Methotrexate (MTX) has been widely used for the treatment of a variety of tumours as well as for inflammatory diseases. MTX-induced pneumonitis has been a serious unpredictable side effect of the treatment and an important clinical problem. However, its mechanism remains largely unclear. Possible causes include allergic, cytotoxic or immunologic reactions to this agent. To elucidate the proinflammatory mechanism of MTX-induced pneumonitis, we evaluated the effect of MTX on the production of IL (interleukin)-8 by human bronchial and alveolar epithelial cells in vitro and the role of p38 MAPK (mitogen-activated protein kinase) in order to clarify the intracellular signal regulating IL-8 expression. MTX induced IL-8 secretion by human bronchial and alveolar epithelial cells in a dose- and time-dependent manner within the range of the clinically observed serum concentrations. Although addition of LPS (lipopolysaccharide) and glucose showed no significant enhancing effect, addition of IL-1β or TNF-α (tumour necrosis factor-α) with MTX to bronchial epithelial cells showed a significant augmenting effect. SB203580, the specific inhibitor of p38 MAPK, inhibited MTX-induced IL-8 production. MTX induced the phosphorylation of Thr180 and Tyr182 on p38 MAPK. These results suggest that MTX activates bronchial and alveolar epithelial cells to induce IL-8 production through p38 MAPK, which might play an important role as one of the mechanisms of MTX-induced lung inflammation.
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June 01 2004
Methotrexate induces interleukin-8 production by human bronchial and alveolar epithelial cells
Yasuhiro YAMAUCHI;
Yasuhiro YAMAUCHI
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Hitoshi OKAZAKI;
Hitoshi OKAZAKI
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Masashi DESAKI;
Masashi DESAKI
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Tadashi KOHYAMA;
Tadashi KOHYAMA
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Shin KAWASAKI;
Shin KAWASAKI
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Kazuhiko YAMAMOTO;
Kazuhiko YAMAMOTO
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Hajime TAKIZAWA
1Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Correspondence: Dr Hajime Takizawa (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
August 06 2003
Revision Received:
December 22 2003
Accepted:
January 13 2004
Accepted Manuscript online:
January 13 2004
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2004 The Biochemical Society
2004
Clin Sci (Lond) (2004) 106 (6): 619–625.
Article history
Received:
August 06 2003
Revision Received:
December 22 2003
Accepted:
January 13 2004
Accepted Manuscript online:
January 13 2004
Citation
Yasuhiro YAMAUCHI, Hitoshi OKAZAKI, Masashi DESAKI, Tadashi KOHYAMA, Shin KAWASAKI, Kazuhiko YAMAMOTO, Hajime TAKIZAWA; Methotrexate induces interleukin-8 production by human bronchial and alveolar epithelial cells. Clin Sci (Lond) 1 June 2004; 106 (6): 619–625. doi: https://doi.org/10.1042/CS20030262
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