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* Department of Internal Medicine/Infectious Diseases, Charité-Universitätsmedizin, Berlin, Germany; and
Institute for Medical Microbiology, Justus-Liebig University, Giessen, Germany
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Abstract |
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B activation initiated by L. monocytogenes in human endothelial cells. Moreover, we show for the first time that Nod1 mediated activation of p38 MAPK signaling induced by L. monocytogenes. Finally, L. monocytogenes- and Nod1-induced IL-8 production was blocked by a specific p38 inhibitor. In conclusion, L. monocytogenes induced a Nod1-dependent activation of p38 MAPK signaling and NF-B which resulted in IL-8 production in endothelial cells. Thus, Nod1 is an important component of a cytoplasmic surveillance pathway. |
Introduction |
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B, a process in which the receptor-interacting protein 2 (Rip2) as well as the IB kinase complex are involved (2). Moreover, we recently indicated that members of the IL-1R/TLR signaling cascade such as IL-1R-associated kinase and TNFR-associated factor 6 are downstream mediators of Nod proteins (7). Listeria monocytogenes is a Gram-positive, facultative intracellular bacteria which is particularly amenable to study pathogenesis of infections with cytosolic bacteria, as it enters and grows rapidly in the cytoplasm of a wide variety of tissue culture cells (8, 9). The infectious process of L. monocytogenes can be separated into different steps including adhesion, invasion, escape from the phagosomal compartment, intracytosolic replication, and cell-to-cell spread. Although listerial internalin (Inl) A and InlB are crucial for host cell adhesion and invasion, listeriolysin O (LLO) mediates the lysis of bacterium-containing vacuoles and is mandatory for cytosolic entry, intracellular survival, and replication (8, 9). Target cell activation triggered by L. monocytogenes is poorly understood, but a cytosolic-triggered cell activation was strongly suggested (10, 11). In contrast to wild-type L. monocytogenes, the nonpathogenic Listeria innocua very poorly invades human cells (12, 13).
In this study, we demonstrate that Nod1 mediates activation of p38 MAPK and NF-B, which contributes to IL-8 production in human endothelial cells infected with invasive Listeria.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The L. monocytogenes serotype 1/2a strain EGD and the L. innocua serotype 6b strain ATCC 33090 (INN; American Type Culture Collection) were grown in brain heart infusion broth (Difco). Recombinant strains of L. monocytogenes and L. innocua were generated as previously described (14, 15). For some experiments, Listeria were heat-inactivated (95°C, 30 min).
RNA interference (RNAi) in HUVEC
RNAi experiments in HUVEC were done as described previously (16): control nonsilencing small interference RNA (siRNA) (sense UUCUCCGAACGUGUCACGUtt, antisense ACGUGACACGUUCGGAGGAGAAtt) and different siRNAs targeting Nod1 (sequence 1: sense GGGUGAGACCAUCUUCAUCtt, antisense GAUGAAGAUGGUCUCACCCtg; se-quence 2: sense GGCCAAAGUCUAUGAAGAUtt, antisense AUCUUCAUAGACUUUGGCCtc), Nod2 (sequence 1: sense GGAAUUACCAGUCCCAUUGtt, antisense CAAUGGGACUGGUAAUUCCtg; sequence 2, sense GGCUGAAAUUCAGAAUAUUtt, antisense AAUAUUCUGAAUUUCAGCCtc), or TLR2 (sense GCCUUGACCUGUCCAACAAtt, antisense UUGUUGGACAGGUCAAGGCtt) were purchased from Ambion. HUVEC were isolated from umbilical cord veins and transfected by using the Amaxa Nucleofector according to the manufacturer’s protocol with 2 µg of siRNA/106 cells (16). Functional studies examining the role of Nod1 in cell activation by Listeria were performed 72 h after siRNA transfection.
Expression plasmids and HEK293 cell overexpression experiments
Expression plasmids for Nod1, Nod2, TLR2, TLR3, and IFN-
luciferase reporter were provided by G. Nuñez (University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, MI), C. Kirschning (Technical University of Munich, Munich, Germany), and D. Golenbock (University of Massachusetts Medical School, Worcester, MA), respectively. For reporter gene assays, human embryonic kidney HEK293 cells (American Type Culture Collection) were cultured in 24-well plates with DMEM (Invitrogen Life Technologies) supplemented with 10% FCS. Cells were cotransfected using the calcium phosphate method (BD Clontech) with 0.05 µg of the NF-B reporter or 0.3 µg of the IFN- reporter, 0.05 µg of the RSV--galactosidase reporter, and 0.2 ng of Nod expression vectors. For the experiments in which phosphorylation of p38 MAPK or IL-8 secretion was assessed, HEK293 cells were cultured in 12- or 24-well plates, respectively, and were transfected with 1.2 µg (12-well plate) or 0.5 µg (24-well plate) of either an empty control vector or Nod1 expression plasmid by using the Superfect reagent (Qiagen).
