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(American Journal of Pathology. 2005;167:1231-1241.)
© 2005 American Society for Investigative Pathology

Natural Killer T (NKT) Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis by Producing Interferon-{gamma}

Ji Hyung Kim*{dagger}, Hye Young Kim*{dagger}, Sanghee Kim{ddagger}, Jin-Haeng Chung*, Weon Seo Park§ and Doo Hyun Chung*{dagger}

From the Department of Pathology,* the Laboratory of Immune Regulation in Graduate Program for Immunology,{dagger} and the Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul; the Division of Specific Organ Cancers,§ National Cancer Center, Seoul; and Natural Products Research Institute,{ddagger} College of Pharmacy, Seoul National University, Seoul, Korea

Pulmonary fibrosis is a progressive illness characterized by interstitial fibrosis. Although the precise mechanism for pulmonary fibrosis is not completely understood, an immune response involving interferon (IFN)-{gamma} appears to play a role. Therefore, we examined the functional roles of natural killer T (NKT) cells, which produce IFN-{gamma} and interleukin-4 on activation, in bleomycin-induced pulmonary fibrosis. In NKT cell-deficient mice, pulmonary fibrosis was worse in terms of histology, hydroxyproline levels, and mortality than in control mice. The transforming growth factor (TGF)-ß1 levels were higher in the lung after injecting bleomycin, and blockade of TGF-ß1 by neutralizing monoclonal antibody attenuated the pulmonary fibrosis in CD1d–/– mice. In contrast, the production of IFN-{gamma} was reduced in lungs from CD1d–/– mice. Moreover, the adoptive transfer of NKT cells into CD1d–/– mice increased IFN-{gamma} and reduced TGF-ß1 production, attenuating pulmonary fibrosis. An in vitro assay demonstrated that IFN-{gamma} was involved in suppressing TGF-ß1 production in cells collected from bronchoalveolar lavage. The adoptive transfer of NKT cells from IFN-{gamma}–/– mice did not reverse pulmonary fibrosis or TGF-ß1 production in lungs of CD1d–/– mice whereas NKT cells from B6 control mice attenuated fibrosis and reduced TGF-ß1 production. In conclusion, IFN-{gamma}-producing NKT cells play a novel anti-fibrotic role in pulmonary fibrosis by regulating TGF-ß1 production.




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