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Interleukin-17 (IL-17) and IL-1 Activate Translation of Overlapping Sets of mRNAs, Including That of the Negative Regulator of Inflammation, MCPIP1*

Open AccessPublished:May 08, 2013DOI:https://doi.org/10.1074/jbc.M113.452649
      Changes in gene expression during inflammation are in part caused by post-transcriptional mechanisms. A transcriptome-wide screen for changes in ribosome occupancy indicated that the inflammatory cytokine IL-17 activates translation of a group of mRNAs that overlaps partially with those affected similarly by IL-1. Included are mRNAs of IκBζ and of MCPIP1, important regulators of the quality and course of immune and inflammatory responses. Evidence for increased ribosome association of these mRNAs was also obtained in LPS-activated RAW264.7 macrophages and human peripheral blood mononuclear cells. Like IL-1, IL-17 activated translation of IκBζ mRNA by counteracting the function of a translational silencing element in its 3′-UTR defined previously. Translational silencing of MCPIP1 mRNA in unstimulated cells resulted from the combined suppressive activities of its 5′-UTR, which contains upstream open reading frames, and of its 3′-UTR, which silences independently of the 5′-UTR. Only the silencing function of the 3′-UTR was counteracted by IL-17 as well as by IL-1. Translational silencing by the 3′-UTR was dependent on a putative stem-loop-forming region previously associated with rapid degradation of the mRNA. The results suggest that translational control exerted by IL-1 and IL-17 plays an important role in the coordination of an inflammatory reaction.
      Background: The role of translational control mechanisms in gene expression during inflammation is incompletely understood.
      Results: The proinflammatory cytokines IL-1 and IL-17 activate translation of certain mRNAs, including that of MCPIP1, a negative regulator of inflammation.
      Conclusion: Translational activation of MCPIP1 contributes to changes in gene expression induced by IL-1 and IL-17.
      Significance: Translational control may determine physiological and pathological consequences of inflammation.

