity with aminoglutethimide or reduction in the expression of Cyp11a1 using short hairpin RNA prevented the IL-4–induced conversion of IFN-γ– to IL-13–producing cells without affecting expression of the lineage-specific transcription factors T-box expressed in T cells (T-bet) or GATA binding protein 3 (GATA3). Adoptive transfer of aminoglutethimide-treated CD8 + T cells into sensitized and challenged CD8-deficient recipients failed to restore airway hyperresponsiveness and inflammation. We demonstrate that Cyp11a1 controls the phenotypic conversion of CD8 + T cells from IFN-γ to IL-13 production, linking steroidogenesis in CD8 + T cells, a nonclassical steroidogenic tissue, to a proallergic differentiation pathway.

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Section: Adoptive Transfer Of Amg-treated Cd8mentioning

confidence: 52%

Section: Cd4mentioning

confidence: 80%

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The level of disease severity in the treated patients and the extent to which BLT1 blockade was achieved in vivo were not defined. We have recently shown that the LTB4-BLT1 pathway may contribute to severe asthma, including steroid-resistant asthma with increased numbers of BLT1-expressing CD8 1 T cells (52).…”

Section: Discussionmentioning

confidence: 99%

Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease

Waseda

Miyahara

Kanehiro

et al. 2011

Am J Respir Cell Mol Biol

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Most of the studies investigating the effectiveness of blocking the leukotriene B4 (LTB4) receptor 1 (BLT1) have been performed in models of primary or acute allergen challenge. The role of the LTB4-BLT1 pathway in secondary challenge models, where airway hyperresponsiveness (AHR) and airway inflammation have been established, has not been defined. We investigated the effects of blocking BLT1 on early-and late-phase development of AHR and airway inflammation in previously sensitized and challenged mice. Female BALB/c mice were sensitized (Days 1 and 14) and challenged (primary, Days 28-30) with ovalbumin. On Day 72, mice were challenged (secondary) with a single OVA aerosol, and the early and late phases of AHR and inflammation were determined. Specific blockade of BLT1 was attained by oral administration of a BLT1 antagonist on Days 70 through 72. Administration of the antagonist inhibited the secondary ovalbumin challenge-induced alterations in airway responses during the late phase but not during the early phase, as demonstrated by decreases in AHR and in bronchoalveolar lavage neutrophilia and eosinophilia 6 and 48 hours after secondary challenge. The latter was associated with decreased levels of KC protein, macrophage inflammatory protein 2, and IL-17 in the airways. These data identify the importance of the LTB4-BLT1 pathway in the development of late-phase, allergen-induced airway responsiveness after secondary airway challenge in mice with established airway disease.

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“…Notwithstanding the well-recognised involvement of cysteinyl leukotrienes in asthma, it is noteworthy that LTB 4 also appears to play an important role in the pathogenesis of severe persistent asthma, as well as aspirin-and exercise-induced asthma, allergic rhinitis and atopic dermatitis [25]. Moreover, corticosteroids, which generally do not affect LTB 4 production by immune and inflammatory cells, have been reported to upregulate the expression of the BLT1 receptor on corticosteroid-resistant cells such as neutrophils, monocytes and effector memory CD8+ T-cells [24][25][26][27]. In the current study, dexamethasone, an agent that does not elevate intracellular cAMP concentrations, had no detectable effects on either elastase or LTB 4 release by activated neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils

Gravett¹,

Theron²,

Steel³

et al. 2010

Eur Respir J

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The research question addressed in the current study was: do formoterol (1 and 10 nM) and montelukast (2 mM) possess interactive inhibitory effects on activated human neutrophils, particularly in relation to alterations in cyclic AMP and cytosolic Ca 2+ fluxes?Isolated human blood neutrophils were activated with the chemoattractant N-formyl-Lmethionyl-L-leucyl-L-phenylalanine (fMLP) (1 mM) in combination with cytochalasin B (CB; 3 mM). Fura-2-acetoxymethyl ester-based spectrofluorimetry, lucigenin-enhanced chemiluminescence, colorimetric and flow cytometric procedures were used to measure cytosolic Ca 2+ fluxes, production of superoxide, elastase release and beta-2 integrin (CR3) expression, respectively, while cyclic AMP and leukotriene (LT)B 4 were assayed using competitive binding ELISA procedures. Activation of the cells with fMLP/CB resulted in abrupt and sustained increases in cytosolic Ca 2+, as well as release of elastase and production of superoxide and LTB 4 , and expression of CR3, all of which were attenuated by formoterol and montelukast individually, and especially by the combination of these agents. These anti-inflammatory effects of each agent, as well as the combination, were associated with significant increases in cyclic AMP.The findings of the current study may explain the efficacy of montelukast and formoterol when used in combination with inhaled corticosteroids in the treatment of severe asthma, possibly by controlling neutrophil-driven inflammation of the airways.

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

Cited by 47 publications

References 50 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease

Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils

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

Cited by 47 publications

References 50 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease

Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils

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Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease