Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway |
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Authors: | Youn-Jung Kim Mee SongJae-Chun Ryu |
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Institution: | Cellular and Molecular Toxicology Laboratory, Korea Institute of Science and Technology (KIST), P.O. Box 131, Cheongryang, Seoul, Republic of Korea |
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Abstract: | Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis (RA), as well as a variety of tumors. However, MTX-induced toxicity is a serious and unpredictable side effect of this therapy and an important clinical problem. We used microarray analysis to examine MTX-induced gene expression in a human lung epithelial cell line (BEAS-2B) and identified 10 differentially expressed genes related to the p38 mitogen-activated protein kinase (MAPK) pathway, including IL-1β, MKK6, and MAPKAPK2. Differential gene expression was confirmed via real-time RT-PCR. To determine the functional significance of MTX-induced p38 MAPK activation, we used a p38 MAPK inhibitor (SB203580) to block the p38 MAPK cascade. We also used protein array technology to investigate the modulated expression of pro- and anti-inflammatory cytokines in BEAS-2B cells. MTX activated IL-1β expression and induced the phosphorylation of various proteins in the p38 MAPK cascade, including TAK1, MKK3/MKK6, p38 MAPK, MAPKAPK2, and HSP27. Finally, HSP27 activation may increase IL-8 secretion, resulting in a pulmonary inflammatory response such as pneumonitis. Although IL-1β and IL-8 expression increased, the expression of IL-4, IL-6, IL-12, TNF-α, MIP-1α, and MIP-1β decreased in a dose-dependent manner. These results suggest that the modulation of cytokine expression may play an important role in MTX-induced pulmonary toxicity. |
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Keywords: | Inflammation Interleukin (IL)-8 Methotrexate (MTX) p38 Mitogen-activated protein kinase (MAPK) Pulmonary toxicity BEAS-2B |
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