Down-regulation of cytokine-induced interleukin-8 requires inhibition of p38 Mitogen-activated Protein Kinase (MAPK) via MAPK phosphatase 1-dependent and -independent mechanisms

Nurlan Dauletbaev, Daniel Eklove, Nadir Mawji, Michele Iskandar, Sergio Di Marco, Imed Gallouzi, Larry C. Lands

Research output: Contribution to journalArticle

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Abstract

Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g. inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α, is regulated by several signaling pathways including nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK).We previously demonstrated that the anti-inflammatory drugs dexamethasone and ibuprofen suppress NF-κB; however, only dexamethasone down-regulates cytokine-induced IL-8, highlighting the importance of non-NF-κB mechanisms. Here, we tested the hypothesis that down-regulation of cytokine-induced IL-8 requires modulation of the MAPK phosphatase (MKP)-1/p38 MAPK/mRNA stability pathway. The effects of dexamethasone (5 nM) and ibuprofen (480 μM) on this pathway and IL-8 were studied in CF (CFTE29o-, CFBE41o-) and non-CF (1HAEo-) airway epithelial cells. We observed that dexamethasone, but not ibuprofen, destabilizes IL-8 mRNA and up-regulates MKP-1 mRNA.Further, siRNA silencing of MKP-1, via p38 MAPK, leads to IL-8 overproduction and diminishes the anti-IL-8 potential of dexamethasone. However, MKP-1 overexpression does not significantly alter IL-8 production. By contrast, direct inhibition of p38 MAPK (inhibitor SB203580) efficiently suppresses IL-8 with potency comparable with dexamethasone. Similar to dexamethasone, SB203580 decreases IL-8mRNAstability. Dexamethasone does not affect p38 MAPK activation, which excludes its effects upstream of p38 MAPK. In conclusion, normal levels of MKP-1 are necessary for a full anti-IL-8 potential of pharmacological agents; however, efficient pharmacological down-regulation of cytokine-induced IL-8 also requires direct effects on p38 MAPK and mRNA stability independently of MKP-1.

Original languageEnglish
Pages (from-to)15998-16007
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
Publication statusPublished - 6 May 2011
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
p38 Mitogen-Activated Protein Kinases
Interleukin-8
Down-Regulation
Cytokines
Dexamethasone
Ibuprofen
Messenger RNA
RNA Stability
Cystic Fibrosis
Epithelial Cells
Pharmacology
Protein Stability
Interleukins
Protein Kinase Inhibitors
Interleukin-1
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Down-regulation of cytokine-induced interleukin-8 requires inhibition of p38 Mitogen-activated Protein Kinase (MAPK) via MAPK phosphatase 1-dependent and -independent mechanisms. / Dauletbaev, Nurlan; Eklove, Daniel; Mawji, Nadir; Iskandar, Michele; Di Marco, Sergio; Gallouzi, Imed; Lands, Larry C.

In: Journal of Biological Chemistry, Vol. 286, No. 18, 06.05.2011, p. 15998-16007.

Research output: Contribution to journalArticle

Dauletbaev, Nurlan ; Eklove, Daniel ; Mawji, Nadir ; Iskandar, Michele ; Di Marco, Sergio ; Gallouzi, Imed ; Lands, Larry C. / Down-regulation of cytokine-induced interleukin-8 requires inhibition of p38 Mitogen-activated Protein Kinase (MAPK) via MAPK phosphatase 1-dependent and -independent mechanisms. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 18. pp. 15998-16007.
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abstract = "Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g. inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α, is regulated by several signaling pathways including nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK).We previously demonstrated that the anti-inflammatory drugs dexamethasone and ibuprofen suppress NF-κB; however, only dexamethasone down-regulates cytokine-induced IL-8, highlighting the importance of non-NF-κB mechanisms. Here, we tested the hypothesis that down-regulation of cytokine-induced IL-8 requires modulation of the MAPK phosphatase (MKP)-1/p38 MAPK/mRNA stability pathway. The effects of dexamethasone (5 nM) and ibuprofen (480 μM) on this pathway and IL-8 were studied in CF (CFTE29o-, CFBE41o-) and non-CF (1HAEo-) airway epithelial cells. We observed that dexamethasone, but not ibuprofen, destabilizes IL-8 mRNA and up-regulates MKP-1 mRNA.Further, siRNA silencing of MKP-1, via p38 MAPK, leads to IL-8 overproduction and diminishes the anti-IL-8 potential of dexamethasone. However, MKP-1 overexpression does not significantly alter IL-8 production. By contrast, direct inhibition of p38 MAPK (inhibitor SB203580) efficiently suppresses IL-8 with potency comparable with dexamethasone. Similar to dexamethasone, SB203580 decreases IL-8mRNAstability. Dexamethasone does not affect p38 MAPK activation, which excludes its effects upstream of p38 MAPK. In conclusion, normal levels of MKP-1 are necessary for a full anti-IL-8 potential of pharmacological agents; however, efficient pharmacological down-regulation of cytokine-induced IL-8 also requires direct effects on p38 MAPK and mRNA stability independently of MKP-1.",
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AU - Mawji, Nadir

AU - Iskandar, Michele

AU - Di Marco, Sergio

AU - Gallouzi, Imed

AU - Lands, Larry C.

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