MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages

Robert M. Rowlett, Carol A. Chrestensen, Mark Nyce, Mary G. Harp, Jared W. Pelo, Fabio Cominelli, Peter B. Ernst, Theresa T. Pizarro, Thomas W. Sturgill, Mark T. Worthington

Research output: Contribution to journalArticle

Abstract

The MNK kinases are downstream of both the p38 and ERK MAP kinase pathways and act to increase gene expression. MNK inhibition using the compound CGP57380 has recently been reported to inhibit tumor necrosis factor (TNF) production in macrophage cell lines stimulated with Escherichia coli lipopolysaccharide (LPS). However, the range of receptors that signal through the MNK kinases and the extent of the resultant cytokine response are not known. We found that TNF production was inhibited in RAW264.7 macrophage cells by CGP57380 in a dose-responsive manner with agonists for Toll-like receptor (TLR) 2 (HKLM), TLR4 (Salmonella LPS), TLR6/2 (FSL), TLR7 (imiquimod), and TLR9 (CpG DNA). CGP57380 also inhibited the peak of TNF mRNA production and increased the rate of TNF mRNA decay, effects not due to the destabilizing RNA binding protein tristetraprolin (TTP). Similar to its effects on TNF, CGP57380 caused dose-responsive inhibition of TTP production from stimulation with either LPS or CpG DNA. MNK inhibition also blocked IL-6 but permitted IL-10 production in response to LPS. Studies using bone marrow-derived macrophages (BMDM) isolated from a spontaneous mouse model of Crohn's disease-like ileitis (SAMP1/YitFc strain) revealed significant inhibition by CGP57380 of the proinflammatory cytokines TNF, IL-6, and monocyte chemoattractant protein-1 at 4 and 24 h after LPS stimulation. IL-10 production was higher in CGP53870-treated BMDM at 4 h but was similar to the controls by 24 h. Taken together, these data demonstrate that MNK kinases signal through a variety of TLR agonists and mediate a potent innate, proinflammatory cytokine response.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

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Toll-Like Receptors
Phosphotransferases
Tumor Necrosis Factor-alpha
Macrophages
Lipopolysaccharides
Cytokines
Tristetraprolin
Interleukin-10
imiquimod
Interleukin-6
Ileitis
Toll-Like Receptor 2
RNA-Binding Proteins
Chemokine CCL2
DNA
Extracellular Signal-Regulated MAP Kinases
RNA Stability
p38 Mitogen-Activated Protein Kinases
Salmonella
Crohn Disease

Keywords

  • Crohn's disease
  • Cytokines
  • ERK
  • Macrophages
  • MNK kinases
  • p38 MAP kinase
  • Toll-like receptor

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. / Rowlett, Robert M.; Chrestensen, Carol A.; Nyce, Mark; Harp, Mary G.; Pelo, Jared W.; Cominelli, Fabio; Ernst, Peter B.; Pizarro, Theresa T.; Sturgill, Thomas W.; Worthington, Mark T.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 294, No. 2, 02.2008.

Research output: Contribution to journalArticle

Rowlett, RM, Chrestensen, CA, Nyce, M, Harp, MG, Pelo, JW, Cominelli, F, Ernst, PB, Pizarro, TT, Sturgill, TW & Worthington, MT 2008, 'MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 294, no. 2. https://doi.org/10.1152/ajpgi.00077.2007
Rowlett, Robert M. ; Chrestensen, Carol A. ; Nyce, Mark ; Harp, Mary G. ; Pelo, Jared W. ; Cominelli, Fabio ; Ernst, Peter B. ; Pizarro, Theresa T. ; Sturgill, Thomas W. ; Worthington, Mark T. / MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2008 ; Vol. 294, No. 2.
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