title: Suppression of inflammatory gene expression in T cells by Porphyromonas gingivalis is mediated by targeting MAPK signaling.
abstract: There is increasing awareness of the effects of Porphyromonas gingivalis on host immune responses. Degradation of cytokines and chemokines by cysteine proteinases has previously been reported. However, the precise mechanisms by which P. gingivalis is able to alter intracellular signaling, and thus proliferation and inflammation, have not been described. We have previously reported suppression of activator protein-1 (AP-1) and degradation of IL-2 by proteinases from P. gingivalis. In the present study, we have analyzed the effects of P. gingivalis on Jurkat T-cell signal transduction and subsequent IL-2 and CXCL8 expression. We found that CXCL8, but not IL-2, gene expression levels were significantly suppressed by viable P. gingivalis. Analysis of intracellular signaling revealed an inhibitory effect of P. gingivalis on c-Jun and c-Fos, but not NFκB (p50 and p65), NFAT or STAT5 expression. This inhibitory effect was not due to suppression of mitogen-activated protein kinase (MAPK) (p38, erk and JNK) gene expression, but was rather due to prevention of protein kinase C (PKC) and p38 phosphorylation, as demonstrated by western blot analysis. Furthermore, SOCS1 and SOCS3 expression levels decreased following treatment of Jurkat T cells with viable P. gingivalis. The results indicate that P. gingivalis is able to suppress inflammatory gene expression by targeting the activity of MAPK pathways in T cells, which was confirmed by using specific inhibitors of NF-κB, PKC, ERK, p38 and JNK.
authors.affiliation: Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
authors.forename: Hazem
authors.initials: H
authors.lastname: Khalaf
authors.forename: Isak
authors.initials: I
authors.lastname: Demirel
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Bengtsson
mesh_terms: D018920:Coculture Techniques; D015536:Down-Regulation; D015870:Gene Expression / Q000276:immunology*; D016762:Genes, fos / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D016966:Porphyromonas gingivalis / Q000502:physiology*; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D007376:Interleukin-2; D016209:Interleukin-8; D016328:NF-kappa B; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Am Heart J. 1999 Nov;138(5 Pt 2):S534-6
references.pmid: 10539867
references.citation: Nature. 2000 Mar 23;404(6776):402-7
references.pmid: 10746729
references.citation: Mol Cell. 2003 Dec;12(6):1413-26
references.pmid: 14690596
references.citation: Toxins (Basel). 2010 Mar;2(3):341-52
references.pmid: 22069588
references.citation: EMBO J. 2000 Oct 16;19(20):5418-28
references.pmid: 11032809
references.citation: Nat Immunol. 2003 Oct;4(10):957-64
references.pmid: 14502285
references.citation: J Cell Sci. 2004 Dec 1;117(Pt 25):5965-73
references.pmid: 15564374
references.citation: J Periodontal Res. 2011 Feb;46(1):31-8
references.pmid: 20825555
references.citation: Mol Cell Biol. 2006 Mar;26(6):2327-36
references.pmid: 16508008
references.citation: Mol Cell Biol. 1999 Jul;19(7):4980-8
references.pmid: 10373548
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1446-51
references.pmid: 15845905
references.citation: Oral Microbiol Immunol. 2003 Feb;18(1):30-6
references.pmid: 12588456
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: J Immunol. 1999 Apr 1;162(7):3819-29
references.pmid: 10201899
references.citation: J Exp Med. 1992 Mar 1;175(3):853-62
references.pmid: 1740667
references.citation: Infect Immun. 2009 Apr;77(4):1451-8
references.pmid: 19168731
references.citation: J Immunol. 2007 May 1;178(9):5690-700
references.pmid: 17442952
references.citation: BMC Immunol. 2010 May 27;11:26
references.pmid: 20507572
references.citation: Infect Immun. 2011 Jul;79(7):2632-7
references.pmid: 21536793
references.citation: Eur J Immunol. 1996 May;26(5):989-94
references.pmid: 8647190
references.citation: Blood. 2001 Jan 1;97(1):221-6
references.pmid: 11133764
references.citation: FEMS Immunol Med Microbiol. 2005 Apr 1;44(1):51-8
references.pmid: 15780578
references.citation: Innate Immun. 2010 Aug;16(4):226-34
references.pmid: 19710093
references.citation: Periodontol 2000. 2007;43:14-40
references.pmid: 17214833
references.citation: J Biol Chem. 2003 Jun 20;278(25):22755-61
references.pmid: 12665516
references.citation: Mem Inst Oswaldo Cruz. 2005 Mar;100 Suppl 1:177-80
references.pmid: 15962119
references.citation: Blood. 2001 Jun 15;97(12):3790-7
references.pmid: 11389018
references.citation: J Periodontal Res. 2002 Dec;37(6):464-8
references.pmid: 12472841
references.citation: Nature. 1992 Apr 16;356(6370):607-9
references.pmid: 1313950
references.citation: J Biol Chem. 1998 Mar 20;273(12):6611-4
references.pmid: 9506956
references.citation: Mol Cell Biol. 2004 May;24(9):3860-73
references.pmid: 15082780
references.citation: Microb Pathog. 2005 Feb-Mar;38(2-3):85-96
references.pmid: 15748810
references.citation: Biochem Biophys Res Commun. 1999 Aug 11;261(3):598-602
references.pmid: 10441472
references.citation: Immunology. 2004 Jun;112(2):183-90
references.pmid: 15147561
references.citation: BMC Microbiol. 2009 May 27;9:107
references.pmid: 19473524
references.citation: Infect Immun. 2007 Aug;75(8):4088-96
references.pmid: 17517867
references.citation: PLoS One. 2012;7(9):e45192
references.pmid: 22984628
references.citation: J Periodontol. 2006 Apr;77(4):622-33
references.pmid: 16584343