The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages

• Published in: FEBS letters Vol. 583; no. 12; pp. 1933 - 1938
• Main Authors: Tudor, Corina, Marchese, Francesco P., Hitti, Edward, Aubareda, Anna, Rawlinson, Lesley, Gaestel, Matthias, Blackshear, Perry J., Clark, Andrew R., Saklatvala, Jeremy, Dean, Jonathan L.E.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 18.06.2009
• Subjects: Act D; actinomycin D; Animals; ARE; AU-rich element; Base Sequence; BMDM; bone marrow-derived macrophages; chemokine (C-X-C motif) ligand 1; COX-2; CXCL1; FCS; foetal calf serum; GAPDH; glutathione-S-transferase; glyceraldehyde-3-phosphate dehydrogenase; GST; In Vitro Techniques; Inflammation Mediators - metabolism; interleukin; Interleukin-10; Interleukin-10 - antagonists & inhibitors; Interleukin-10 - genetics; Interleukin-12 Subunit p40 - biosynthesis; Interleukin-6 - biosynthesis; lipopolysaccharide; LPS; Macrophages - metabolism; MAP Kinase Signaling System; MAPK; Mice; Mice, Inbred C57BL; Mice, Knockout; mitogen-activated protein kinase; p38 Mitogen-activated protein kinase; p38 Mitogen-Activated Protein Kinases - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; TNF; Tristetraprolin; Tristetraprolin - deficiency; Tristetraprolin - genetics; Tristetraprolin - metabolism; TTP; tumour necrosis factor; untranslated region; UTR; IL; p38 Mitogen-activated protein kinase; Interleukin-10; COX-2; Tristetraprolin; GST; CXCL1; BMDM; MAPK; TNF; LPS; TTP; UTR; ARE; Act D; FCS; GAPDH
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2009.04.039

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-1α. 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.