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Enhanced Expression of Interleukin-18 and its Receptor in Idiopathic Pulmonary Fibrosis

Departments of Internal Medicine 1, Pathology, and Forensic Medicine, Kurume University School of Medicine, Kurume; Department of Respiratory Medicine, the National Kyushu Medical Center, Fukuoka; Department of Respiratory Medicine, the National Omuta Hospital, Omuta; Nagata Hospital, Yanagawa; Department of Microbiology and Immunology, School of Medicine, Tohoku University, Sendai; Carna Biosciences, Inc., Kobe, Japan; and Laboratory of Cellular Biology, Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea

Address correspondence to: Dr. Tomoaki Hoshino, Department of Internal Medicine 1, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail: hoshino{at}med.kurume-u.ac.jp

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti–IL-18 antibodies and a new monoclonal antibody for IL-18R (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18R was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18R expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18R expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.

Abbreviations: antibody, Ab • alveolar macrophage, AM • bronchoalveolar lavage fluid, BALF • lung diffusing capacity for carbon monoxide, DL_CO • established fibrosis, EF • fibroblastic foci, FF • high-resolution computed tomography, HRCT • interferon, IFN • immunoglobulin, Ig • interleukin, IL • IL-18 receptor , IL-18R • interstitial lung disease, ILD • interstitial mononuclear cell, IMNC • idiopathic pulmonary fibrosis, IPF • monoclonal Ab, mAb • natural killer, NK • observation field, OF • transforming growth factor, TGF • T helper cell type, Th • tumor necrosis factor, TNF • usual interstitial pneumonia, UIP

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