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Journal of Inflammation
Published in: Journal of Inflammation 1/2015

Open Access 01-12-2015 | Research

TLR2 and AP-1/NF-kappaB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells

Authors: Puthiyaveetil Kochumon Shihab, Areej Al-Roub, Moneera Al-Ghanim, Anfal Al-Mass, Kazem Behbehani, Rasheed Ahmad

Published in: Journal of Inflammation | Issue 1/2015

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Abstract

Background

MMP-9 is crucial for a normal immune response, but excessive release of this enzyme leads to severe tissue damage. Listeria monocytogenes (LM) is an opportunistic food-borne pathogen causing listerosis, meningitis and sepsis. Heat killed Listeria monocytogenes (HKLM) activates immune system and leads production of cytokines and chemokines. However, nothing is known about the involvement of HKLM in MMP-9 regulation. Therefore we investigated the role of HKLM in the regulation of MMP-9 gene expression in THP-1 cells.

Methods

Commercially available heat killed Listeria monocytogenes was used in this study. HKLM-induced MMP-9 expression was assessed with quantitative real-time qPCR and ELISA. Action of HKLM in different signaling pathways were studied by using THP-1-XBlue™ cells (THP-1-cells with NF-κB/AP-1 reporter construct), THP-1-XBlue™-defMyD cells (MyD88−/− THP-1 cells), anti-TLR2 mAb and pharmacological inhibitors. Phospho and total proteins were determined by Western blotting.

Results

Increased MMP-9 production (mRNA: 395-Fold; Protein: 8141 pg/ml; P < 0.05) was observed in HKLM stimulated THP-1 cells as compared to the un-stimulated THP-1 cells. This production of MMP-9 was completely abrogated by anti-TLR2 blocking mAb (P = 0.0024). Furthermore, THP-1-XBlue™-defMyD cells were unable to produce MMP-9 in response to HKLM. HKLM- induced activation of NF-kappaB/AP-1 was also observed in THP-1-XBlue™ Cells. In addition, inhibitors of JNK (SP600125), MEK/ERK (U0126; PD98056), p38 MAPK (SB203580) and NF-kappaB (BAY 11–7085, Triptolide and Resveratrol) significantly suppressed (P < 0.05) HKLM-stimulated MMP-9 expression.

