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J. Biol. Chem., Vol. 277, Issue 5, 3065-3068, February 1, 2002

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ACCELERATED PUBLICATION
MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels^*

Armin Neininger, Dimitris Kontoyiannis^§, Alexey Kotlyarov, Reinhard Winzen^¶, Rolf Eckert, Hans-Dieter Volk, Helmut Holtmann^¶, George Kollias^§, and Matthias Gaestel^**

From the Innovationskolleg Zellspezialisierung, Martin-Luther-Universität Halle/Wittenberg, 06120 Halle, Germany, the ^§ Helenic Pasteur Institut, 11521 Athens, Greece, the  Institut für Medizinische Immunologie, Humboldt-Universität, 10098 Berlin, Germany, and the ^¶ Institut für Pharmakologie, Medizinische Hochschule Hannover, 30623 Hannover, Germany

Received for publication, November 29, 2001

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

We demonstrate that lipopolysaccharide-induced tumor necrosis factor (TNF) biosynthesis becomes independent of MAPKAP kinase 2 (MK2) when the AU-rich element (ARE) of the TNF gene is deleted. In spleen cells and macrophages where TNF biosynthesis is restored as a result of this deletion, interleukin (IL)-6 biosynthesis is still dependent on MK2. In MK2-deficient macrophages the half-life of IL-6 mRNA is reduced more than 10-fold, whereas the half-life of TNF mRNA is only weakly decreased. It is shown that the stability of a reporter mRNA carrying the AU-rich 3'-untranslated region (3'-UTR) of IL-6 is increased by MK2. The data provide in vivo evidence that the AU-rich 3'-UTRs of TNF and IL-6 are downstream to MK2 signaling and make MK2 an essential component of mechanisms that regulate biosynthesis of IL-6 at the levels of mRNA stability, and of TNF mainly through TNF-ARE-dependent translational control.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

The role of the stress-activated p38 MAPK/SAPK2¹ protein kinase cascade (reviewed in Ref. 1) in inflammation has been defined several years ago by the anti-inflammatory effect of the p38 MAPK,/SAPK2a,b inhibitor SB203580 and related compounds (reviewed in Ref. 2). Accordingly, it was expected that several components of this kinase cascade may be essential components for early signaling in the inflammatory response and, hence, targets for an anti-inflammatory therapy. Targeted disruption of p38 MAPK/SAPK2a in mice results in embryonic lethality and impaired IL-1 signaling in differentiated embryonic stem cells in one study (3) and in defective erythropoietin expression in a second study (22). Deletion of one of the two known specific upstream activators of p38 MAPK/SAPK2, the dual-specific MAPK kinase MKK3, leads to a reduction in IL-12 production (4) and impaired tumor necrosis factor (TNF)-induced cytokine expression (5). Interestingly, mice lacking one of the several kinases downstream to p38 MAPK/SAPK2, the serine/threonine kinase MK2 (also designated as MAPK-activated protein (MAPKAP) kinase 2), show a reduction of the bacterial lipopolysaccharide (LPS)-induced biosynthesis of TNF-, interferon (IFN)-, IL-1, IL-6, and nitric oxide resembling the effect of SB203580 at least in part (6). The different phenotypes of the mice mutated in components of the p38 MAPK/SAPK2 cascade analyzed so far demonstrate the complexity of this signaling module, which is far away from being a linear step by step reaction (cf. Ref. 1).

In the last few years it became evident that the 3'-untranslated region (UTR) of mRNA contributes to regulation of gene expression by influencing subcellular localization of mRNA, its translation or degradation (reviewed in Ref. 7). AU-rich elements (AREs) in the 3'-UTR have been identified as cis-elements that affect mRNA stability (8, 9) and translation (10). Recently, it has been shown that the p38 MAPK/SAPK2 cascade is involved in regulating mRNA stability via 3'-UTRs of IL-8, IL-6, c-Fos, GM-CSF mRNAs (11), via the 3'-UTR of cyclooxygenase 2 mRNA (12), via the 3'-UTR of vascular endothelial growth factor mRNA (13), and also via the 3'-UTR of TNF mRNA (14). Furthermore, a significant p38 MAPK/SAPK2-dependent contribution to translational control of the ARE in the 3'-UTR of TNF mRNA has also been demonstrated (15, 23). In the case of 3'-UTR-dependent stability of IL-8 mRNA, a role for the kinase MK2 downstream to p38 MAPK/SAPK2 was evident, since mutants of MK2 interfered with IL-8 mRNA stability (11).

For the mice lacking MK2 it was not clear whether the relatively complex phenotype resulted from secondary effects of the reduced TNF level after LPS induction or whether MK2 is involved in regulation of the different cytokines in response to LPS in parallel. In this paper, we present evidence that deletion of the ARE in the 3'-UTR of the TNF gene restored LPS-induced TNF production in MK2-deficient mice and could even increase TNF production above the wild type level. We analyzed the effect of lacking MK2 on IL-6 biosynthesis in mice where the TNF production was restored and found that IL-6 biosynthesis is still impaired. From the data obtained, a parallel ARE-dependent regulation of TNF and IL-6 biosynthesis by MK2 is proposed.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

Mouse Strains and Genotyping-- The MK2^/ and TNF^ARE/ mice used for the crossing were on a mixed 129Sv × C57BL/6 background. Genotyping for MK2 was carried out using a three-primer PCR with the oligonucleotides 5'-cgtgggggtggggtgacatgctggttgac (5'-MK2), 5'-ggtgtcaccttgacatcccggtgag (3'-MK2), and 5'-tgctcgctcgatgcgatgtttcgc (Neo). A fragment length of about 500 bp indicates wild type and 800-bp stands for the deletion. For genotyping of TNF the primers 5'-ccttcctcacagagccagccccctc (sense) and 5'-aattacggttaggctcctgtttcc (antisense) were used for PCR. The fragments obtained are about 500 bp for wild type and 620 bp for ARE.

Spleen Cell Culture, Macrophage Preparations, and Stimulation-- Spleen cell culture and stimulation was done as described in Ref. 6.

For macrophage assays, total exudate peritoneal macrophages (TEPM) were isolated by peritoneal lavage from 10-week-old mice, 3 days after a single peritoneal injection of 1.0 ml of thioglycollate broth (4%, Difco Laboratories). For cytokine measurements, TEPM were plated at a density of 5 × 10⁵ cells/well in 24-well tissue culture tissue culture plates. Following adherence, cultures were stimulated with 1 ml of complete RPMI medium + 5% fetal bovine serum in the presence or absence 1 µg/ml LPS (Salmonella enteriditis, Sigma L-6011) for the indicated time points.

For the detection of lymphocyte derived TNF, total splenocytes were isolated from mouse spleens via mechanical dissociation. Following erythrocyte lysis, cells were set onto tissue culture plates to remove the adherent fraction of splenocytes corresponding to myeloid cells. The nonadherent fraction was collected, counted, and plated into 24-well plates at a density of 5 × 10⁶ cells/ml/well in the presence or absence of coated 10 µg/ml agonistic monoclonal anti-CD3 antibody (Clone 145-2C11, Low Endotoxin/PharMingen) to activate T-lymphocytes. Supernatants were collected following centrifugation at the indicated time points.

Measurement of Cytokines-- Murine TNF immunoreactivity of cultured supernatants (diluted 1/4-) was measured using specific ELISA as described previously (15). Murine IL-6 immunoreactivity of cultured supernatants (diluted 1/2-) was measured using a specific ELISA (Endogen) according to the manufacturer's instructions.

Detection of mRNA and Determination of RNA Stability-- Bone marrow-derived macrophages were treated with 5 µg/ml LPS (Escherichia coli, Sigma L-6529) for 1 h and subsequent adding of actinomycin D (10 µg/ml). Total RNA was isolated from 1 × 10⁴ cells at different times after actinomycin D treatment using RNApure (PeqLab). RNAs were separated in 1.25% agarose-formaldehyde gels, transfered to nitrocellulose, and hybridized to ³²P-labeled IL-6 or TNF cDNA probes (6). The mRNA levels were normalized by stripping and reprobing the membranes with a 514-bp -actin cDNA probe. Northern blots were analyzed by phosphorimaging.

Decay of -globin mRNA carrying an insertion of the IL-6 3'-UTR (nucleotides 767-1022) was monitored using the tet-off system as described previously for IL-8 3'-UTR (11).

For detection of mRNA levels in spleen cells, mice were injected with LPS (S. typhosa; Sigma L-7895) at 5 mg/kg body weight. After 90 min total RNA was isolated from spleens, and 20 µg of RNA were analyzed as described above.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

Restoration of TNF Biosynthesis in Cells from MK2^//ARE/+ Animals-- To test whether the post-transcriptional regulation of TNF biosynthesis by MK2 proceeds via the ARE of the TNF gene, we analyzed LPS-induced TNF production in systems where both MK2 and the ARE are deleted. In the case that the ARE is a downstream regulatory element of MK2 signaling for TNF biosynthesis, its deletion should lead to MK2 independence of LPS-induced TNF production. We crossed MK2^/ animals with the mouse strain carrying a 69-base pair deletion of the ARE in the 3'-UTR of the TNF gene TNF^ARE/ (15). Since offspring carrying the genotype MK2^/TNF^ARE/ARE were not viable, we selected mice with the genotypes MK2^+/+TNF^+/+, MK2^/TNF^+/+, MK2^+/+TNF^ARE/+, and MK2^/TNF^ARE/+ from the F2 generation for further analysis. Splenocytes from these mice were stimulated with LPS in vitro. As seen from Fig. 1A, deletion of the ARE in only one allele leads to an almost complete restoration of LPS-induced TNF biosynthesis in the absence of MK2. When thioglycollate-elicited peritoneal macrophages of the different genotypes were stimulated by LPS in vitro (Fig. 1B), a similar result was obtained: deletion of the ARE leads to a re-establishment of TNF production leading to wild type levels after 3 and 6 h and to levels even significantly above the wild type macrophages 12 h after stimulation. This findings indicate that the ARE is downstream to the protein kinase MK2 at the same genetically defined LPS-signaling pathway and that MK2 directly or indirectly targets this element in the TNF- mRNA.

View larger version (19K): [in this window] [in a new window]   Fig. 1.   Deletion of the ARE in the 3'-UTR of TNF restores TNF biosynthesis in MK2/ mice. A, LPS-induced TNF production (mean + S.E.) in in vitro cultivated spleen cells from mice with different genotypes for MK2 and TNF-. TNF was measured by biotin sandwich ELISA 4 h after stimulation with 5 µg/ml LPS. B, time course of LPS-induced TNF production of thioglycollate-elicited peritoneal macrophages derived from animals with different genotypes. C, T-cell receptor (CD3)-stimulated TNF production in cultivated spleen cells at different times after stimulation.

Interestingly, when a spleen cell population was stimulated by antibodies against the CD3 component of the T-cell receptor, deletion of the ARE even leads to a significant increase of TNF production compared with wild type animals, and this increase was independent of MK2 (Fig. 1C). Since it has already been shown that other hemopoietic cell types such as T-cells overproduce TNF as well (15), this finding indicates that the MK2/ARE axis is also functioning in these cells to activate TNF production following CD3 or antigen engagement similar to the case of LPS-induced macrophages.

MK2-dependent IL-6 Production Is Independent of TNF Biosynthesis-- So far, it was not clear whether the reduced biosynthesis of cytokines like IL-6, IL-1, and IFN- in MK2^/ animals is an indirect effect due to the lack of production of the pro-inflammatory cytokine TNF. Alterations in the serum level of IL-6 have been observed as a secondary effect, e.g. in mice lacking TNF (16) and IL-1 (17). To decide whether this is also the case in MK2^/ animals, we analyzed IL-6 production in splenocytes and macrophages of the MK2^/ TNF^ARE/+ animals. Although the absolute values of IL-6 production are lower in the ARE/+ spleen cell population probably due to a reduced representation of IL-6 producing cells, a comparable relative reduction of IL-6 levels (to about 30%) as a result of ablation of MK2 is observed in both the MK2^/ TNF^ARE/+ and the MK2^/ TNF^+/+ background (Fig. 2A). Analysis of LPS-stimulated IL-6 production of thioglycollate-elicited peritoneal macrophages shows similar and even more clear data (Fig. 2B). For the same MK2 genotype, there is no significant difference in IL-6 production between the ARE/+ background, where TNF production is restored and even increased above wild type levels and the TNF +/+ background. This result clearly indicates that the defect in IL-6 biosynthesis in MK2^/ animals is not a secondary effect of reduced TNF production but independent of TNF.

View larger version (27K): [in this window] [in a new window]   Fig. 2.   Reduction of IL-6 biosynthesis and mRNA level is MK2-dependent and could not be restored by increase of TNF production. A, LPS-induced IL-6 production in in vitro cultivated spleen cells from mice with different genotypes for MK2 and TNF- after 4 h. B, time course of LPS-induced IL-6 production of thioglycollate-elicited peritoneal macrophages derived from animals with different genotypes. C, Northern blot analysis of IL-6 mRNA in the LPS-stimulated spleen cells with different genotypes for MK2 and TNF (cf. A).

When looking at IL-6 mRNA levels in the different spleen cell cultures analyzed (Fig. 2C), a reduction of IL-6 mRNA, which correlates to the decreased biosynthesis of this cytokine in MK2^/TNF^+/+ and MK2^/TNF^ARE/+ cells (as shown in Fig. 2A), is observed. This indicates that the production of IL-6 is regulated at the level of transcription or stability of mRNA.

MK2 Regulates Stability of Cytokine mRNAs Differentially-- To further analyze the mechanism by which MK2 determines the level of IL-6 mRNA we blocked transcription in LPS-stimulated macrophages from MK2^+/+ and MK2^/ animals by using actinomycin D and analyzed half-life of the mRNA by Northern blotting. For comparison, we also determined the stability of TNF mRNA (Fig. 3A). As a control, actin mRNA was detected and used to normalize the IL-6 and TNF mRNA level to equal loading. A quantitative evaluation of the mRNA decay (Fig. 3B) reveals a half-life of more than 20 h for IL-6 mRNA in LPS-stimulated MK2^+/+ macrophages. Interestingly, in macrophages lacking MK2 its half-life is reduced 10-fold to about 2 h. This result provides the first direct genetic evidence for the involvement of MK2 in regulating mRNA stability.

View larger version (32K): [in this window] [in a new window]   Fig. 3.   Decreased stability of IL-6 mRNA in LPS-treated macrophages lacking MK2. A, Northern blot analysis of stability of IL-6 and TNF mRNA in wild type (MK2+/+) and MK2-deficient (MK2/) mouse macrophages after LPS treatment and blocking of transcription by actinomycin D. As a control, actin mRNA was detected in parallel. B, estimation of the half-lives of IL-6 and TNF mRNA. Relative mRNA values were obtained as the ratio between the IL-6 or TNF and the actin mRNA signal quantified by phosphorimaging.

TNF mRNA is about 20-fold less stable than IL-6 mRNA in MK2^+/+ cells. This is probably due to the more classical ARE in the TNF 3'-UTR compared with the AU-rich ARE-like motifs in the IL-6 3'-UTR (see below). Remarkably, the lack of MK2 in the macrophages leads only to a weak further destabilization of TNF mRNA reducing the half-life from 76 to 51 min. These data indicate that MK2 can regulate the stability of different cytokine mRNAs to a different degree. For IL-6 the 10-fold destabilization of mRNA could well explain the about 70% decrease in IL-6 protein biosynthesis in response to LPS in macrophages lacking MK2. However, the very weak destabilization of TNF mRNA in MK2-deficient macrophages compared with wild type cells cannot explain the 90% reduction of TNF biosynthesis observed. This finding supports the notion that MK2 regulates TNF biosynthesis mainly at the level of mRNA translation (10, 15).

MK2 Regulates IL-6 mRNA Stability via an AU-rich 3'-UTR-- Since AREs in the 3'-UTR of cytokine mRNAs are made responsible for both translational control (10, 18) and mRNA stability (8, 9), we examined whether the ARE-containing 3'-UTR of IL-6 is sufficient to confer MK2-dependent stabilization to a reporter mRNA. It is interesting to note that in the 3'-UTR of mouse or human IL-6 mRNA there are no overlapping pentanucleotide cores of AUUUA. Instead, they are scattered in an ARE-like region with varying U stretches of 2-5 nucleotides in length (Fig. 4A). These regions of the human and mouse gene exhibit high homology to each other. To clarify their functional role we inserted the 3'-UTR region of human IL-6, including several AU-rich sequences (nt 767-1022, Fig. 4A), into the 3'-UTR of a -globin genomic sequence and expressed the chimeric RNA using the tet-off system in HeLa cells (11). After addition of doxycycline to the cells transcription of the reporter mRNA (BBB-IL-6_767-1022) is blocked, and mRNA decay can be followed. As seen in Fig. 4B the reporter construct shows a relatively short half-life (~30 min) in HeLa cells co-transfected with a control vector, indicating that the IL-6 3'-UTR-derived sequence destabilizes the globin mRNA, which is very stable in its nonfused form (half-life > 300 min, Ref. 19). Co-expression of a constitutively active mutant of MK2, MK2_EE (20), as well as of the activator for p38 MAPK/SAPK2, MKK6_2E (21), lead to a significant stabilization of the reporter mRNA (half-life about 120 min). Furthermore, a negative interfering mutant of MK2, MK2_K76R (11), can at least partially block the MKK6_2E-stimulated stabilization of the reporter mRNA (Fig. 4B, half-life of about 120 min reduced to about 60 min). Stability of a -globin reporter RNA carrying the 3'-UTR of murine IL-6 was affected in the same way (not shown). These data indicate that MK2 can regulate IL-6 mRNA stability in an 3'-UTR-dependent manner.

View larger version (52K): [in this window] [in a new window]   Fig. 4.   The 3'-UTR of IL-6 mRNA confers MK2-dependent stabilization to a reporter mRNA. A, AU-rich elements in the 3'-UTR of human IL-6 mRNA (nt 767-1022) used for the reporter construct in B and comparison with the corresponding region in murine IL-6 mRNA. B, influence of MK2 on the stability of a -globin-IL-6 reporter mRNA. HeLa cells were transiently transfected with the ptetBBB-IL-6767-1022 plasmid and expression vectors for a constitutively active MK2 (MK2EE), of MKK6 (MKK62E), and a negative interfering mutant of MK2 (MK2K76R) as indicated. Northern blotting was performed on total RNA isolated at the indicated times after stopping transcription by addition of doxycycline. Ethidium bromide staining of 28 S rRNA is shown to allow comparison of RNA amounts loaded.

We have demonstrated that in the LPS response AU-rich elements are downstream to the protein kinase MK2 and that MK2 regulates TNF- and IL-6 biosynthesis independently. Regulation of TNF proceeds through the ARE in the mRNA, since deletion of this ARE leads to restoration of TNF biosynthesis in the absence of MK2. In cells where TNF biosynthesis is re-established, MK2 is still necessary for IL-6 induction, indicating that reduced IL-6 levels are not a secondary effect of the reduction of TNF. The defect of IL-6 synthesis correlates with decreased mRNA levels, and it is shown that the absence of MK2 leads to a 10-fold increased degradation rate of IL-6 mRNA in LPS-stimulated macrophages. Furthermore, MK2 can stabilize an mRNA reporter construct carrying the IL-6 3'-UTR, which contains ARE-like motifs. The data presented do not directly exclude that MK2 is also necessary for transcriptional stimulation of the IL-6 gene. However, since it is known that activated MK2 is rapidly translocated to the cytoplasm of the cell (24), it seems likely that regulation of the IL-6 mRNA level by MK2 is mainly the result of altered stability of its mRNA in the cytoplasm.

Interestingly, degradation of TNF mRNA in the absence of MK2 is increased only marginally. This is in agreement with the finding that the p38 MAPK/ARE axis mainly regulates translation of TNF mRNA and not its absolute level or stability (6, 15) and that TNF mRNA stability and hypoadenylation are not significantly altered in LPS-stimulated macrophages (23). Other studies also indicate that, depending on the cellular context, TNF mRNA is also regulated on the stability level, and ARE-binding proteins such as tristetraprolin (TTP) (25) or HuR (26), which decrease or increase its half-life, have been described. However, ARE-binding proteins such as TIAR (27) and TIA-1 (28) confer specific translational regulation of the TNF mRNA. Deletion of TIA-1 from mouse macrophages does not alter transcript stability but increases the level of TNF mRNA that is associated with the polysomes (28), strongly indicating translational control of TNF.

Obviously, MK2 is an element of a signaling mechanism that can regulate biosynthesis of different cytokines via their different AU-rich 3'-UTRs in parallel and on different levels. So far, it is not clear whether there is a signaling branch point downstream to MK2 with different ARE-binding protein substrates such as TTP or HuR responsible for regulation of stability and others such as TIAR and TIA-1 responsible for regulation of translation. To us, it also seems possible that MK2 phosphorylates a so far unknown target, which can directly or indirectly interact with AREs and which regulates stability and/or translation of the mRNA, depending on the context of the particular ARE and other ARE-binding proteins.

	FOOTNOTES

^* This work was supported by Grants INK20 and Ga 453/6-1 from the Deutsche Forschungsgemeinschaft.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to the work.

^** To whom correspondence should be addressed: Medical School Hannover, Inst. of Biochemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: 49-511-532-2825; Fax: 49-511-532-2827; E-mail: gaestel.matthias@mh-hannover.de.

Published, JBC Papers in Press, December 6, 2001, DOI 10.1074/jbc.C100685200

	ABBREVIATIONS

The abbreviations used are: MAPK, mitogen-activated protein kinase; SAPK, stress-activated protein kinase; IL, interleukin; TNF, tumor necrosis factor; LPS, lipopolysaccharide; IFN, interferon; UTR, untranslated region; ARE, AU-rich element; ELISA, enzyme-linked immunosorbent assay; TEPM, total exudate peritoneal macrophage; nt, nucleotide(s); TTP, tristetraprolin.

	REFERENCES

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