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β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells.

Kato G, Takahashi K, Tashiro H, Kurata K, Shirai H, Kimura S, Hayashi S - BMC Immunol. (2014)

Bottom Line: The BMDCs adoptive transfer experiment indicated that dendritic cells mediate the effect of FORM, since FORM treatment of BMDCs in vitro attenuated airway inflammation.These results suggested that FORM modulates dendritic cell function and attenuates Th2 and Th17 responses induced by HDM.Thus, we propose that the clinical significance of LABAs should be re-investigated taking into account these immune-modulating effects.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. go.kato.go@gmail.com.

ABSTRACT

Background: Long-acting β2 adrenergic agonists (LABAs) are commonly used combined with inhaled corticosteroids (ICS) to treat asthmatic patients. Previous reports suggest that LABAs have an anti-inflammatory effect in bronchial asthma, and this should be further investigated. The aim of this study was to investigate whether LABAs inhibit allergic airway inflammation and how this occurs.

Results: We assessed the effect of the LABA formoterol (FORM) on inflammatory cell responses in airway, lung and regional lymph nodes, using an HDM-induced murine allergic asthma model in vivo. The effect of FORM on cytokine production from bone marrow derived dendritic cells (BMDCs) stimulated with HDM was evaluated in vitro. Adoptive transfer of BMDCs pulsed with HDM in the presence or absence of FORM to naïve mice was performed and the inflammatory response to subsequent HDM challenge was analyzed. FORM treatment suppressed HDM-induced changes and caused an increase in the number of eosinophils and neutrophils in bronchoalveolar lavage. The concentration of IL-4 and IL-17 in lung tissue homogenate was elevated and led to an accumulation of IL-4, IL-13, IL-5 and IL-17 producing cells in regional lymph nodes. FORM inhibited the production of IL-6 and IL-23 from BMDCs stimulated with HDM in vitro, and enhanced IL-10 production. The BMDCs adoptive transfer experiment indicated that dendritic cells mediate the effect of FORM, since FORM treatment of BMDCs in vitro attenuated airway inflammation.

Conclusion: These results suggested that FORM modulates dendritic cell function and attenuates Th2 and Th17 responses induced by HDM. Thus, we propose that the clinical significance of LABAs should be re-investigated taking into account these immune-modulating effects.

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Related in: MedlinePlus

Protocols for the HDM-induced airway inflammation model. (a) HDM-induced airway inflammation model. Female BALB/c mice were sensitized three times intranasally with 25 μg HDM at days 0, 7 and 14, and challenged three times intranasally with 5 μg HDM at days 21–23. Twenty-four hours after the final challenge, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving PBS at sensitization and challenge were used as controls. (b) BM cells were harvested from BALB/c mice. DCs were generated by culturing BM cells with 10% FBS and 10 ng/ml GM-CSF in the culture medium for 7 days. On day 7, DCs were stimulated with HDM or HDM + FORM or PBS (control) for 24 hours. One million DCs were intranasally injected into BALB/c mice on the following day. After 10 days, recipient mice were challenged intranasally with 25 μg HDM. Twenty-four hours after the injection, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving unstimulated DCs served as controls.
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Fig1: Protocols for the HDM-induced airway inflammation model. (a) HDM-induced airway inflammation model. Female BALB/c mice were sensitized three times intranasally with 25 μg HDM at days 0, 7 and 14, and challenged three times intranasally with 5 μg HDM at days 21–23. Twenty-four hours after the final challenge, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving PBS at sensitization and challenge were used as controls. (b) BM cells were harvested from BALB/c mice. DCs were generated by culturing BM cells with 10% FBS and 10 ng/ml GM-CSF in the culture medium for 7 days. On day 7, DCs were stimulated with HDM or HDM + FORM or PBS (control) for 24 hours. One million DCs were intranasally injected into BALB/c mice on the following day. After 10 days, recipient mice were challenged intranasally with 25 μg HDM. Twenty-four hours after the injection, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving unstimulated DCs served as controls.

Mentions: Mice were inoculated intranasally with 25 μg HDM or vehicle on days 0, 7 and 14. Mice were challenged intranasally with 5 μg HDM on days 21, 22 and 23. On day 24, mice were euthanized by intraperitoneal injection of sodium pentobarbital. Serum, bronchoalveolar lavage (BAL) fluid and lung tissue were harvested for further analysis (Figure 1a). FORM (12.5 ng/animal) was administered subcutaneously three times per week. FORM was dissolved in ethanol 10 mg/ml as a central stock, then was diluted optimal concentration using PBS. On the day when HDM was given, FORM was administered 30 minutes before the HDM inoculation.Figure 1


β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells.

