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Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma.

Authors
Kim, SH; Choi, GS; Ye, YM; Jou, I; Park, HS; Park, SM
Citation
Clinical and experimental immunology, 160(3):489-497, 2010
Journal Title
Clinical and experimental immunology
ISSN
0009-91041365-2249
Abstract
Diisocyanate is a leading cause of occupational asthma (OA). Diisocyanate-induced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose- and time-dependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, 15-deoxy-Delta(12,14)-PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK-Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.
MeSH terms
Active Transport, Cell Nucleus/drug effectsActive Transport, Cell Nucleus/immunologyAdultApoferritins/biosynthesisApoferritins/immunology*Asthma/chemically inducedAsthma/immunology*Asthma/metabolismAsthma/pathologyCatalase/biosynthesisCatalase/immunologyCell LineCell Nucleus/immunologyCell Nucleus/metabolismCell Nucleus/pathologyChemical Industry*FemaleGene Expression Regulation/drug effects*Gene Expression Regulation/immunologyGlutathione Peroxidase/biosynthesisGlutathione Peroxidase/immunologyHeme Oxygenase-1/biosynthesisHeme Oxygenase-1/immunology*HumansHypoglycemic Agents/pharmacologyImmunologic Factors/pharmacologyMAP Kinase Signaling System/drug effectsMAP Kinase Signaling System/immunologyMaleMiddle AgedMitogen-Activated Protein Kinase Kinases/antagonists & inhibitorsMitogen-Activated Protein Kinase Kinases/immunologyMitogen-Activated Protein Kinase Kinases/metabolismNF-E2-Related Factor 2/immunologyNF-E2-Related Factor 2/metabolismOccupational Exposure/adverse effects*PPAR gamma/agonistsPPAR gamma/immunologyPPAR gamma/metabolismPeroxiredoxins/biosynthesisPeroxiredoxins/immunologyProstaglandin D2/analogs & derivativesRespiratory Mucosa/immunologyRespiratory Mucosa/metabolismRespiratory Mucosa/pathologyThiazolidinediones/pharmacologyThioredoxins/biosynthesisThioredoxins/immunologyToluene 2,4-Diisocyanate/toxicity*Transferrin/biosynthesisTransferrin/immunology
DOI
10.1111/j.1365-2249.2010.04118.x
PMID
20345975
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Regional Clinical Trial Center
Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
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