Suppression of cytokine production by glucocorticoids is mediated by MKP-1 in human lung epithelial cells
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Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression is induced by inflammatory factors and serves as an endogenous p38 MAPK suppressor to limit inflammatory response. Glucocorticoids are very effective anti-inflammatory drugs and they are used for the treatment of many inflammatory diseases, such as asthma and COPD. We investigated the role of MKP-1 in the inhibition of cytokine production by dexamethasone in human A549 bronchial epithelial cells. We found that dexamethasone increased MKP-1 expression, inhibited p38 MAPK phosphorylation, and suppressed TNF and MIP-3α production in A549 cells. Interestingly, the suppression of p38 MAPK phosphorylation and the inhibition of TNF expression by dexamethasone were attenuated in cells, where MKP-1 expression was silenced by siRNA. In conclusion, these data suggest that dexamethasone increases MKP-1 expression and this results in the suppression of p38 MAPK signaling leading to the inhibition of cytokine production in human bronchial epithelial cells. These results point to the role of MKP-1 as an important factor in the therapeutic effects of glucocorticoids in the treatment of inflammatory lung diseases.
KeywordsMKP-1 DUSP1 Cytokine Inflammation
Chronic obstructive pulmonary disease
Inducible nitric oxide synthase
Jun N-terminal kinase
Mitogen-activated protein kinase
Macrophage inflammatory protein
Mitogen-activated protein kinase phosphatase
- NF- κB
Nuclear factor κB
Small interfering RNA
Tumor necrosis factor
We would like to warmly thank Mrs Salla Hietakangas and Mrs Terhi Salonen for their excellent technical assistance and Mrs Heli Määttä for skillful secretarial help.
Participated in research design: TK, RK, EM. Conducted experiments: TK. Performed data analysis: TK, RK, EM. Wrote or contributed to the writing of the manuscript: TK, RK, EM.
This work was financially supported by the Grants from Finnish Cultural Foundation, Pirkanmaa Regional fund, from Ida Montin Foundation, from the Academy of Finland, from the Competitive Research Funding of the Pirkanmaa Hospital District, and from Tampere Tuberculosis Foundation.
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