Submitted on January 14, 2008
Accepted on October 14, 2008
Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation
Masakata Yoshioka1*, Hironori Sagara2, Fumiyuki Takahashi1, Norihiro Harada1, Kazuto Nishio3, Akio Mori4, Hiroko Ushio5, Kazue Shimizu1, Takenori Okada2, Mayumi Ota2, Yoichi M Ito6, Osamu Nagashima1, Ryo Atsuta1, Toshihiro Suzuki7, Takeshi Fukuda2, Yoshinosuke Fukuchi1, and Kazuhisa Takahashi1
1 Respiratory Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
2 Pulmonary Medicine and Clinical Immunology, Dokkyo University, School of Medicine, Mibu, Tochigi, Japan
3 Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan
4 Clinical Research Center for Allergy and Reumatology, National Sagamihara Hospital, Sagamihara, Kanagawa, Japan
5 Atopy Resarch Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
6 Biostatistics, The University of Tokyo, School of Pubulic Health, Bunkyo-ku, Tokyo, Japan
7 Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: seigo{at}juntendo.ac.jp.
Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotrienes (CysLTs)-export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice (mrp1+/+) and MRP1 deficient mice (mrp1-/-) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1-/- mice as compared with mrp1+/+ mice. Furthermore, CysLTs levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1-/- mice were significantly lower than those from OVA-exposed mrp1+/+ mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1-/- mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells were markedly impaired by MRP1-deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLTs export from mast cells.