      Introduction

      Post-transcriptional mechanisms play an important part in the changes of gene expression during an inflammatory response (
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      ). A number of studies including our own have demonstrated that IL-1, a central mediator of inflammation, can induce stabilization of certain mRNAs, which encode proteins involved in inflammatory and immune reactions. More recently, we observed that IL-1 also activates translation of distinct mRNAs (
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      Interleukin-1 activates synthesis of interleukin-6 by interfering with a KSRP-dependent translational silencing mechanism.
      ). We now present evidence that translation of several of its target mRNAs is also activated by the proinflammatory cytokine IL-17.
      IL-17 is a product of the Th17 subset of T-lymphocytes, but is also produced by other cell types. Through induction of various proteins, including cytokines, chemokines, and transcription factors, IL-17 plays an important part in host defense and autoimmunity (
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      ) or poly(I:C) (
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      ). The IL-17 family contains several isoforms that homo- or heterodimerize and bind to members of a distinct family of IL-17 receptors. Signal transduction of IL-17 is incompletely understood (
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      ). Although several pathways, including NF-κB and MAP kinase pathways, appear to contribute to transcriptional activation, it is well established that part of the effects of IL-17 on gene expression is caused by stabilization of mRNAs (
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      IL-17 enhances chemokine gene expression through mRNA stabilization.
      ). Stabilization of cyclooxygenase-2 mRNA was found to depend on p38 MAP kinase (
      • Faour W.H.
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      T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade: role of distal sequences in the 3′-untranslated region of COX-2 mRNA.
      ), whereas CXCL1 (KC) mRNA was stabilized independently of p38 MAP kinase and of AU-rich elements (AREs)
      The abbreviations used are:ARE, AU-rich element; RT-qPCR, reverse transcription and quantitative PCR; KSRP, K homology-type splicing regulatory protein.
      (
      • Hartupee J.
      • Liu C.
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      • Sun D.
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      • Hamilton T.A.
      IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6.
      ,
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      • Hamilton T.
      IL-17 regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence.
      ), through a mechanism that, according to most recent evidence, involves inducible IκB kinase, TRAF5, and SF2 (
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      Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).
      ,
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      ). In this study, we provide evidence that IL-17 can induce proteins by activating translation of distinct target mRNAs, including those of IκBζ and MCPIP1.
      IκBζ, an atypical member of the IκB family of proteins, can modify the NF-κB response by activating expression of certain NF-κB-dependent genes while suppressing expression of others, probably due to differential interaction with NF-κB dimers, but may also regulate transcription independently. Deletion of its gene can cause proinflammatory and atopic dermatitis-like symptoms and results in impaired Th17 cell development (Ref.
      • Hayden M.S.
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      and references therein). Induction of IκBζ by IL-1 involves post-transcriptional mechanisms (
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      Stimulus-specific induction of a novel nuclear factor-κB regulator, IκB-ζ, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization.
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      • Taghipour A.
      • Kuehne N.
      • Kracht M.
      • Holtmann H.
      IL-1-induced post-transcriptional mechanisms target overlapping translational silencing and destabilizing elements in IκBζ mRNA.
      ).
      MCPIP1, also named ZC3H12A or regnase-1, was identified as a protein induced by the chemokine MCP-1 (
      • Zhou L.
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      • Graham S.
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      • Adamski F.M.
      • Younce C.
      • Binkley P.F.
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      Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction.
      ). It can induce cell death and contributes to the pathophysiological role of MCP-1 in the development of ischemic heart disease (
      • Niu J.
      • Kolattukudy P.E.
      Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications.
      ). MCPIP1 has transcription factor-like activity and is involved in MCP-1-induced angiogenesis by increasing cadherin expression (
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      • Fatma S.
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      Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1-induced protein (MCPIP).
      ). A hallmark of MCPIP1, documented in several recent studies, is its suppression of inflammatory processes. MCPIP1 negatively affects inflammatory gene expression and NF-κB activation in response to LPS (
      • Liang J.
      • Wang J.
      • Azfer A.
      • Song W.
      • Tromp G.
      • Kolattukudy P.E.
      • Fu M.
      A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages.
      ). Mice deficient in MCPIP1 are anemic and die within 12 weeks (
      • Matsushita K.
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      • Kumagai Y.
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      Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay.
      ). Their macrophages show a highly increased production of IL-6 and IL-12 p40, an effect ascribed to impaired mRNA degradation. In that study, evidence was presented for RNase activity of MCPIP1, which contributed to rapid degradation of IL-6 mRNA (
      • Matsushita K.
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      • Kato H.
      • Tsujimura T.
      • Nakamura H.
      • Akira S.
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      ), but also appears to functionally counteract DICER by cleaving the terminal loops of pre-microRNAs (
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      • Matsuyama H.
      • Choi Y.L.
      • Ueno T.
      • Mano H.
      • Sugimoto K.
      • Miyazono K.
      MCPIP1 ribonuclease antagonizes Dicer and terminates microRNA biogenesis through precursor microRNA degradation.
      ). In an independent study, MCPIP1-deficient mice developed a fatal inflammatory syndrome, which also supports an important role for MCPIP1 in limiting inflammatory and autoimmune processes (
      • Liang J.
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      • Lei T.
      • Wang J.
      • Qi D.
      • Yang Q.
      • Kolattukudy P.E.
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      MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-κB signaling.
      ). An inhibitory function of MCPIP1 on JNK and NF-κB activity through deubiquitination of TNF receptor-associated factor (TRAF) proteins was observed in that study.
      MCPIP1 is induced upon macrophage activation with LPS (
      • Liang J.
      • Wang J.
      • Azfer A.
      • Song W.
      • Tromp G.
      • Kolattukudy P.E.
      • Fu M.
      A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages.
      ) and in different types of cells in response to stress (
      • Qi D.
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      • Miao R.
      • She Z.G.
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      • Chang Y.
      • Liu J.
      • Fan D.
      • Chen Y.E.
      • Fu M.
      Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress.
      ) and to IL-1 (
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      • Naumann K.
      • Gretz N.
      • Fischer H.P.
      • Bode J.G.
      • Merfort I.
      Genome-wide comparison between IL-17 and combined TNF-α/IL-17 induced genes in primary murine hepatocytes.
      ,
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      • Piechota M.
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      • Koj A.
      Identification of interleukin-1 and interleukin-6-responsive genes in human monocyte-derived macrophages using microarrays.
      ,
      • Qi Y.
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      • Fu M.
      MCP-induced protein 1 suppresses TNFα-induced VCAM-1 expression in human endothelial cells.
      ). In primary hepatocytes, MCPIP1 mRNA is induced synergistically by TNF and IL-17 (
      • Sparna T.
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      • Schmich K.
      • Albrecht U.
      • Naumann K.
      • Gretz N.
      • Fischer H.P.
      • Bode J.G.
      • Merfort I.
      Genome-wide comparison between IL-17 and combined TNF-α/IL-17 induced genes in primary murine hepatocytes.
      ). Transcriptional induction by IL-1β has been demonstrated to involve the NF-κB and ERK pathways and Elk-1 transcription factor (
      • Skalniak L.
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      ,
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      Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression.
      ). Most recently, post-transcriptional mechanisms controlling MCPIP1 have been reported that act through the IκB kinase complex, which controls ubiquitination and degradation of MCPIP1 protein and through MCPIP1 itself, which controls degradation of its own mRNA (
      • Iwasaki H.
      • Takeuchi O.
      • Teraguchi S.
      • Matsushita K.
      • Uehata T.
      • Kuniyoshi K.
      • Satoh T.
      • Saitoh T.
      • Matsushita M.
      • Standley D.M.
      • Akira S.
      The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.
      ).
      The results presented here demonstrate that MCPIP1 expression is also limited by inhibitory effects of its 5′- and 3′-UTRs on translation. Furthermore, the inhibitory effect of the 3′-UTR is overcome by stimulation of the cells with IL-17, as well as with IL-1. Thus translational mechanisms activated by these cytokines increase the expression of factors such as MCPIP1 and IκBζ, which determine the extent and specificity of protein expression in inflammatory reactions.

