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PMID: 19542371 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 183 ·No. 2 ·2009-07-15 ·Pages 1197-206

Schaljo B, Kratochvill F, Gratz N, Sadzak I, Sauer I, Hammer M, Vogl C, Strobl B, Müller M, Blackshear PJ, Poli V, Lang R, Murray PJ, Kovarik P

Abstract

IL-10 is essential for inhibiting chronic and acute inflammation by decreasing the amounts of proinflammatory cytokines made by activated macrophages. IL-10 controls proinflammatory cytokine and chemokine production indirectly via the transcription factor Stat3. One of the most physiologically significant IL-10 targets is TNF-alpha, a potent proinflammatory mediator that is the target for multiple anti-TNF-alpha clinical strategies in Crohn's disease and rheumatoid arthritis. The anti-inflammatory effects of IL-10 seem to be mediated by several incompletely understood transcriptional and posttranscriptional mechanisms. In this study, we show that in LPS-activated bone marrow-derived murine macrophages, IL-10 reduces the mRNA and protein levels of TNF-alpha and IL-1alpha in part through the RNA destabilizing factor tristetraprolin (TTP). TTP is known for its central role in destabilizing mRNA molecules containing class II AU-rich elements in 3' untranslated regions. We found that IL-10 initiates a Stat3-dependent increase of TTP expression accompanied by a delayed decrease of p38 MAPK activity. The reduction of p38 MAPK activity releases TTP from the p38 MAPK-mediated inhibition, thereby resulting in diminished mRNA and protein levels of proinflammatory cytokines. These findings establish that TTP is required for full responses of bone marrow-derived murine macrophages to IL-10.

MeSH Terms
Animals Bone Marrow Cells Cells, Cultured Cytokines/antagonists & inhibitors Inflammation/immunology Interleukin-10/immunology Macrophages/cytology,immunology Mice RNA Stability Tristetraprolin/genetics,physiology Up-Regulation/genetics p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
Cytokines Tristetraprolin Interleukin-10 p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Schaljo Barbara
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Kratochvill Franz
Gratz Nina
Sadzak Iwona
Sauer Ines
Hammer Michael
Vogl Claus
Strobl Birgit
Müller Mathias
Blackshear Perry J
Poli Valeria
Lang Roland
Murray Peter J
Kovarik Pavel
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0803883
Published
2009-07-15
Epub
2009-00-19
Pages
1197-206
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2755621
Subset
IM
Grants
NIAID NIH HHS · AI062921 · United States
NIAID NIH HHS · R01 AI062921-05 · United States
NCI NIH HHS · P30 CA021765-30 · United States
Austrian Science Fund FWF · F 2805 · Austria
NCI NIH HHS · P30 CA021765 · United States
NIAID NIH HHS · R01 AI062921 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0803883 PMC Full Text View journal details
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