Macrophage-activating lipopeptide Infection of HUVEC and HEK293 cells
For experiments studying MAPK or MAPK-activated protein kinase 2 (MAPKAPK2) activation, cells were medium starved for 3 h before stimulation. HUVEC or HEK293 cells were inoculated with L. monocytogenes or L. innocua at a multiplicity of infection (MOI) of 0.05–5, as indicated, in MCDB131 or DMEM, respectively. Plates were centrifuged at 600 x g for 30 min to enhance the contact of bacteria with HUVEC. After 60 min, HUVEC were washed with PBS and fresh culture medium containing 100 µg/ml gentamicin was added to the cells. Cells were then incubated for a further 1 h (MAPK or MAPKAPK2 phosphorylation) or overnight (IL-8 or Nod expression), respectively. For some experiments, cells were incubated with the specific p38 MAPK inhibitor SB202190 (Calbiochem) or an inactive control peptide SB202474 (Calbiochem), in concentrations as indicated. TNF-
(10–30 ng/ml), LPS (1 µg/ml), poly(I:C) (25 µg/ml), or macrophage-activating lipopeptide 2 (MALP-2) (100 ng/ml) were used as controls. To investigate NF-B activation in HEK293 cells by heat-inactivated Listeria, heat-inactivated bacteria were added to the cells in the presence of calcium phosphate (during cDNA transfection) for 5 h to allow their entry into the host cells as reported (4, 6).
Confocal laser scanning microscopy
HUVEC monolayers were infected with Listeria, subsequently fixed with 3% paraformaldehyde (w/v; Sigma-Aldrich) for 20 min, and 4',6'-diamidino-2-phenylindole (DAPI; Sigma-Aldrich) staining for cellular and bacterial DNA was performed. For visualization of intracellular L. monocytogenes, Listeria mutants or L. innocua, additional F-actin staining was conducted with Phalloidin Alexa488 (Molecular Probes). Fluorescent images were acquired using an Axioskop 2 mot (objective: PlanNeoFluar x100, NA 1.4) equipped with an AxioCam MRm cooled greyscale camera (Zeiss). Deconvolution and digital image processing was executed by ImageProPlus 5.0 software (Media Cybernetics). To reach higher contrast for bacterial DNA and F-actin cladding in overlay images, red color was given for the DAPI channel.
Luciferase assay
Relative luciferase activities were obtained as described previously (7, 16).
IL-8 ELISA
IL-8 concentrations in HUVEC or HEK293 cell supernatants were assessed as described previously (16).
Antibiotic protection assay
HUVEC were transfected with siRNAs as described above, and cultured in 48-well plates. Listerial invasion of HUVEC and potential influence of Nod1-siRNAs hereon was assessed by antibiotic protection assay. HUVEC were infected with L. monocytogenes at a MOI of 0.5, and centrifuged at 600 x g for 30 min to enhance the contact of bacteria with HUVEC. After 60 min, cells were washed twice with PBS and fresh culture medium containing 100 µg/ml gentamicin (to kill extracellular bacteria) was added to the cells for 1 h. Cells were again washed twice with PBS, and incubated overnight with culture medium containing no antibiotics. Subsequently, HUVEC were lysed with 0.2% Triton X-100 for 20 min, and plated on brain-heart infusion (BHI) agar to asses numbers of intracellular Listeria. Control experiments demonstrated sufficient killing of extracellular Listeria (data not shown).
RT-PCR analysis
Total RNA from HUVEC or HEK293 cells was isolated with the RNeasy Mini kit (Qiagen) and reverse-transcribed using AMV reverse transcriptase (Promega). The generated cDNA was amplified by PCR using specific primers (Nod1: sense, 5'-AAGCGAAGAGCTGACCAAAT-3', antisense, 5'-TTCATAGACTTTGGCCTCCTC-3'; Nod2: sense, 5'-AGCCATTGTCAGGAGGCTC-3', antisense, 5'-CGTCTCTGCTCCATCATAGG-3'). Primers were purchased from TIB MOLBIOL. After 31 (Nod1) or 34 (Nod2) amplification cycles, the PCR products were analyzed on 1.5% agarose gels, stained with ethidium bromide, and subsequently visualized. To confirm equal amounts of RNA in each experiment, all samples were checked for GAPDH mRNA expression.