Conclusion

Our results indicate that HKLM activates TLR2 and NF-κB/AP-1 signaling pathways, leading to up-regulation of MMP-9 production in THP-1 cells. Thus, MMP-9 could be an appropriate therapeutic target to stop severe tissue damage caused by infection or chronic inflammation.
Literature
1.
Hamon M, Bierne H, Cossart P. Listeria monocytogenes: a multifaceted model. Nat Rev Microbiol. 2006;4:423–34.CrossRefPubMed
2.
Swaminathan B, Gerner-Smidt P. The epidemiology of human listeriosis. Microbes Infect. 2007;9:1236–43.CrossRefPubMed
3.
Ooi ST, Lorber B. Gastroenteritis due to Listeria monocytogenes. Clin Infect Dis. 2005;40:1327–32.CrossRefPubMed
4.
5.
Creagh EM, O’Neill LA. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 2006;27:352–7.CrossRefPubMed
6.
7.
Ahmad R, El Bassam S, Cordeiro P, Menezes J. Requirement of TLR2-mediated signaling for the induction of IL-15 gene expression in human monocytic cells by HSV-1. Blood. 2008;112:2360–8.CrossRefPubMed
8.
Cossart P, Mengaud J. Listeria monocytogenes. A model system for the molecular study of intracellular parasitism. Mol Biol Med. 1989;6:463–74.PubMed
9.
Czuprynski CJ, Brown JF. Effects of purified anti-Lyt-2 mAb treatment on murine listeriosis: comparative roles of Lyt-2+ and L3T4+ cells in resistance to primary and secondary infection, delayed-type hypersensitivity and adoptive transfer of resistance. Immunology. 1990;71:107–12.PubMedCentralPubMed
10.
11.
12.
13.
Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. TRAF6 is a signal transducer for interleukin-1. Nature. 1996;383:443–6.CrossRefPubMed
14.
15.
Cao Z, Henzel WJ, Gao X. IRAK: a kinase associated with the interleukin-1 receptor. Science. 1996;271:1128–31.CrossRefPubMed
16.
Gohda J, Matsumura T, Inoue J. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol. 2004;173:2913–7.CrossRefPubMed
17.
18.
Gosselin J, Flamand L, D’Addario M, Hiscott J, Menezes J. Infection of peripheral blood mononuclear cells by herpes simplex and Epstein-Barr viruses. Differential induction of interleukin 6 and tumor necrosis factor-alpha. J Clin Invest. 1992;89:1849–56.CrossRefPubMedCentralPubMed
19.
Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines. Lancet. 1997;349:490–5.CrossRefPubMed
20.
21.
Ebnet K, Vestweber D. Molecular mechanisms that control leukocyte extravasation: the selectins and the chemokines. Histochem Cell Biol. 1999;112:1–23.CrossRefPubMed
22.
Woessner Jr JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991;5:2145–54.PubMed
23.
Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol. 2002;3:207–14.CrossRefPubMed
24.
Goetzl EJ, Banda MJ, Leppert D. Matrix metalloproteinases in immunity. J Immunol. 1996;156:1–4.PubMed
25.
Tchetina EV, Demidova NV, Karateev DE, Nasonov EL. Rheumatoid factor positivity is associated with increased joint destruction and upregulation of matrix metalloproteinase 9 and cathepsin k gene expression in the peripheral blood in rheumatoid arthritic patients treated with methotrexate. Int J Rheumatol. 2013;2013:457876.CrossRefPubMedCentralPubMed
26.
Medina C, Radomski MW. Role of matrix metalloproteinases in intestinal inflammation. J Pharmacol Exp Ther. 2006;318:933–8.CrossRefPubMed
27.
Leifler KS, Svensson S, Abrahamsson A, Bendrik C, Robertson J, Gauldie J, et al. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J Immunol. 2013;190:4420–30.CrossRefPubMedCentralPubMed
28.
Okamoto T, Akuta T, Tamura F, van Der Vliet A, Akaike T. Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation. Biol Chem. 2004;385:997–1006.CrossRefPubMed
29.
Tsai CL, Chen WC, Lee IT, Chi PL, Cheng SE, Yang CM. c-Src-dependent transactivation of PDGFR contributes to TNF-alpha-induced MMP-9 expression and functional impairment in osteoblasts. Bone. 2014;60:186–97.CrossRefPubMed
30.
Lin CC, Kuo CT, Cheng CY, Wu CY, Lee CW, Hsieh HL, et al. IL-1 beta promotes A549 cell migration via MAPKs/AP-1- and NF-kappaB-dependent matrix metalloproteinase-9 expression. Cell Signal. 2009;21:1652–62.CrossRefPubMed
31.
Abraham M, Shapiro S, Lahat N, Miller A. The role of IL-18 and IL-12 in the modulation of matrix metalloproteinases and their tissue inhibitors in monocytic cells. Int Immunol. 2002;14:1449–57.CrossRefPubMed
32.
Yeung VP, Gieni RS, Umetsu DT, DeKruyff RH. Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses. J Immunol. 1998;161:4146–52.PubMed
33.
McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG. Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry. 2011;1:e36.CrossRefPubMedCentralPubMed
34.
Miller MA, Skeen MJ, Ziegler HK. Protective immunity to Listeria monocytogenes elicited by immunization with heat-killed Listeria and IL-12. Potential mechanism of IL-12 adjuvanticity. Ann N Y Acad Sci. 1996;797:207–27.CrossRefPubMed
35.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25:402–8.CrossRefPubMed
36.
Ahmad R, Sylvester J, Ahmad M, Zafarullah M. Adaptor proteins and Ras synergistically regulate IL-1-induced ADAMTS-4 expression in human chondrocytes. J Immunol. 2009;182:5081–7.CrossRefPubMed
