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Dual Modulation of Airway Smooth Muscle Contraction by Th2 Cytokines via Matrix Metalloproteinase-1 Production¹

Yoshinori Ohta^*,, Masayuki Hayashi^*, Takaaki Kanemaru, Kihachiro Abe, Yushi Ito^* and Masahiro Oike^2,*

^* Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Special Patient Oral Care Unit and Morphology Core Unit, Kyushu University Hospital, Fukuoka, Japan

Altered contractility of airway smooth muscle (SM) is one of the main causes of allergic asthma, in which the predominance of Th2 over Th1 cytokines plays a central role. In the present study, we examine the effects of Th2 cytokines on airway SM contraction. Treatment with a low concentration of IL-4 (0.2 ng/ml) for 6 h augmented, whereas higher concentrations (2–20 ng/ml) inhibited, agonist-induced contractions of collagen gels containing bovine tracheal SM cells. Another Th2 cytokine (IL-13) showed an augmentation of gel contraction in the concentration range of 20–200 ng/ml. IL-4 and IL-13 increased mRNA expression and protein secretion of matrix metalloproteinase (MMP)-1, but these cytokines did not affect Ca²⁺-mobilizing properties and phosphorylation levels of myosin L chain in bovine tracheal SM cells. These changes were sensitive to wortmannin, an inhibitor of PI3K, but not to leflunomide, an inhibitor of STAT6. Scanning electron microscope observation revealed that collagen fibers twining around SM cells were completely dissolved in 20 ng/ml IL-4-treated gels and reorganized into basket-like structure in 20 ng/ml IL-13-treated gels. Exogenous application of high and low concentrations of MMP-1 also induced the inhibition and augmentation of gel contraction, respectively. Furthermore, nonselective MMP inhibitor galardin suppressed the effects of IL-4 and IL-13 on gel contraction, and MMP-1-targeted small-interfering RNA reversed the inhibitory effects of IL-4 on gel contraction to the augmentation. This indicates that Th2 cytokines modulate airway contraction without affecting cellular contractility but by secreting MMP-1 from the SM cells via PI3K activation and changing cell-to-matrix interactions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-In-Aid from the Japan Society for the Promotion of Science (No. 18390075).

² Address correspondence and reprint requests to Dr. Masahiro Oike, Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582 Japan. E-mail address: moike{at}pharmaco.med.kyushu-u.ac.jp

³ Abbreviations used in this paper: SM, smooth muscle; MMP, matrix metalloproteinase; BTSMC, bovine tracheal SM cell; BAEC, bovine aortic endothelial cell; MLC, myosin L chain; [Ca²⁺]_i, intracellular calcium concentration; MLC, myosin L chain; TIMP, tissue inhibitor of metalloprotease 1; siRNA, small-interfering RNA.