Immunoblotting
Cytoplasmatic cell extracts were separated by SDS-PAGE and blotted. Membranes were exposed to Abs specific to phosphospecific p38 MAPK (Cell Signaling Technology), phosphospecific MAPKAPK2 Thr222 (BIOMOL) or p42 MAPK (Santa Cruz Biotechnology), respectively. Subsequently, membranes were simultaneously incubated with secondary Abs (IRDye 800-labeled anti-rabbit and Cy5.5-labeled anti-mouse (Rockland Immunochemicals), respectively). Simultaneous detection of target proteins and a loading control requires primary Abs of different species, therefore, we used Abs against p42 (mouse) to check equal loading in the pp38 or pMAPKAPK2 (rabbit Ab) immunoblots. Proteins were detected by using an Odyssey infrared imaging system (LI-COR).
Statistics
Stimulatory effects of Listeria as well as inhibitory effects of siRNA or inhibitors used were statistically evaluated using the Student t test. Throughout the figures, p values of <0.05 are indicated by one asterisk, p values of <0.01 by double asterisks.
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Results |
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To characterize host cell activation by intracellular vs extracellular bacteria, we incubated HUVEC with wild-type L. monocytogenes (EGD), InlB-negative, or LLO-negative mutants of L. monocytogenes, or nonpathogenic L. innocua (INN). Wild-type L. monocytogenes could be seen in the cytoplasm of human endothelial cells examined and recruited host cell actin (Fig. 1A). L. monocytogenes deficient in InlB hardly entered, and L. innocua failed to enter, into the host cell cytoplasm. Moreover, the LLO-negative L. monocytogenes could not be seen neither in actin or in DAPI staining, demonstrating an insufficient entry of the bacteria into the cytoplasm, and suggesting a deficient propagation of the bacteria and/or sufficient killing of these vacuole-trapped bacteria (Fig. 1A). Interestingly, the induction of IL-8 in endothelial cells strongly correlated with the invasiveness: only wild-type L. monocytogenes, but not the nonvirulent strain L. innocua or the invasion-deficient L. monocytogenes mutants, induced IL-8 in HUVEC (Fig. 1B). Moreover, overexpression of LLO in L. innocua resulted only in very little restoration of the capability to activate HUVEC with respect to IL-8 secretion (data not shown). For Listeria, the ability to reside within the cytoplasm of HUVEC seemed therefore to be essential for cell activation, raising the question of whether intracellular immune receptors might be involved.
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In the next step, we tested the hypothesis that cytoplasmic Nod proteins mediate proinflammatory activation of endothelial cells by intracellular Listeria. We detected Nod1-mRNA in HUVEC by RT-PCR experiments (Fig. 2A), whereas only very little Nod2-mRNA could be found in HUVEC after listerial infection (Fig. 2B). In contrast, Nod2 was clearly seen in control cells overexpressing Nod2, indicating the reliability of our assay. To address the role of Nod1 and Nod2 in L. monocytogenes-induced IL-8 secretion in endothelial cells, we performed RNAi experiments to inhibit the expression of endogenous Nod1 and Nod2. First, we evaluated different siRNAs for their ability to reduce Nod mRNA expression. Only the Nod1- or Nod2-specific oligonucleotides, respectively, inhibited Nod1 or Nod2 mRNA levels (Fig. 2, C and D). Both siRNAs targeting Nod1 (but not the nonsilencing siRNA or Nod2 siRNAs) significantly blocked the IL-8 production induced by L. monocytogenes in HUVEC (Fig. 2E, left panel, and F). In contrast, the TNF--related cytokine production was not reduced by any siRNA used. Moreover, while Listeria-induced IL-8 secretion was clearly reduced by Nod1-siRNA, IL-8 production stimulated by LPS (TLR-dependent) was not affected by the siRNAs (Fig. 2E, right panel). Nod2 has been indicated as an antibacterial factor constraining bacterial survival (17, 18). Thus, we examined whether Nod1 siRNAs affect Listeria-induced IL-8 production indirectly by altering numbers of intracellular bacteria. In our antibiotic protection assay, we could not see a significant influence of any siRNAs used on the numbers of intracellular Listeria 20 h postinfection (Fig. 2G). Overall, our observations demonstrate that Nod1 is important for L. monocytogenes-induced, but not TNF-- or LPS-induced, signaling leading to IL-8 production in HUVEC.