37.
Suzaki A, Komine-Aizawa S, Hayakawa S. Suppression of osteoblast toll-like receptor 2 signaling by endothelin-1. J Orthop Res. 2014;32:910–4.CrossRefPubMed
38.
Yang CM, Lin CC, Lee IT, Lin YH, Chen WJ, Jou MJ, et al. Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes. J Neuroinflammation. 2012;9:12.CrossRefPubMedCentralPubMed
39.
Suh SJ, Kwak CH, Chung TW, Park SJ, Cheeeei M, Park SS, et al. Pimaric acid from Aralia cordata has an inhibitory effect on TNF-alpha-induced MMP-9 production and HASMC migration via down-regulated NF-kappaB and AP-1. Chem Biol Interact. 2012;199:112–9.CrossRefPubMed
40.
Lavelle EC, Murphy C, O’Neill LA, Creagh EM. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010;3:17–28.CrossRefPubMedCentralPubMed
41.
Liang KC, Lee CW, Lin WN, Lin CC, Wu CB, Luo SF, et al. Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. J Cell Physiol. 2007;211:759–70.CrossRefPubMed
42.
Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-kappaB pathway, and MMP-9 expression. Exp Cell Res. 2011;317:1746–62.CrossRefPubMed
43.
Bond M, Fabunmi RP, Baker AH, Newby AC. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Lett. 1998;435:29–34.CrossRefPubMed
44.
Himelstein BP, Lee EJ, Sato H, Seiki M, Muschel RJ. Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell line. Oncogene. 1997;14:1995–8.CrossRefPubMed
45.
Ilhan F, Ulusoy Y, Haligur M. Matrix metalloproteinase expression in sheep with listerial meningoencephalitis. Res Vet Sci. 2012;92:269–72.CrossRefPubMed
46.
Ahmad R, Shihab PK, Jasem S, Behbehani K. FSL-1 induces MMP-9 production through TLR-2 and NF-kappaB /AP-1 signaling pathways in monocytic THP-1 cells. Cell Physiol Biochem. 2014;34:929–42.CrossRefPubMed
47.
Lin HY, Tang CH, Chen JH, Chuang JY, Huang SM, Tan TW, et al. Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c-Jun, and AP-1 pathways in microglia. J Cell Physiol. 2011;226:1573–82.CrossRefPubMed
48.
Wang YY, Myhre AE, Pettersen SJ, Dahle MK, Foster SJ, Thiemermann C, et al. Peptidoglycan of Staphylococcus aureus induces enhanced levels of matrix metalloproteinase-9 in human blood originating from neutrophils. Shock. 2005;24:214–8.CrossRefPubMed
49.
Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, et al. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep. 2004;5:1000–6.CrossRefPubMedCentralPubMed
50.
Giambartolomei GH, Zwerdling A, Cassataro J, Bruno L, Fossati CA, Philipp MT. Lipoproteins, not lipopolysaccharide, are the key mediators of the proinflammatory response elicited by heat-killed Brucella abortus. J Immunol. 2004;173:4635–42.CrossRefPubMed
51.
Scian R, Barrionuevo P, Giambartolomei GH, Fossati CA, Baldi PC, Delpino MV. Granulocyte-macrophage colony-stimulating factor- and tumor necrosis factor alpha-mediated matrix metalloproteinase production by human osteoblasts and monocytes after infection with Brucella abortus. Infect Immun. 2011;79:192–202.CrossRefPubMedCentralPubMed
52.
53.
Zhang G, Ghosh S. Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. J Clin Invest. 2001;107:13–9.CrossRefPubMedCentralPubMed
54.
Tseng HC, Lee IT, Lin CC, Chi PL, Cheng SE, Shih RH, et al. IL-1beta promotes corneal epithelial cell migration by increasing MMP-9 expression through NF-kappaB- and AP-1-dependent pathways. PLoS One. 2013;8:e57955.CrossRefPubMedCentralPubMed
55.
Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol. 1995;13:437–57.CrossRefPubMed
56.
Cho HJ, Kang JH, Kwak JY, Lee TS, Lee IS, Park NG, et al. Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms. Carcinogenesis. 2007;28:1104–10.CrossRefPubMed
57.
Abate C, Patel L, Rauscher 3rd FJ, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990;249:1157–61.CrossRefPubMed
58.
Fan H, Sun B, Gu Q, Lafond-Walker A, Cao S, Becker LC. Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart. Am J Physiol Heart Circ Physiol. 2002;282:H1778–86.CrossRefPubMed
59.
Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, et al. Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Biofactors. 2001;15:87–9.CrossRefPubMed
60.
Lee SW, Han SI, Kim HH, Lee ZH. TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB. J Biochem Mol Biol. 2002;35:371–6.CrossRefPubMed
61.
Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995;9:2723–35.CrossRefPubMed
62.
Lee FS, Hagler J, Chen ZJ, Maniatis T. Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell. 1997;88:213–22.CrossRefPubMed
63.
Tapon N, Nagata K, Lamarche N, Hall A. A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. EMBO J. 1998;17:1395–404.CrossRefPubMedCentralPubMed
Metadata
Title
TLR2 and AP-1/NF-kappaB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells
Authors
Puthiyaveetil Kochumon Shihab
Areej Al-Roub
Moneera Al-Ghanim
Anfal Al-Mass
Kazem Behbehani
Rasheed Ahmad
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2015
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-015-0077-0

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