Currently, LTRAs are widely used for the treatment of asthma, which is a highly prevalent disease and a major cause of morbidity. CysLTs (leukotrienes C4, D4, and E4) are central mediators in asthma pathophysiology, because they cause bronchoconstriction, vascular hyperpermeability, and mucous hypersecretion.6–8
In the present study, using a murine model of allergic asthma, the LTRA, Prl, significantly attenuated allergic airway inflammation to a lower extent than the corticosteroid Dex, consistent with our previous reports.9
Besides their proinflammatory effects, cysLTs potentially play an important role in antimicrobial defense against harmful infections. Infection caused by Trypanosoma cruzi
in mice that are genetically deficient for 5-lipoxygenase (5-LO), a primary enzyme for LT synthesis, is more severe than that in wild-type mice.15,18
In contrast, cysLTs contribute to Escherichia coli
penetration of the blood–brain barrier.19
Thus, the exact role of cysLTs in antimicrobial defense against harmful infections is still to be determined. The present study was performed to evaluate whether the use of LTRA for asthma might regulate the function of airway DCs against harmful pathogens. The major findings of the present study are that, in contrast to Dex, which inhibited immunoregulatory cytokine production regardless of infectious pathogens, LTRA selectively up-regulated immunoregulatory cytokine production against RSV infection.
There is increasing evidence of a critical interaction between cysLTs and DCs. Murine and human bone marrow–derived DCs express LT-synthesizing enzymes as well as receptors for cysLTs.14,20
Additionally, these DCs produce cysLTs after exposure to aeroallergens.14,20
LTs also induce DC migration to draining lymph nodes.13
We previously showed17
that in vitro
LTRA treatment of DCs selectively regulated the production of immunoregulatory cytokines that suppress allergic airway inflammation in vivo
. In the present study, we showed that in vivo
treatment with LTRA results in the selective production of allergen-specific immunoregulatory cytokines from pulmonary DCs in vitro
. The combined data indicate that not only do cysLTs play an important role in exacerbation of established asthma, but that they also interact with DCs in the development of asthma.
Interaction between viral infection and cysLTs has been well studied. The concentration of cysLTs in induced sputum is significantly increased in virus-proven exacerbated asthmatic patients.21
The LTRA montelukast significantly reduces virus-induced exacerbation in childhood asthma.22
We have also reported that Prl significantly inhibits RSV-induced exacerbation of allergic airway inflammation in a murine model of allergic asthma.23
Nevertheless, few studies have evaluated the effects of LTRA used for asthma on DC function in antimicrobial defense. In the present study, Dex significantly inhibited the induction of cytokine production from pulmonary DCs sensitized with mite allergen by LPS, a cellular component of Gram-negative bacteria. These findings agree with the fact that systemic corticosteroids suppress antimicrobial immunity. In contrast, LTRA did not significantly reduce cytokine production regardless of infection. Interestingly, the present study showed that LTRA significantly increased IL-10 and IL-12 production from mite allergen–sensitized pulmonary DC after RSV infection. The role of IL-10 in the interaction between allergy and infection is controversial. In the development of allergy, high amounts of IL-10, and low amounts of IL-12 induce naive CD4+
T cells to Th2 cells, whereas low amounts of IL-10 and high amounts of IL-12 induce Th1 cells.24
In antimicrobial immunity IL-10 reduces morbidity in an infection25
as a regulatory cytokine to broadly suppress immune responses. Thus, IL-10 seems to be a bad player in the development of allergy and a good player in the antimicrobial immunity. IL-12 is a Th1-like cytokine and inhibits Th2-dominant allergic airway inflammation.26
Thus, an increase in the production of IL-12 after D. farinae
stimulation and an increase in both IL-10 and IL-12 from LPS and RSV exposed pulmonary DCs in LTRA-treated mice might suppress allergic airway inflammation in the former and also enhance antimicrobial immunity in the latter. In fact, to the best of our knowledge, no report has indicated that LTRA can cause severe infectious diseases in asthmatic patients.
In conclusion, LTRA that is used for asthma treatment potentially up-regulates antimicrobial immunity through the regulation of DC function against some respiratory infections without immune suppression. However, it should be also emphasized that the response of DCs to various agents in mice could not be always established in humans.20
Because viral respiratory tract infection represents a major cause of acute exacerbation in adult and childhood asthma27,28
and because systemic corticosteroids increase viral load in the airway,29
it will be an interesting issue for future clinical research to combine LTRA and corticosteroids for the treatment of virus infection–induced acute exacerbation of asthma.