Inflammation in Methotrexate-induced Pulmonary Toxicity occurs via the p38 MAPK pathway

Title
Inflammation in Methotrexate-induced Pulmonary Toxicity occurs via the p38 MAPK pathway
Authors
김연정송미류재천
Keywords
Inflammation; Interleukin (IL)-8; Methotrexate (MTX); p38 Mitogen-activated protein kinase (MAPK); Pulmonary toxicity; BEAS-2B
Issue Date
2009-02
Publisher
Toxicology
Citation
VOL 256, NO 3, 183-190
Abstract
Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis (RA), aswell 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 , MKK6, and MAPKAPK2. Differential gene expressionwas 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 expression and induced the phosphorylation of various proteins in the p38MAPKcascade, 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 and IL-8 expression increased, the expression of IL-4, IL-6, IL-12, TNF- , MIP-1 , and MIP-1 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.
URI
http://pubs.kist.re.kr/handle/201004/35656
ISSN
0300-483X
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