Abstract
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.
Highlights
Interleukin (IL)-221,2 is a member of the IL-10 cytokine family sharing some fundamental structural and biological properties with IL-10, IL-20, IL-24, and IL-6
Since mRNA expression of IL-22-related IL-1025,28 and IL-625,29 is known to be modulated by TTP and post-transcriptional gene regulation is frequently organized in functional units[30], we set out to investigate in detail the role of TTP in IL-22 expression
In accord with the picture of uncontrolled persistent inflammation, we report for the first time on significantly elevated systemic levels of IL-22 in TTP−/− mice as compared to wildtype littermates (Fig. 2a)
Summary
Interleukin (IL)-221,2 is a member of the IL-10 cytokine family sharing some fundamental structural and biological properties with IL-10, IL-20, IL-24, and IL-6 This is exemplified by the shared ability of aforementioned cytokines to mediate robust activation of the transcription factor signal transducer and activator of transcription (STAT)-3 and associated STAT3-dependent downstream events connecting to proliferation, anti-apoptosis, strengthening of host-defense, and regulation of inflammatory responses. IL-22 exerts tissue-protective/anti-microbial functions in infection- and/or injury-driven diseases at biological barriers such as intestine, lung, and liver[5]. Sequence analysis reveals a remarkable density of adenylate- and uridylate (AU)-rich elements (ARE) in the 3′ -untranslated region (3′ -UTR) of human and murine IL-22 mRNA (Fig. 1) The presence of those elements at this location suggests post-transcriptional regulation by modulation of mRNA stability[23,24,25]. Since mRNA expression of IL-22-related IL-1025,28 and IL-625,29 is known to be modulated by TTP and post-transcriptional gene regulation is frequently organized in functional units[30], we set out to investigate in detail the role of TTP in IL-22 expression
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