Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF)
Introduction
Various cytokines, especially the Th2 cytokines IL-4, IL-13, and IL-5, have been reported to play causative roles in allergic inflammation and airway hyperresponsiveness in asthma [1], [2], [3], [4], [5]. Granulocyte–macrophage colony-stimulating factor (GM-CSF), which is produced by both Th2 and Th1 cells, is also a key cytokine for eosinophil survival, as is IL-5. GM-CSF is responsible for promoting the differentiation of eosinophils from promyelocytes [6], [7]. It also activates eosinophils and prolongs eosinophil survival in the peripheral tissues [8], [9]. In addition, GM-CSF is also a key cytokine for growth and differentiation of antigen-presenting cells (APC) [10], [11]. It has been shown that hyperexpression of GM-CSF promotes sensitization to allergens, resulting in augmentation of airway inflammation [12], [13]. Because GM-CSF is produced by macrophages, eosinophils and epithelial cells at the site of asthma [14], [15], endogenous production of GM-CSF may also play an important role in the pathogenesis of asthma.
We previously report that GM-CSF plays a central role in airway hyperresponsiveness caused by diesel exhaust particulates (DEP), a significant air pollutant [16]. Intranasal administration of antibody raised against GM-CSF, but not against IL-4, abolished DEP-evoked increases in airway responsiveness and mucus-secreting cell hyperplasia. In the present study, we aimed to clarify the effects of endogenous GM-CSF in airway hyperresponsiveness induced in an allergen-dependent manner. We found that both airway hyperresponsiveness and mucus-producing cell hyperplasia are significantly inhibited by a GM-CSF-specific neutralizing antibody administered during aeroallergen exposure. Our study indicates that GM-CSF plays a critical role in the development of airway hyperresponsiveness and therefore may represent a therapeutic target.
Section snippets
Reagents
Goat anti-mouse GM-CSF-neutralizing antibodies were purchased from R&D Systems (Minneapolis, MN); This antibody neutralizes 0.8 ng/ml mGM-CSF. The antibody dose was . Goat IgG was from Chemicon International (Temecula, CA), pentobarbital sodium from Pitman More (Mundelein, IL), and pancuronium bromide from Organ (Teknika, The Netherlands).
Sensitization
Male A/J mice (5 weeks old), which have native airway hyperresponsiveness to acetylcholine [17], [18], were purchased from SLC (Sizuoka,
Bronchial hyperresponsiveness induced by OA inhalation
First, we determined whether OA inhalation did affect airway hyperresponsiveness in A/J mice, which carry a genetic background conferring hypersensitivity to acetylcholine [17], [18]. As shown in Fig. 1, there is a significant increase in AHR in the OA-immunized/non-challenged mice (▴) compared to the non-immunized control mice (•) after inhalation of 5.0 mg/ml Ach (p<0.05). There was, however, a striking increase in AHR in the OA inhalation group (□) compared with the other two groups after
Discussion
In the study presented here, we have shown in a mouse model of asthma that allergic inflammation and airway responsiveness to acetylcholine were abolished by neutralization of endogenous GM-CSF during aeroallergen exposure. It has been established that GM-CSF possesses adjuvant effects when administered during immunization, because it is critical for the maturation of dendritic cells [12], [13], [22], [23]. Because antigen presentation is not only required during immunization but also for
Acknowledgments
We wish to thank Miss Yukiko Matsuo and Miss Maya Kuwabara for their expert technical assistance.
References (39)
- et al.
Blood
(1980) - et al.
Blood
(1986) - et al.
J. Allergy Clin. Immunol.
(1999) J. Allergy Clin. Immunol.
(1989)- et al.
Lancet
(2000) - et al.
J. Exp. Med.
(1996) - et al.
J. Exp. Med.
(1996) - et al.
Science
(1998) Science
(1998)- et al.
Science
(1998)
J. Clin. Invest.
J. Immunol.
J. Clin. Invest.
Proc. Natl. Acad. Sci. USA
J. Leukoc. Biol.
J. Clin. Invest.
Am. J. Physiol.
N. Engl. J. Med.
Am. J. Physiol.
Cited by (91)
Cellular and molecular mechanisms of allergic asthma
2022, Molecular Aspects of MedicineTargeting GM-CSF in inflammatory and autoimmune disorders
2021, Seminars in ImmunologyLeukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model
2017, Allergology InternationalCitation Excerpt :Airway responsiveness to Ach and bronchoalveolar lavage fluid (BALF) was observed on day 56. The assessment of airway responsiveness was undertaken on day 56, as previously described.11 In brief, after the administration of pentobarbital anesthesia, mice were tracheostomized, connected to a Harvard ventilator with 0.3 mL tidal volume and a respiratory frequency of 120/min, followed by injection of pancuronium bromide.
Prostaglandin D<inf>2</inf> and leukotriene E<inf>4</inf> synergize to stimulate diverse T<inf>H</inf>2 functions and T<inf>H</inf>2 cell/neutrophil crosstalk
2015, Journal of Allergy and Clinical Immunology