      DISCUSSION

      An inherent property of inflammatory stimuli is to activate mechanisms that counteract their activity, serving to limit and finally resolve the inflammatory reaction. The recently identified negative feedback regulator MCPIP1 is expressed in response to various inducers of inflammation. Here we provide evidence that induction of MCPIP1 by IL-1 and IL-17 involves activated translation of its mRNA. MCPIP1 expression is limited by suppressive effects of the 5′- and 3′-UTRs on translation. Unlike the EGR2 mRNA, which contains an internal ribosomal entry site element in its 5′-UTR that is activated by IL-1 (
      • Rübsamen D.
      • Blees J.S.
      • Schulz K.
      • Döring C.
      • Hansmann M.L.
      • Heide H.
      • Weigert A.
      • Schmid T.
      • Brüne B.
      IRES-dependent translation of egr2 is induced under inflammatory conditions.
      ), the MCPIP1 5′-UTR suppressed translation in a manner not affected by treatment with IL-1 (Fig. 6A). This function may serve to prevent formation of excess MCPIP1, which has been shown to cause cell death (
      • Zhou L.
      • Azfer A.
      • Niu J.
      • Graham S.
      • Choudhury M.
      • Adamski F.M.
      • Younce C.
      • Binkley P.F.
      • Kolattukudy P.E.
      Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction.
      ), and thus to balance MCPIP1 levels during inflammatory responses. Such conditions can diminish suppression mediated by the 3′-UTR of MCPIP1, as shown here for stimulation with IL-1 or IL-17.
      The signaling induced by IL-1 and IL-17 originates from different types of receptors and associated molecules. The similarities between the response to IL-17 and IL-1, which both stabilize and activate translation of MCPIP1 and IκBζ mRNAs, suggest that they share some common downstream mechanism. It remains to be found out at which point the pathways converge to effect post-transcriptional control. The mechanisms controlling MCPIP1 and IκBζ mRNAs appear distinct from a second type of control, which is activated only by IL-1 and targets IL-6 mRNA. This is suggested by the following observations. 1) Neither IκBζ nor MCPIP1 mRNA contain typical AREs in their 3′-UTRs, which distinguishes them from IL-6 mRNA, whose translation and stability are regulated by IL-1 but not by IL-17 (Figs. 1B and 3A) (
      • Dhamija S.
      • Kuehne N.
      • Winzen R.
      • Doerrie A.
      • Dittrich-Breiholz O.
      • Thakur B.K.
      • Kracht M.
      • Holtmann H.
      Interleukin-1 activates synthesis of interleukin-6 by interfering with a KSRP-dependent translational silencing mechanism.
      ). 2) IL-6 mRNA but not MCPIP1 mRNA is among the top 10 mRNAs identified as targets for destabilization by the ARE-binding protein KSRP (
      • Winzen R.
      • Thakur B.K.
      • Dittrich-Breiholz O.
      • Shah M.
      • Redich N.
      • Dhamija S.
      • Kracht M.
      • Holtmann H.
      Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets.
      ). Translation of IL-6 mRNA is controlled by KSRP as well; its siRNA-mediated depletion increased translation of IL-6 mRNA (
      • Dhamija S.
      • Kuehne N.
      • Winzen R.
      • Doerrie A.
      • Dittrich-Breiholz O.
      • Thakur B.K.
      • Kracht M.
      • Holtmann H.
      Interleukin-1 activates synthesis of interleukin-6 by interfering with a KSRP-dependent translational silencing mechanism.
      ), but had no significant effect on the ribosome association of MCPIP1 mRNA (supplemental Fig. S2B). 3) Correspondingly, the group of mRNAs redistributed to polysomes upon depletion of KSRP (
      • Dhamija S.
      • Kuehne N.
      • Winzen R.
      • Doerrie A.
      • Dittrich-Breiholz O.
      • Thakur B.K.
      • Kracht M.
      • Holtmann H.
      Interleukin-1 activates synthesis of interleukin-6 by interfering with a KSRP-dependent translational silencing mechanism.
      ) did not overlap with those redistributed to polysomes in response to IL-17 (Table 1).
      We speculate that KSRP function is targeted by IL-1 but not by IL-17. Our observations complement earlier studies showing that instability of CXCL1 mRNA, which responds to IL-17-induced stabilization, was independent of the presence of an ARE and of KSRP (
