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Am J Physiol Gastrointest Liver Physiol 294: G452-G459, 2008. First published November 21, 2007; doi:10.1152/ajpgi.00077.2007
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INFLAMMATION/IMMUNITY/MEDIATORS

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

Robert M. Rowlett,1 Carol A. Chrestensen,2 Mark Nyce,1 Mary G. Harp,1 Jared W. Pelo,1 Fabio Cominelli,1 Peter B. Ernst,1 Theresa T. Pizarro,1 Thomas W. Sturgill,2 and Mark T. Worthington3

1Department of Medicine and 2Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia; and 3Division of Digestive Diseases, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 13 February 2007 ; accepted in final form 19 November 2007

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.

MNK kinases; p38 MAP kinase; ERK; macrophages; cytokines; Crohn's disease; Toll-like receptor


Address for reprint requests and other correspondence: M. T. Worthington, 4940 Eastern Ave., Rm. A501, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224-2780 (e-mail: mworthi3{at}jhmi.edu)






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