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2015 ; 5
(ä): 15112
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Tristetraprolin regulation of interleukin-22 production
#MMPMID26486958
Härdle L
; Bachmann M
; Bollmann F
; Pautz A
; Schmid T
; Eberhardt W
; Kleinert H
; Pfeilschifter J
; Mühl H
Sci Rep
2015[Oct]; 5
(ä): 15112
PMID26486958
show ga
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.
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