      • Hartupee J.
      • Liu C.
      • Novotny M.
      • Sun D.
      • Li X.
      • Hamilton T.A.
      IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6.
      ,
      • Datta S.
      • Novotny M.
      • Pavicic Jr., P.G.
      • Zhao C.
      • Herjan T.
      • Hartupee J.
      • Hamilton T.
      IL-17 regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence.
      ). In the latter study, evidence was also presented against a role for the ARE-binding protein tristetraprolin, which is known for its destabilizing function but also involved in translational silencing of TNF mRNA (
      • Tiedje C.
      • Ronkina N.
      • Tehrani M.
      • Dhamija S.
      • Laass K.
      • Holtmann H.
      • Kotlyarov A.
      • Gaestel M.
      The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation.
      ). To what extent stabilization and redistribution to polysomes are mechanistically linked remains unclear at present.
      It is also not clear whether MCPIP1 and IκBζ mRNAs are regulated by the same mechanism. Both mRNAs harbor regulatory elements in their 3′-UTRs. The previously defined translational silencing element of IκBζ mRNA contains putative stem-loop structures essential for its function (
      • Dhamija S.
      • Doerrie A.
      • Winzen R.
      • Dittrich-Breiholz O.
      • Taghipour A.
      • Kuehne N.
      • Kracht M.
      • Holtmann H.
      IL-1-induced post-transcriptional mechanisms target overlapping translational silencing and destabilizing elements in IκBζ mRNA.
      ). A stem-loop-forming sequence in the MCPIP1 3′-UTR has been reported to mediate control of its stability (
      • Iwasaki H.
      • Takeuchi O.
      • Teraguchi S.
      • Matsushita K.
      • Uehata T.
      • Kuniyoshi K.
      • Satoh T.
      • Saitoh T.
      • Matsushita M.
      • Standley D.M.
      • Akira S.
      The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.
      ). As shown in Fig. 6C, deletion of that sequence also impaired translational silencing. Because MCPIP1 itself has been implied in the degradation of its own mRNA (
      • Iwasaki H.
      • Takeuchi O.
      • Teraguchi S.
      • Matsushita K.
      • Uehata T.
      • Kuniyoshi K.
      • Satoh T.
      • Saitoh T.
      • Matsushita M.
      • Standley D.M.
      • Akira S.
      The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.
      ), it will be important to find out whether MCPIP1 also controls translation of its own mRNA and whether it targets IκBζ mRNA as well. Of note, we detected no obvious sequence homology between the MCPIP1 3′-UTR and the IκBζ translational silencing element or a region in CXCL1 mRNA essential for IL-17 regulation (
      • Datta S.
      • Novotny M.
      • Pavicic Jr., P.G.
      • Zhao C.
      • Herjan T.
      • Hartupee J.
      • Hamilton T.
      IL-17 regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence.
      ).
      Our results so far suggest that at least two different mechanisms of post-transcriptional control are activated by IL-1, ARE- and KSRP-dependent and -independent, and that the latter is activated by IL-17 as well (supplemental Fig. S2C). This latter mechanism is likely to contribute to negative feedback regulation of inflammatory stimuli by increasing expression of MCPIP1. By inducing MCPIP1, IL-17 may limit the extent and/or duration of its own effects, but may also limit the response to other agents. MCPIP1 has a protective role in ischemic stroke, and its induction contributes to the tolerance to ischemic stroke induced by preconditioning with LPS (
      • Liang J.
      • Wang J.
      • Saad Y.
      • Warble L.
      • Becerra E.
      • Kolattukudy P.E.
      Participation of MCP-induced protein 1 in lipopolysaccharide preconditioning-induced ischemic stroke tolerance by regulating the expression of proinflammatory cytokines.
      ). In view of our results, it appears likely that translational activation of MCPIP1 plays an important role in such conditions.

      Acknowledgments

      We thank Monika Barsch and Heike Schneider for skillful technical assistance.

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