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

B Schaljo, F Kratochvill, N Gratz, I Sadzak… - The journal of …, 2009 - journals.aai.org
B Schaljo, F Kratochvill, N Gratz, I Sadzak, I Sauer, M Hammer, C Vogl, B Strobl, M Müller…
The journal of immunology, 2009journals.aai.org
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-α, a potent proinflammatory mediator
that is the target for multiple anti-TNF-α clinical strategies in Crohn's disease and rheumatoid
arthritis. The anti-inflammatory effects of IL-10 seem to be mediated by several incompletely …
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-α, a potent proinflammatory mediator that is the target for multiple anti-TNF-α 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-α and IL-1α 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.
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