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Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells.
J Pharmacol Exp Ther. 2010 Apr; 333(1):310-8.JP

Abstract

Mitogen-activated protein kinase phosphatase (MKP)-1 is a protein phosphatase that regulates the activity of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2-terminal kinase (JNK) and, to lesser extent, p42/44 extracellular signal-regulated kinase. Studies with MKP-1(-/-) mice show that MKP-1 is a regulating factor suppressing excessive cytokine production and inflammatory response. The data on the role of MKP-1 in the regulation of inflammatory gene expression in human cells are much more limited. In the present study, we investigated the effect of MKP-1 on the expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 in response to stimulation with cytokines (tumor necrosis factor, IL-1beta, and interferon-gamma; 10 ng/ml each) in A549 human lung epithelial cells. Cytokines enhanced p38 and JNK phosphorylation and MKP-1 expression. p38 MAP kinase inhibitors 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB 796) inhibited cytokine-induced phosphorylation of p38 substrate MAP kinase-activated protein kinase 2 and expression of IL-6, IL-8, and COX-2. An aminopyridine-based JNK inhibitor, N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (JNK inhibitor VIII), inhibited phosphorylation of a JNK substrate c-Jun but did not have any effect on IL-6, IL-8, or COX-2 expression. Down-regulation of MKP-1 with small interfering RNA enhanced p38 and JNK phosphorylation and increased IL-6, IL-8, and COX-2 expression in A549 cells. In conclusion, cytokine-induced MKP-1 expression was found to negatively regulate p38 phosphorylation and the expression of IL-6, IL-8, and COX-2 in human pulmonary epithelial cells. Our results suggest that MKP-1 is an important negative regulator of inflammatory gene expression in human pulmonary epithelial cells, and compounds that enhance MKP-1 may have anti-inflammatory effects and control inflammatory response in the human lung.

Authors+Show Affiliations

The Immunopharmacology Research Group, Medical School, University of Tampere, FIN-33014 Tampere, Finland.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20089808

Citation

Turpeinen, Tuija, et al. "Mitogen-activated Protein Kinase Phosphatase-1 Negatively Regulates the Expression of Interleukin-6, Interleukin-8, and Cyclooxygenase-2 in A549 Human Lung Epithelial Cells." The Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 1, 2010, pp. 310-8.
Turpeinen T, Nieminen R, Moilanen E, et al. Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. J Pharmacol Exp Ther. 2010;333(1):310-8.
Turpeinen, T., Nieminen, R., Moilanen, E., & Korhonen, R. (2010). Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. The Journal of Pharmacology and Experimental Therapeutics, 333(1), 310-8. https://doi.org/10.1124/jpet.109.157438
Turpeinen T, et al. Mitogen-activated Protein Kinase Phosphatase-1 Negatively Regulates the Expression of Interleukin-6, Interleukin-8, and Cyclooxygenase-2 in A549 Human Lung Epithelial Cells. J Pharmacol Exp Ther. 2010;333(1):310-8. PubMed PMID: 20089808.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. AU - Turpeinen,Tuija, AU - Nieminen,Riina, AU - Moilanen,Eeva, AU - Korhonen,Riku, Y1 - 2010/01/20/ PY - 2010/1/22/entrez PY - 2010/1/22/pubmed PY - 2010/4/23/medline SP - 310 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 333 IS - 1 N2 - Mitogen-activated protein kinase phosphatase (MKP)-1 is a protein phosphatase that regulates the activity of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2-terminal kinase (JNK) and, to lesser extent, p42/44 extracellular signal-regulated kinase. Studies with MKP-1(-/-) mice show that MKP-1 is a regulating factor suppressing excessive cytokine production and inflammatory response. The data on the role of MKP-1 in the regulation of inflammatory gene expression in human cells are much more limited. In the present study, we investigated the effect of MKP-1 on the expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 in response to stimulation with cytokines (tumor necrosis factor, IL-1beta, and interferon-gamma; 10 ng/ml each) in A549 human lung epithelial cells. Cytokines enhanced p38 and JNK phosphorylation and MKP-1 expression. p38 MAP kinase inhibitors 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB 796) inhibited cytokine-induced phosphorylation of p38 substrate MAP kinase-activated protein kinase 2 and expression of IL-6, IL-8, and COX-2. An aminopyridine-based JNK inhibitor, N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (JNK inhibitor VIII), inhibited phosphorylation of a JNK substrate c-Jun but did not have any effect on IL-6, IL-8, or COX-2 expression. Down-regulation of MKP-1 with small interfering RNA enhanced p38 and JNK phosphorylation and increased IL-6, IL-8, and COX-2 expression in A549 cells. In conclusion, cytokine-induced MKP-1 expression was found to negatively regulate p38 phosphorylation and the expression of IL-6, IL-8, and COX-2 in human pulmonary epithelial cells. Our results suggest that MKP-1 is an important negative regulator of inflammatory gene expression in human pulmonary epithelial cells, and compounds that enhance MKP-1 may have anti-inflammatory effects and control inflammatory response in the human lung. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20089808/Mitogen_activated_protein_kinase_phosphatase_1_negatively_regulates_the_expression_of_interleukin_6_interleukin_8_and_cyclooxygenase_2_in_A549_human_lung_epithelial_cells_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20089808 DB - PRIME DP - Unbound Medicine ER -