Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10.
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.
Schaljo
Barbara
B
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Kratochvill
Franz
F
Gratz
Nina
N
Sadzak
Iwona
I
Sauer
Ines
I
Hammer
Michael
M
Vogl
Claus
C
Strobl
Birgit
B
Müller
Mathias
M
Blackshear
Perry J
PJ
Poli
Valeria
V
Lang
Roland
R
Murray
Peter J
PJ
Kovarik
Pavel
P
D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D020871:RNA Stability; D051816:Tristetraprolin / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D051816:Tristetraprolin; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases