Kim, Youn-Jung Song, Mee Ryu, Jae-Chun 2024-01-20T22:01:02Z 2024-01-20T22:01:02Z 2021-09-03 2009-02-27 0300-483X https://pubs.kist.re.kr/handle/201004/132726 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-1 beta, 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-1 beta 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-1 beta and IL-8 expression increased, the expression of IL-4, IL-6, IL-12, TNF-alpha, MIP-1 alpha, and MIP-1 beta 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved. English ELSEVIER IRELAND LTD INTERSTITIAL LUNG-DISEASES RHEUMATOID-ARTHRITIS EPITHELIAL-CELLS GENE-EXPRESSION ALVEOLAR MACROPHAGES FIBROSIS GROWTH INTERLEUKIN-8 RELEASE TAK1 Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway Article 10.1016/j.tox.2008.11.016 1 TOXICOLOGY, v.256, no.3, pp.183 - 190 TOXICOLOGY 256 3 183 190 scie scopus 000263635500006 2-s2.0-58349116235 Pharmacology & Pharmacy Toxicology Pharmacology & Pharmacy Toxicology Article INTERSTITIAL LUNG-DISEASES RHEUMATOID-ARTHRITIS EPITHELIAL-CELLS GENE-EXPRESSION ALVEOLAR MACROPHAGES FIBROSIS GROWTH INTERLEUKIN-8 RELEASE TAK1 Inflammation Interleukin (IL)-8 Methotrexate (MTX) p38 Mitogen-activated protein kinase (MAPK) Pulmonary toxicity BEAS-2B