The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.
p38 mitogen-activated protein kinase (MAPK) stabilises pro-inflammatory mediator mRNAs by inhibiting AU-rich element (ARE)-mediated decay. We show that in bone-marrow derived murine macrophages tristetraprolin (TTP) is necessary for the p38 MAPK-sensitive decay of several pro-inflammatory mRNAs, including cyclooxygenase-2 and the novel targets interleukin (IL)-6, and IL-1alpha. TTP(-/-) macrophages also strongly overexpress IL-10, an anti-inflammatory cytokine that constrains the production of the IL-6 despite its disregulation at the post-transcriptional level. TTP directly controls IL-10 mRNA stability, which is increased and insensitive to inhibition of p38 MAPK in TTP(-/-) macrophages. Furthermore, TTP enhances deadenylation of an IL-10 3'-untranslated region RNA in vitro.
Kennedy Institute of Rheumatology Division, Imperial College London, London, United Kingdom.
Corina
C
Tudor
Francesco P
FP
Marchese
Edward
E
Hitti
Anna
A
Aubareda
Lesley
L
Rawlinson
Matthias
M
Gaestel
Perry J
PJ
Blackshear
Andrew R
AR
Clark
Jeremy
J
Saklatvala
Jonathan L E
JL
Dean
D000818:Animals; D001483:Base Sequence; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051816:Tristetraprolin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases