Publications by authors named "Matthias Gaestel"

175 Publications

-Cre-Mediated Genetic Deletion of Reveals a Role of Septins in Macrophage Cytokinesis and -Driven Tumorigenesis.

Front Cell Dev Biol 2021 6;9:795798. Epub 2022 Jan 6.

Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany.

By crossing -floxed mice with -Cre mice carrying the Cre recombinase inserted in the Lysozyme-M () gene locus we aimed the specific deletion of septin7 in myeloid cells, such as monocytes, macrophages and granulocytes. :Cre mice show no alterations in the myeloid compartment. -deleted macrophages (BMDMs) were isolated and analyzed. The lack of Septin7 expression was confirmed and a constitutive double-nucleation was detected in Septin7-deficient BMDMs indicating a defect in macrophage cytokinesis. However, phagocytic function of macrophages as judged by uptake of labelled particles and LPS-stimulated macrophage activation as judged by induction of TNF mRNA expression and TNF secretion were not compromised. In addition to myeloid cells, Lyz2-Cre is also active in type II pneumocytes (AT2 cells). We monitored lung adenocarcinoma formation in these mice by crossing them with the conditional knock-in -LSL-G12D allele. Interestingly, we found that control mice without septin7 depletion die after 3-5 weeks, while the Septin7-deficient animals survived 11 weeks or even longer. Control mice sacrificed in the age of 4 weeks display a bronchiolo-alveolar hyperplasia with multiple adenomas, whereas the Septin7-deficient animals of the same age are normal or show only a weak multifocal brochiolo-alveolar hyperplasia. Our findings indicate an essential role of Septin7 in macrophage cytokinesis but not in macrophage function. Furthermore, septin7 seems absolutely essential for oncogenic -driven lung tumorigenesis making it a potential target for anti-tumor interventions.
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http://dx.doi.org/10.3389/fcell.2021.795798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772882PMC
January 2022

Involvement of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) in endothelial dysfunction associated with pulmonary hypertension.

Life Sci 2021 Dec 20;286:120075. Epub 2021 Oct 20.

Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India. Electronic address:

Aims: Increased proliferation, inflammation, and endothelial microparticle (EMP) generation in the pulmonary vasculature lead to endothelial dysfunction in pulmonary hypertension (PH). Interestingly, MK2, a downstream of p38MAPK, is a central regulator of inflammation, proliferation, and EMP generation in cardiovascular diseases. However, the role of MK2 in pulmonary endothelial dysfunction remains unexplored.

Main Methods: The Human Pulmonary Artery Endothelial cells (HPAECs) were exposed to hypoxia (1% O) for 72 h, and MK2 inhibition was achieved by siRNA treatment. Western blotting, qualitative RT-PCR, immunocytochemistry, flow cytometry and enzyme-linked immunoassays were conducted to study pathological alterations and molecular mechanisms. Neoangiogenesis was studied using cell migration and tubule formation assays. For in vivo study, Male Sprague Dawley rats and MK2 knock-out mice with littermate control were treated with monocrotaline (MCT) 60 mg/kg and 600 mg/kg, respectively (s.c. once in rat and weekly in mice) to induce PH. MMI-0100 (40 μg/kg, i.p. daily for 35 days), was administered in rats to inhibit MK2.

Key Findings: MK2 inhibition significantly decreased inflammation, cell proliferation, apoptosis resistance, and improved mitochondrial functions in hypoxic HPAECs. Hypoxia promoted cell migration, VEGF expression, and angiogenesis in HPAECs, which were also reversed by MK2 siRNA. MK2 inhibition decreased EMP generation and increased the expression of p-eNOS in hypoxic HPAECs, a marker of endothelial function. Furthermore, MK2 deficiency and inhibition both reduced the EMP generation in mice and rats, respectively.

Significance: These findings proved that MK2 is involved in endothelial dysfunction, and its inhibition may be beneficial for endothelial function in PH.
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http://dx.doi.org/10.1016/j.lfs.2021.120075DOI Listing
December 2021

Cdc42-Borg4-Septin7 axis regulates HSC polarity and function.

EMBO Rep 2021 Dec 18;22(12):e52931. Epub 2021 Oct 18.

Institute of Molecular Medicine, Ulm University, Ulm, Germany.

Aging of hematopoietic stem cells (HSCs) is caused by the elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (Borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal Septin network. Here, we show that Cdc42 interacts with Borg4, which in turn interacts with Septin7 to regulate the polar distribution of Cdc42, Borg4, and Septin7 within HSCs. Genetic deletion of either Borg4 or Septin7 results in a reduced frequency of HSCs polar for Cdc42 or Borg4 or Septin7, a reduced engraftment potential and decreased lymphoid-primed multipotent progenitor (LMPP) frequency in the bone marrow. Taken together, our data identify a Cdc42-Borg4-Septin7 axis essential for the maintenance of polarity within HSCs and for HSC function and provide a rationale for further investigating the role of Borgs and Septins in the regulation of compartmentalization within stem cells.
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http://dx.doi.org/10.15252/embr.202152931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647144PMC
December 2021

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate.

Proc Natl Acad Sci U S A 2021 07;118(29)

Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain;

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α-MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.
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http://dx.doi.org/10.1073/pnas.2024562118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307377PMC
July 2021

The p38/MK2 Axis in Monocytes of Fibromyalgia Syndrome Patients: An Explorative Study.

Medicina (Kaunas) 2021 Apr 19;57(4). Epub 2021 Apr 19.

Department of Rehabilitation Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany.

: The aetiology and pathomechanism of fibromyalgia syndrome 12 (FMS) as one of chronic pain syndromes still need to be further elucidated. Mitogen-activated protein kinase (MAPK) pathway has been proposed as a novel approach in pain management. Since the major symptom of fibromyalgia syndrome (FMS) patients is pain, it became of interest whether MAPK pathways, such as the stress-activated p38 MAPK/MK2 axis, are activated in FMS patients. Therefore, this study aimed at determining p38 MAPK/MK2 in FMS patients. : Phosphorylation of MAPK-activated protein kinases 2 (MK2), a direct target of p38 MAPK, was measured in monocytes of FMS and healthy controls (HCs) to monitor the activity of this pathway. : The mean level of phosphorylated MK2 was fivefold higher in FMS patients as compared to HCs ( < 0.001). Subgroup analysis revealed that antidepressants did not influence the activity of MK2 in FMS patients. : This result indicates that the p38/MK2 pathway could be involved in the pathomechanism of FMS, could act as a clinical marker for FMS, and could be a possible target for pain management in FMS patients.
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http://dx.doi.org/10.3390/medicina57040396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072914PMC
April 2021

Cytokine Storm.

N Engl J Med 2021 Apr;384(16):e59

Massachusetts Institute of Technology, Cambridge, MA

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http://dx.doi.org/10.1056/NEJMc2036236DOI Listing
April 2021

Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension.

Hypertension 2021 04 1;77(4):1248-1259. Epub 2021 Mar 1.

From the Division of Pharmacology (M.S., K.J., K.H.), CSIR-Central Drug Research Institute, Lucknow, India.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15229DOI Listing
April 2021

MK2-Deficient Mice Are Bradycardic and Display Delayed Hypertrophic Remodeling in Response to a Chronic Increase in Afterload.

J Am Heart Assoc 2021 02 3;10(4):e017791. Epub 2021 Feb 3.

Department of Medicine Université de Montréal Québec Canada.

Background Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2-null (MK2) mice. Methods and Results Survival curves for male MK2 and MK2 mice did not differ (Mantel-Cox test, =0.580). At 12 weeks of age, MK2 mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2 and MK2 mice. MK2 mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including , , , and were increased in hearts from MK2 mice. For equivalent respiration rates, mitochondria from MK2 hearts showed a significant decrease in Ca sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2 and MK2 mice; however, after 2 weeks the increase was significant in MK2 but not MK2 mice. Finally, the pressure overload-induced decrease in systolic function was attenuated in MK2 mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta. Conclusions Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.
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http://dx.doi.org/10.1161/JAHA.120.017791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955338PMC
February 2021

IL-3 is essential for ICOS-L stabilization on mast cells, and sustains the IL-33-induced RORγt T generation via enhanced IL-6 induction.

Immunology 2021 05 27;163(1):86-97. Epub 2021 Jan 27.

Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.

IL-33 is a member of the IL-1 family. By binding to its receptor ST2 (IL-33R) on mast cells, IL-33 induces the MyD88-dependent activation of the TAK1-IKK2 signalling module resulting in activation of the MAP kinases p38, JNK1/2 and ERK1/2, and of NFκB. Depending on the kinases activated in these pathways, the IL-33-induced signalling is essential for production of IL-6 or IL-2. This was shown to control the dichotomy between RORγt and Helios T , respectively. SCF, the ligand of c-Kit (CD117), can enhance these effects. Here, we show that IL-3, another growth factor for mast cells, is essential for the expression of ICOS-L on BMMCs, and costimulation with IL-3 potentiated the IL-33-induced IL-6 production similar to SCF. In contrast to the enhanced IL-2 production by SCF-induced modulation of the IL-33 signalling, IL-3 blocked the production of IL-2. Consequently, IL-3 shifted the IL-33-induced T dichotomy towards RORγt T at the expense of RORγt Helios T . However, ICOS-L expression was downregulated by IL-33. In line with that, ICOS-L did not play any important role in the T modulation by IL-3/IL-33-activated mast cells. These findings demonstrate that different from the mast cell growth factor SCF, IL-3 can alter the IL-33-induced and mast cell-dependent regulation of T subpopulations by modulating mast cell-derived cytokine profiles.
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http://dx.doi.org/10.1111/imm.13305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044339PMC
May 2021

Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38-MK2 axis and affects NF-κB-mediated transcription.

Sci Rep 2020 07 9;10(1):11388. Epub 2020 Jul 9.

Department of Pharmacy, UiT The Arctic University of Norway, 9037, Tromsø, Norway.

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth.
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http://dx.doi.org/10.1038/s41598-020-68219-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347898PMC
July 2020

The IL-33-induced p38-/JNK1/2-TNFα axis is antagonized by activation of β-adrenergic-receptors in dendritic cells.

Sci Rep 2020 05 18;10(1):8152. Epub 2020 May 18.

Institute of Immunology, Jena University Hospital, 07743, Jena, Germany.

IL-33, an IL-1 cytokine superfamily member, induces the activation of the canonical NF-κB signaling, and of Mitogen Activated Protein Kinases (MAPKs). In dendritic cells (DCs) IL-33 induces the production of IL-6, IL-13 and TNFα. Thereby, the production of IL-6 depends on RelA whereas the production of IL-13 depends on the p38-MK2/3 signaling module. Here, we show that in addition to p65 and the p38-MK2/3 signaling module, JNK1/2 are essential for the IL-33-induced TNFα production. The central roles of JNK1/2 and p38 in DCs are underpinned by the fact that these two MAPK pathways are controlled by activated β-adrenergic receptors resulting in a selective regulation of the IL-33-induced TNFα response in DCs.
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http://dx.doi.org/10.1038/s41598-020-65072-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235212PMC
May 2020

p38 MAPK signalling regulates cytokine production in IL-33 stimulated Type 2 Innate Lymphoid cells.

Sci Rep 2020 02 26;10(1):3479. Epub 2020 Feb 26.

Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dundee, DD1 5EH, UK.

Type 2 Innate lymphoid cells (ILC2s) are implicated in helminth infections and asthma where they play a role in the production of Th2-type cytokines. ILC2s express the IL-33 receptor and are a major cell type thought to mediate the effects of this cytokine in vivo. To study the signalling pathways that mediate IL-33 induced cytokine production, a culture system was set up to obtain pure populations of ILC2s from mice. Inhibitors of the p38α/β and ERK1/2 MAPK pathways reduced the production of IL-5, IL-6, IL-9, IL-13 and GM-CSF by ILC2 in response to IL-33, with inhibition of p38 having the greatest effect. MK2 and 3 are kinases activated by p38α; MK2/3 inhibitors or knockout of MK2/3 in mice reduced the production of IL-6 and IL-13 (two cytokines implicated in asthma) but not IL-5, IL-9 or GM-CSF in response to IL-33. MK2/3 inhibition also suppressed IL-6 and IL-13 production by human ILC2s. MK2/3 were required for maximal S6 phosphorylation, suggesting an input from the p38α-MK2/3 pathway to mTOR1 activation in ILC2s. The mTORC1 inhibitor rapamycin also reduced IL-6 and IL-13 production, which would be consistent with a model in which MK2/3 regulate IL-6 and IL-13 via mTORC1 activation in ILC2s.
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http://dx.doi.org/10.1038/s41598-020-60089-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044202PMC
February 2020

Tristetraprolin regulates necroptosis during tonic Toll-like receptor 4 (TLR4) signaling in murine macrophages.

J Biol Chem 2020 04 24;295(14):4661-4672. Epub 2020 Feb 24.

Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

The necrosome is a protein complex required for signaling in cells that results in necroptosis, which is also dependent on tumor necrosis factor receptor (TNF-R) signaling. TNFα promotes necroptosis, and its expression is facilitated by mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2) but is inhibited by the RNA-binding protein tristetraprolin (TTP, encoded by the gene). We have stimulated murine macrophages from WT, , , , , and mice with graded doses of lipopolysaccharide (LPS) and various inhibitors to evaluate the role of various genes in Toll-like receptor 4 (TLR4)-induced necroptosis. Necrosome signaling, cytokine production, and cell death were evaluated by immunoblotting, ELISA, and cell death assays, respectively. We observed that during TLR4 signaling, necrosome activation is mediated through the adaptor proteins MyD88 and TRIF, and this is inhibited by MK2. In the absence of MK2-mediated necrosome activation, lipopolysaccharide-induced TNFα expression was drastically reduced, but MK2-deficient cells became highly sensitive to necroptosis even at low TNFα levels. In contrast, during tonic TLR4 signaling, WT cells did not undergo necroptosis, even when MK2 was disabled. Of note, necroptosis occurred only in the absence of TTP and was mediated by the expression of TNFα and activation of JUN N-terminal kinase (JNK). These results reveal that TTP plays an important role in inhibiting TNFα/JNK-induced necrosome signaling and resultant cytotoxicity.
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http://dx.doi.org/10.1074/jbc.RA119.011633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135981PMC
April 2020

SEPT7 Interacts with KIF20A and Regulates the Proliferative State of Neural Progenitor Cells During Cortical Development.

Cereb Cortex 2020 05;30(5):3030-3043

Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

Balanced proliferation and differentiation of neural progenitor cells (NPCs) are critical for brain development, but how the process is regulated and what components of the cell division machinery is involved are not well understood. Here we report that SEPT7, a cell division regulator originally identified in Saccharomyces cerevisiae, interacts with KIF20A in the intercellular bridge of dividing NPCs and plays an essential role in maintaining the proliferative state of NPCs during cortical development. Knockdown of SEPT7 in NPCs results in displacement of KIF20A from the midbody and early neuronal differentiation. NPC-specific inducible knockout of Sept7 causes early cell cycle exit, precocious neuronal differentiation, and ventriculomegaly in the cortex, but surprisingly does not lead to noticeable cytokinesis defect. Our data uncover an interaction of SEPT7 and KIF20A during NPC divisions and demonstrate a crucial role of SEPT7 in cell fate determination. In addition, this study presents a functional approach for identifying additional cell fate regulators of the mammalian brain.
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http://dx.doi.org/10.1093/cercor/bhz292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197076PMC
May 2020

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3.

J Immunol 2019 10 16;203(8):2291-2300. Epub 2019 Sep 16.

Institute of Cell Biochemistry, Center of Biochemistry, Hannover Medical School, D-30625 Hannover, Germany;

Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38 Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.
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http://dx.doi.org/10.4049/jimmunol.1801221DOI Listing
October 2019

TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation.

EMBO Mol Med 2019 10 30;11(10):e10018. Epub 2019 Aug 30.

Department for Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end-stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti-hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co-factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.
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http://dx.doi.org/10.15252/emmm.201810018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783653PMC
October 2019

Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide.

Sci Rep 2019 07 30;9(1):11021. Epub 2019 Jul 30.

Clinic for Gastroenterology, Hepatology and Infectiology, University Hospital, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

The p38 downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2 or MK2/3 animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)α subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-β. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-β. In the absence of MK2, MK3 also delayed the nuclear translocation of NFκB by delaying the ubiquitination and subsequent degradation of IκBβ, reflecting the substantial plasticity of the response of BMDM to LPS.
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http://dx.doi.org/10.1038/s41598-019-46791-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667695PMC
July 2019

IL-33-activated murine mast cells control the dichotomy between RORγt and Helios T via the MK2/3-mediated IL-6 production in vitro.

Eur J Immunol 2019 12 30;49(12):2159-2171. Epub 2019 Jul 30.

Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.

In mast cells, IL-33 typically induces the activation of NF-κB, which results in the production of cytokines such as IL-6 and IL-2. Here, we demonstrate that the IL-33-induced IL-6 production in murine mast cells and the formation of RORγt T essentially depends on the MAPKAPs, MK2, and MK3 (MK2/3) downstream of MyD88. In contrast to this, the IL-33-induced and MyD88-dependent IL-2 production in mast cells contributes to the maintenance of Helios T . Thereby, the IL-33-induced IL-2 response and, thus, the maintenance of Helios T are limited by an IL-6-mediated autocrine negative feedback stimulation acting on mast cells. Collectively, we present MK2/3 in IL-33-activated mast cells as a signaling node, which controls the dichotomy between RORγt T and Helios T in vitro.
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http://dx.doi.org/10.1002/eji.201948154DOI Listing
December 2019

Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2.

Cell Rep 2019 06;27(10):2859-2870.e6

Institute of Cell Biochemistry, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address:

Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5' UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties.
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http://dx.doi.org/10.1016/j.celrep.2019.05.024DOI Listing
June 2019

The MK2 cascade regulates mGluR-dependent synaptic plasticity and reversal learning.

Neuropharmacology 2019 09 23;155:121-130. Epub 2019 May 23.

(a)Bradford School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, United Kingdom. Electronic address:

The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP.
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http://dx.doi.org/10.1016/j.neuropharm.2019.05.024DOI Listing
September 2019

Transcript levels for extracellular matrix proteins are altered in MK5-deficient cardiac ventricular fibroblasts.

J Mol Cell Cardiol 2019 07 16;132:164-177. Epub 2019 May 16.

Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3C 3J7, Canada; Department of Pharmacology and Physiology, Université de Montréal, Montréal, Québec H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montréal, Québec H3C 3J7, Canada; Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada. Electronic address:

MK5 is a protein serine/threonine kinase activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. Although little is known of the physiological role of MK5 in the heart, both hypertrophic growth and the increase in collagen 1-α mRNA induced by increased afterload are attenuated in hearts of MK5 haploinsufficient (MK5) mice. MK5 transcripts are detected at high levels in the left ventricular myocardium; however, MK5 immunoreactivity is detected in adult cardiac fibroblasts, but not myocytes. The present study was to determine if MK5 has a potential role in remodeling of the extracellular matrix. Ventricular fibroblasts were isolated from MK5, MK5, or MK5 mice and maintained in culture on either compliant (8 kPa) or rigid substrates to obtain quiescent fibroblasts or activated myofibroblasts, respectively. In quiescent fibroblasts, reduced MK5 had little effect: BMP7 and TGF-β1 mRNA was increased in MK5 and MK5.cells, respectively. Ang-II altered the abundance of numerous transcripts in an MK5-sensitive manner. Both collagen 1-α mRNA and secreted type 1 collagen immunoreactivity were increased by Ang-II in wild type but not MK5-deficient fibroblasts. The effects of deleting MK5 were quite different in myofibroblasts: both the abundance of collagen 1-α mRNA and secreted type 1 collagen immunoreactivity elevated in the absence of added Ang-II and addition of Ang-II failed to evoke a further increase in either. In addition, whereas type I collagen immunoreactivity was distributed throughout the cytosol of wild-type myofibroblasts, it was perinuclear in MK5 myofibroblasts. Furthermore, in MK5-deficient myofibroblasts the abundance of collagen 3-α, Timp3, Smad 6, Smad 7, TGF-β3, and snail homolog 1 transcripts was increased whereas integrin β3, latent TGF-β binding protein 1, thrombospondin 1, hepatocyte growth factor, and interleukin 13 were decreased. Finally, fibroblast contraction was decreased upon knocking down MK5. These results indicate that MK5 may be involved in fibroblast-mediated regulation of extracellular matrix homeostasis.
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http://dx.doi.org/10.1016/j.yjmcc.2019.05.014DOI Listing
July 2019

Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1100-1112

From the Department of Pharmacology, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India (D.T., B.B., A.M., A.S., D.G., K.J.).

Objective- This study investigates the functional significance of mitochondria present in endothelial microparticles (EMP) and how MK2 (MAPKAPK2 [MAPK-activated protein kinase 2]) governs EMP production and its physiological effect on cardiac hypertrophy. Approach and Results- Flow cytometric analysis, confocal imaging, oxygen consumption rate measurement through Seahorse were used to confirm the presence of functionally active mitochondria in nontreated EMP (EMP derived from untreated control cells), lipopolysaccharide, and oligomycin treatment increased mitochondrial reactive oxygen species activity in EMP (EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin, respectively). The dysfunctional mitochondria contained in EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin induced the expression of proinflammatory mediators in the target endothelial cells leading to the augmented adhesion of human monocytic cell line on EA.hy926 cells. Multiphoton real-time imaging detected the increased adherence of EMP derived from cells treated with oligomycin at the site of carotid artery injury as compared to EMP derived from untreated control cells. MK2 regulates EMP generation during inflammation by reducing E-selectin expression and regulating the cytoskeleton rearrangement through ROCK-2 (Rho-associated coiled-coil containing protein kinase 2) pathway. MK2-deficient EMP reduced the E-selectin and ICAM-1 (intracellular adhesion molecule-1) expression on target endothelial cells leading to reduced monocyte attachment and reduced cardiac hypertrophy in mice. Conclusions- MK2 promotes the proinflammatory effect of EMP mediated through dysfunctional mitochondria. MK2 modulates the inflammatory effect induced during cardiac hypertrophy through EMP.
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http://dx.doi.org/10.1161/ATVBAHA.119.312533DOI Listing
June 2019

GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling.

Cell Rep 2019 03;26(13):3511-3521.e4

Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address:

Inflammatory signaling is restricted through degradation and the translational repression of cytokine mRNAs. A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs. Here, we show that the RBP ZNF598 contributes to the same regulatory module in a TTP-like manner. Similar to TTP, ZNF598 harbors three proline-rich motifs that bind the GYF domain of GIGYF1. RNA sequencing experiments showed that ZNF598 is required for the regulation of known TTP targets, including IL-8 and CSF2 mRNA. Furthermore, we demonstrate that ZNF598 binds to IL-8 mRNA, but not TNF mRNA. Collectively, our findings highlight that ZNF598 functions as an RBP that buffers the level of a range of mRNAs. We propose that ZNF598 is a TTP-like factor that can contribute to the regulation of the inflammatory potential of cytokine-producing cells.
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http://dx.doi.org/10.1016/j.celrep.2019.03.006DOI Listing
March 2019

MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair.

Am J Physiol Heart Circ Physiol 2019 06 22;316(6):H1281-H1296. Epub 2019 Mar 22.

Department of Biochemistry and Molecular Medicine, Université de Montréal , Montreal, Quebec, Canada.

MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5 and wild-type littermate (MK5) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5 and MK5 mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5 and LADL-MK5 mice. Area at risk did not differ between LADL-MK5 and LADL-MK5 hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5 hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5 hearts compared with LADL-MK5. Although inflammatory cell infiltration was similar in LADL-MK5 and LADL-MK5 hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5 mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5 mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.
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http://dx.doi.org/10.1152/ajpheart.00532.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285621PMC
June 2019

IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.

Immunol Cell Biol 2019 01 19;97(1):54-71. Epub 2018 Oct 19.

Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.

IL-33 is an IL-1-related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2-like immune response. We show here that bone marrow-derived mast cells produce IL-13, IL-6, TNF, GM-CSF, CCL3 and CCL4 in response to IL-33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL-33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM-CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA-binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP-related protein Brf1 (Zfp36 l1) in IL-33-stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL-33-stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitoneal injection of IL-33.
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http://dx.doi.org/10.1111/imcb.12200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378613PMC
January 2019

T cell LFA-1-induced proinflammatory mRNA stabilization is mediated by the p38 pathway kinase MK2 in a process regulated by hnRNPs C, H1 and K.

PLoS One 2018 26;13(7):e0201103. Epub 2018 Jul 26.