Kato G, Takahashi K, Tashiro H, Kurata K, Shirai H, Kimura S, Hayashi S - BMC Immunol. (2014)

Protocols for the HDM-induced airway inflammation model. (a) HDM-induced airway inflammation model. Female BALB/c mice were sensitized three times intranasally with 25 μg HDM at days 0, 7 and 14, and challenged three times intranasally with 5 μg HDM at days 21–23. Twenty-four hours after the final challenge, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving PBS at sensitization and challenge were used as controls. (b) BM cells were harvested from BALB/c mice. DCs were generated by culturing BM cells with 10% FBS and 10 ng/ml GM-CSF in the culture medium for 7 days. On day 7, DCs were stimulated with HDM or HDM + FORM or PBS (control) for 24 hours. One million DCs were intranasally injected into BALB/c mice on the following day. After 10 days, recipient mice were challenged intranasally with 25 μg HDM. Twenty-four hours after the injection, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving unstimulated DCs served as controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4228181&req=5

Fig1: Protocols for the HDM-induced airway inflammation model. (a) HDM-induced airway inflammation model. Female BALB/c mice were sensitized three times intranasally with 25 μg HDM at days 0, 7 and 14, and challenged three times intranasally with 5 μg HDM at days 21–23. Twenty-four hours after the final challenge, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving PBS at sensitization and challenge were used as controls. (b) BM cells were harvested from BALB/c mice. DCs were generated by culturing BM cells with 10% FBS and 10 ng/ml GM-CSF in the culture medium for 7 days. On day 7, DCs were stimulated with HDM or HDM + FORM or PBS (control) for 24 hours. One million DCs were intranasally injected into BALB/c mice on the following day. After 10 days, recipient mice were challenged intranasally with 25 μg HDM. Twenty-four hours after the injection, blood samples, BAL fluid and lung tissues were collected. BALB/c mice receiving unstimulated DCs served as controls.
Mentions: Mice were inoculated intranasally with 25 μg HDM or vehicle on days 0, 7 and 14. Mice were challenged intranasally with 5 μg HDM on days 21, 22 and 23. On day 24, mice were euthanized by intraperitoneal injection of sodium pentobarbital. Serum, bronchoalveolar lavage (BAL) fluid and lung tissue were harvested for further analysis (Figure 1a). FORM (12.5 ng/animal) was administered subcutaneously three times per week. FORM was dissolved in ethanol 10 mg/ml as a central stock, then was diluted optimal concentration using PBS. On the day when HDM was given, FORM was administered 30 minutes before the HDM inoculation.Figure 1

Bottom Line: The BMDCs adoptive transfer experiment indicated that dendritic cells mediate the effect of FORM, since FORM treatment of BMDCs in vitro attenuated airway inflammation.These results suggested that FORM modulates dendritic cell function and attenuates Th2 and Th17 responses induced by HDM.Thus, we propose that the clinical significance of LABAs should be re-investigated taking into account these immune-modulating effects.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. go.kato.go@gmail.com.

ABSTRACT

Background: Long-acting β2 adrenergic agonists (LABAs) are commonly used combined with inhaled corticosteroids (ICS) to treat asthmatic patients. Previous reports suggest that LABAs have an anti-inflammatory effect in bronchial asthma, and this should be further investigated. The aim of this study was to investigate whether LABAs inhibit allergic airway inflammation and how this occurs.

Results: We assessed the effect of the LABA formoterol (FORM) on inflammatory cell responses in airway, lung and regional lymph nodes, using an HDM-induced murine allergic asthma model in vivo. The effect of FORM on cytokine production from bone marrow derived dendritic cells (BMDCs) stimulated with HDM was evaluated in vitro. Adoptive transfer of BMDCs pulsed with HDM in the presence or absence of FORM to naïve mice was performed and the inflammatory response to subsequent HDM challenge was analyzed. FORM treatment suppressed HDM-induced changes and caused an increase in the number of eosinophils and neutrophils in bronchoalveolar lavage. The concentration of IL-4 and IL-17 in lung tissue homogenate was elevated and led to an accumulation of IL-4, IL-13, IL-5 and IL-17 producing cells in regional lymph nodes. FORM inhibited the production of IL-6 and IL-23 from BMDCs stimulated with HDM in vitro, and enhanced IL-10 production. The BMDCs adoptive transfer experiment indicated that dendritic cells mediate the effect of FORM, since FORM treatment of BMDCs in vitro attenuated airway inflammation.

Conclusion: These results suggested that FORM modulates dendritic cell function and attenuates Th2 and Th17 responses induced by HDM. Thus, we propose that the clinical significance of LABAs should be re-investigated taking into account these immune-modulating effects.

Show MeSH
Related in: MedlinePlus