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B activation in HEK293 cells, but is not crucial for Listeria-induced IL-8 secretion in HUVECTLR2 has been implicated in Listeria-induced cell activation (Chinese hamster ovary fibroblast cell lines) and host responses against Listeria in mice (19, 20). As can be seen in Fig. 3A, HEK293 cells overexpressing TLR2 responded to L. monocytogenes and L. innocua, indicating that TLR2 mediated HEK293 cell activation by invasive and noninvasive bacteria. The behavior of TLR2/HEK293 cells is in contrast to our results obtained in HUVEC, showing that only intracellular Listeria but not the noninvasive bacteria induced IL-8 secretion in these cells, thus suggesting a minor role of TLR2 in HUVEC activation by Listeria. To further exclude an involvement of TLR2 in Listeria-induced HUVEC activation, we performed RNAi experiments: siRNA targeting TLR2 did not abrogate IL-8 production induced by L. monocytogenes in HUVEC, but did significantly inhibited the HUVEC activation by the TLR2 agonist MALP-2 (Fig. 3B). Overall, our data indicate that TLR2 is not crucial for Listeria-induced IL-8 production in HUVEC.
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B activation by L. monocytogenes in HEK293 cells
To further confirm the role of Nod proteins in target cell activation by Listeria, we performed overexpression assays. Therefore, HEK293 cells were transfected with an NF-B reporter, and with an empty control vector, Nod1 or Nod2 expression vectors. Intracellular stimulation with heat-inactivated bacteria was done as it has been performed earlier (4, 6), and as described in Materials and Methods. In this experiment, bacteria activated the NF-B reporter only when Nod1 or Nod2 were overexpressed (Fig. 4A). In contrast to the NF-B reporter, an IFN- promoter-dependent reporter was only very slightly activated by Listeria via Nod1 or Nod2 but cells responded with strong IFN- promoter activation after stimulation with poly(I:C) through TLR3 (Fig. 4B). Overall, data obtained indicate that Nod proteins mediated L. monocytogenes-induced NF-B activation but are not likely involved in IFN- induction.
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Besides NF-B signaling, activation of p38 MAPK has been shown to be fundamental for inflammatory processes (21). To address the question of whether Nod1 activates p38 MAPK, we used HUVEC, which were infected with L. monocytogenes. Indeed, L. monocytogenes induced phosphorylation of p38 MAPK in HUVEC (Fig. 5). The Listeria-induced activation of p38 examined was reduced by siRNAs targeting Nod1, but not by a nonspecific control siRNA (Fig. 5). Thus, our results strongly suggest an involvement of Nod1 in L. monocytogenes-induced activation of p38.
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To further clarify the association of Nod1 with MAPK activation, we performed overexpression studies in HEK293 cells. Cells were transfected with either a control vector or with Nod1, and infected with L. monocytogenes. The L. monocytogenes-induced phosphorylation of p38 MAPK in HEK293 cells was increased following overexpression of Nod1 (Fig. 6), confirming the critical role of Nod1 for p38 MAPK activation induced by intracellular bacteria. The somewhat moderate effects of Nod1 overexpression could be explained by the fact that in our transient overexpression assays, only 50% of the cells expressed the transfected gene of interest (data not shown).
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p38 MAPK signaling leads to phosphorylation and activation of downstream effector proteins such as the MAPKAPK2 (22). To address the question of whether Nod1 also mediates MAPKAPK2 activation by Listeria, we used HUVEC that were infected with L. monocytogenes. Indeed, Nod1 siRNAs inhibited the L. monocytogenes-induced phosphorylation of MAPKAPK2 in HUVEC (Fig. 7). Thus, our results indicated that in Listeria infection of HUVEC, Nod1 is important for signaling events downstream of p38.
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Following our observation that L. monocytogenes induced p38 MAPK activation as well as IL-8 secretion via Nod1 in HUVEC, we sought to examine the role of p38 MAPK in IL-8 production induced by L. monocytogenes and Nod1. Therefore, cells were pretreated with a specific p38 inhibitor (SB202190) or with an inactive control peptide (SB202474). L. monocytogenes-induced IL-8 production in HUVEC was reduced in a dose-dependent fashion by the p38 MAPK inhibitor (Fig. 8A). In contrast, the control peptide hardly showed any inhibitory effect with respect to L. monocytogenes-related IL-8 secretion. Moreover, TNF--induced IL-8 secretion was only slightly affected by any inhibitor used.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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B signaling, and subsequent IL-8 production via Nod1. The identification of p38 MAPK as a downstream kinase of Nod1 expands the potential biological effector systems affected by Nod1-dependent cell stimulation.
