Tristetraprolin regulation of interleukin-22 production.
Interleukin (IL)-22 is a STAT3-activating cytokine displaying characteristic AU-rich elements (ARE) in the 3'-untranslated region (3'-UTR) of its mRNA. This architecture suggests gene regulation by modulation of mRNA stability. Since related cytokines undergo post-transcriptional regulation by ARE-binding tristetraprolin (TTP), the role of this destabilizing protein in IL-22 production was investigated. Herein, we demonstrate that TTP-deficient mice display augmented serum IL-22. Likewise, IL-22 mRNA was enhanced in TTP-deficient splenocytes and isolated primary T cells. A pivotal role for TTP is underscored by an extended IL-22 mRNA half-life detectable in TTP-deficient T cells. Luciferase-reporter assays performed in human Jurkat T cells proved the destabilizing potential of the human IL-22-3'-UTR. Furthermore, overexpression of TTP in HEK293 cells substantially decreased luciferase activity directed by the IL-22-3'-UTR. Transcript destabilization by TTP was nullified upon cellular activation by TPA/A23187, an effect dependent on MEK1/2 activity. Accordingly, IL-22 mRNA half-life as determined in TPA/A23187-stimulated Jurkat T cells decreased under the influence of the MEK1/2 inhibitor U0126. Altogether, data indicate that TTP directly controls IL-22 production, a process counteracted by MEK1/2. The TTP-dependent regulatory pathway described herein likely contributes to the role of IL-22 in inflammation and cancer and may evolve as novel target for pharmacological IL-22 modulation.
pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Germany.
Lorena
L
Härdle
pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Germany.
Malte
M
Bachmann
Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Franziska
F
Bollmann
Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Andrea
A
Pautz
Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Germany.
Tobias
T
Schmid
pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Germany.
Wolfgang
W
Eberhardt
Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Hartmut
H
Kleinert
pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Germany.
Josef
J
Pfeilschifter
pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Germany.
Heiko
H
Mühl
D063307:AU Rich Elements / Q000235:genetics*; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D051379:Mice; D009570:Nitriles / Q000008:administration & dosage; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D000097043:Interleukin-22
D002070:Butadienes; D007378:Interleukins; D048369:MAP Kinase Kinase 1; D009570:Nitriles; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D051816:Tristetraprolin; D000097043:Interleukin-22; C494086:STAT3 protein, human; C113580:U 0126; C482125:MAP2K1 protein, human