Journal
BIOCHEMICAL JOURNAL
Volume 425, Issue -, Pages 595-602Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20091062
Keywords
extracellular-signal-regulated kinase 1/2 (ERK1/2); interleukin-1 (IL-1); interleukin-10 (IL-10); lipopolysaccharide (LPS); macrophage; mitogen- and stress-activated kinase 1 (MSK1); nuclear factor kappa B (NF-kappa B)
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Funding
- Medical Research Council (U.K.) [18084]
- AstraZeneca
- Boehringer
- Ingelbeim
- GlaxoSmithKline
- Merck-Serono
- Pfizer
- MRC [MC_U127081014] Funding Source: UKRI
- Medical Research Council [MC_U127081014] Funding Source: researchfish
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The activity of the pro-inflammatory cytokine IL (interleukin)-1 is closely regulated in vivo via a variety of mechanisms, including both the control of IL-1 production and secretion as well as naturally occurring inhibitors of IL-1 function, such as IL-1ra (IL-1 receptor antagonist). IL-1ra is homologous with IL-1, and is able to bind but not activate the IL-1 receptor. IL-1ra can be produced by a variety of cell types, and its production is stimulated by inflammatory signals. In the present study, we show that in macrophages the TLR (Toll-like receptor)-mediated induction of IL-1ra from both its proximal and distal promoters involves the p38 and ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) cascades. In addition, we show that MSK1 and 2 (mitogen- and stress-activated kinase 1 and 2), kinases activated by either ERK1/2 or p38 in vivo, are required for the induction of both IL-1ra mRNA and protein. MSKs regulate IL-1ra transcription via both IL-10-dependent and -independent mechanisms in cells. Consistent with this, knockout of MSK in mice was found to result in a decrease in IL-1ra production following LPS (lipopolysaccharide) injection. MSKs therefore let as important negative regulators of inflammation following TLR activation.
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