Our results are consistent with recently published studies indicating a cytosol-specific surveillance mechanism involved in L. monocytogenes-induced target cell activation (10, 11). It was shown that cytosol-, but not the vacuole-, localized bacteria induced NF-B and p38 phosphorylation (11). Moreover, two recently published studies demonstrated that IFN- induction by Listeria was independent on the TLRs, and was also independent on Rip2 and Nod2 (23, 24). In this study, we demonstrate that Nod1 is also unlikely to be crucial for IFN- induction. A possible explanation would be that a so far unidentified receptor might be involved in the IFN- induction induced by Listeria. Taken in consideration that in the TLR family all members mediate NF-B activation but only some members are involved in type I IFN induction (25), we propose a model in which Nod1 (and Nod2 in Nod2-expressing cells (Fig. 4A and Ref.26) mediates NF-B and MAPK activation by Listeria, whereas other innate immune receptors mediate activation of IFN regulatory factors leading to IFN- induction.
One of the initial reports about Nod protein functions demonstrated that JNK activation induced by Shigella flexneri was inhibited by dominant-negative Nod1 in epithelial cells (27). Our results obtained by RNAi experiments add p38 MAPK signaling to the events triggered by intracellular bacteria via Nod1. Our data furthermore suggest that p38 MAPK are involved in Nod1-induced signaling and subsequent gene expression. Hence, Nod1-related p38 MAPK activation may contribute significantly to L. monocytogenes-induced epigenetic modifications paving the way to forced expression of inflammatory genes (28).
Our results demonstrating a fundamental role of Nod1 in L. monocytogenes-triggered cell activation are in line with the fact that Nod1 recognizes peptidoglycan containing meso-diaminopimelic acid (3, 4), found primarily in Gram-negative bacteria but also in Gram-positive L. monocytogenes (29). Nod2 seemed to not be critically involved in endothelial cell activation by Listeria, because RT-PCR analysis show very little Nod2 expression in HUVEC, and siRNA targeting Nod2 did not significantly inhibit the HUVEC activation by L. monocytogenes. However, Nod2 is very likely to be involved in Listeria recognition in other cell types (Fig. 4A and Ref.26).
A critical involvement of TLRs in L. monocytogenes-induced endothelial cell activation is unlikely. TLR2 would be the candidate for sensing bacteria examined (19, 20), but TLR2 siRNA did not abrogate Listeria-induced HUVEC activation (Fig. 3B). Moreover, both L. monocytogenes and L. innocua are equally capable of activating TLR2-expressing HEK293, but only the cytosol-localized L. monocytogenes induced IL-8 secretion in HUVEC (Figs. 1B and 3A).
In summary, we have identified Nod1 as a fundamental mediator of endothelial cell innate immune responses. Our results suggest a signaling pathway triggered by L. monocytogenes in HUVEC, involving Nod1, p38, as well as NF-B, leading to gene expression. Thus, our data expand the knowledge about the recently described cytosolic surveillance system in eukaryotic cells.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported in part by grants given by the Bundesministerium für Bildung und Forschung (BMBF) to S.H. (BMBF-NBL3, CAPNetz C15), to N.S. (CAPNetz C4), to T.C. (NGFN), and the Deutsche Forschungsgemeinschaft to N.S. (DFG Kr1143/4-1). Parts of this work will be included in the doctoral theses of A.P., S.F., and W.B. 
2 Address correspondence and reprint requests to Dr. Stefan Hippenstiel, Department of Internal Medicine/Infectious Diseases, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail address: stefan.hippenstiel{at}charite.de
3 Abbreviations used in this paper: Nod, nucleotide-binding oligomerization domain; Rip2, receptor-interacting protein 2; Inl, internalin; LLO, listeriolysin O; RNAi, RNA interference; siRNA, small interference RNA; MAPKAPK2, MAPK-activate protein kinase 2; MOI, multiplicity of infection; MALP-2, macrophage-activating lipopeptide; DAPI, 4',6'-diamidino-2-phenylindole; BHI, brain heart infusion.
Received for publication June 8, 2005. Accepted for publication October 24, 2005.
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References |
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B kinase-binding kinase 1. J. Immunol. 174: 1602-1607. B and JNK activation by invasive Shigella flexneri. EMBO Rep. 2: 736-742. [Medline]This article has been cited by other articles:
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J. L. Snider, C. Allison, B. H. Bellaire, R. L. Ferrero, and J. A. Cardelli The {beta}1 Integrin Activates JNK Independent of CagA, and JNK Activation Is Required for Helicobacter pylori CagA+-induced Motility of Gastric Cancer Cells J. Biol. Chem., May 16, 2008; 283(20): 13952 - 13963. [Abstract] [Full Text] [PDF]
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