Department of Internal Medicine, Section of Cardiovascular Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Activation of the β2 integrin lymphocyte function-associated antigen-1 (LFA-1) in T cells induces stabilization of proinflammatory AU-rich element (ARE)-bearing mRNAs, by triggering the nuclear-to-cytoplasmic translocation of the mRNA-binding and -stabilizing protein HuR. However, the mechanism by which LFA-1 engagement controls HuR localization is not known. Here, we identify and characterize four key regulators of LFA-1-induced changes in HuR activity: the p38 pathway kinase MK2 and the constitutive nuclear proteins hnRNPs C, H1 and K. LFA-1 engagement results in rapid, sequential activation of p38 and MK2. Post-LFA-1 activation, MK2 inducibly associates with both hnRNPC and HuR, resulting in the dissociation of HuR from hnRNPs C, H1 and K. Freed from the three hnRNPs, HuR translocates from the nucleus to the cytoplasm, and mediates the stabilization of labile cytokine transcripts. Our results suggest that the modulation of T cell cytokine mRNA half-life is an intricate process that is negatively regulated by hnRNPs C, H1 and K and requires MK2 as a critical activator.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201103PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065199PMC
January 2019

Differentiated macrophages acquire a pro-inflammatory and cell death-resistant phenotype due to increasing XIAP and p38-mediated inhibition of RipK1.

J Biol Chem 2018 07 13;293(30):11913-11927. Epub 2018 Jun 13.

From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M8, Canada,

Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations, and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that specifically depended on tumor necrosis factor α (TNFα) expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)-RipK3-caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of pro-inflammatory cytokines but reduced RipK1-dependent cell death and the RipK3-caspase-8 interaction. The expression of the anti-apoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIP), also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogen-activated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/MK2 pathway overrides apoptosis inhibition by XIAP and that acquisition of resistance to cell death by increased expression of XIAP and cFLIP may allow inflammatory macrophages to participate in pathogen control for a longer duration.
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http://dx.doi.org/10.1074/jbc.RA118.003614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066316PMC
July 2018

Septins: Active GTPases or just GTP-binding proteins?

Cytoskeleton (Hoboken) 2019 01 30;76(1):55-62. Epub 2018 Aug 30.

Hannover Medical School, Institute of Cell Biochemistry, Hannover, 30625, Germany.

Septins are conserved cytoskeletal proteins with unique filament forming capabilities and roles in cytokinesis and cell morphogenesis. Septins undergo hetero-oligomerization and assemble into higher order structures including filaments, rings, and cages. Hetero- and homotypic interactions of septin isoforms involve alternating GTPase (G)-domain interfaces and those mediated by N- and C-terminal extensions. While most septins bind GTP, display weak GTP-hydrolysis activity and incorporate guanine nucleotides in their interaction interfaces, studies using GTPase-inactivating mutations have failed to conclusively establish a crucial role for GTPase activity in mediating septin functions. In this mini-review, we will critically assess the role of GTP-binding and -hydrolysis on septin assembly and function. The relevance of G-domain activity will also be discussed in the context of human septin mutations as well as the development of specific small-molecules targeting septin polymerization. As structural determinants of septin oligomer interfaces, G-domains are attractive targets for ligand-based inhibition of septin assembly. Whether such an intervention can predictably alter septin function is a major question for future research.
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http://dx.doi.org/10.1002/cm.21451DOI Listing
January 2019

To die or not to die: Regulatory feedback phosphorylation circuits determine receptor-interacting protein kinase-1 (RIPK1) function.

Mol Cell Oncol 2018 30;5(1):e1396389. Epub 2017 Nov 30.

Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany.

Complex posttranslational modifications determine the effects of receptor-interacting protein kinase-1 (RIPK1) on cell survival and death. Studies from us and others have revealed a p38/MK2-dependent checkpoint in RIPK1 signaling. MAPKAP kinase 2 (MK2) phosphorylates RIPK1 to suppress RIPK1-mediated apoptosis and necroptosis in response to diverse stimuli relevant to inflammation, infection, genotoxic stress and chemotherapy.
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http://dx.doi.org/10.1080/23723556.2017.1396389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791865PMC
November 2017

The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells.

J Immunol 2018 02 29;200(3):1198-1206. Epub 2017 Dec 29.

Institute of Immunology, Jena University Hospital, 07743 Jena, Germany;

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-κB signaling and activation of MAPKs. In bone marrow-derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33-induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33-induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38-Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow-derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3-dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33-induced cytokine production in dendritic cells.
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http://dx.doi.org/10.4049/jimmunol.1700727DOI Listing
February 2018
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