title: Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis.
abstract: BACKGROUND
  Sarcoidosis is an inflammatory disease of unknown etiology. However, an infectious cause has been proposed suggesting a role for pattern-recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding domain, leucin-rich repeat containing family proteins (NLRs), in the pathogenesis.
  
  
  OBJECTIVE
  Our aim was to investigate whether differences in TLR2 and TLR4 expression, and the response to TLR2, TLR4, and NOD2 stimulation, are associated with sarcoidosis.
  
  
  METHODS
  Blood mononuclear cells from sarcoidosis patients (n = 24) and healthy subjects (n = 19) were incubated with the TLR2 ligands PGN and Pam3CSK4, the TLR4 ligand LPS, the NOD2 ligand MDP, or medium alone. After 16 h, monocyte TLR2 and TLR4 expression and cytokine secretion, including TNFalpha, IL-1 beta, IL-6, IL-8, IL-10, and IL-12p70, were measured using flow cytometry and cytometric bead array.
  
  
  RESULTS
  TLR2 and TLR4 expression at baseline was significantly higher in patients. Combined TLR2 and NOD2 stimulation induced a four-fold higher secretion of TNFalpha and a 13-fold higher secretion of IL-1 beta in patients. Additionally, there was a synergistic effect of TLR2 with NOD2 stimulation on induction of IL-1 beta in patients, whereas IL-10 was synergistically induced in healthy subjects.
  
  
  CONCLUSIONS
  Increased TLR expression and enhanced secretion of pro-inflammatory cytokines after combined TLR2 and NOD2 stimulation may be related to the pathogenesis of sarcoidosis.
authors.affiliation: Department of Medicine, Respiratory Medicine Unit, Karolinska Institutet, Lung Research Laboratory L4:01, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden. Maria.Wiken@ki.se
authors.forename: Maria
authors.initials: M
authors.lastname: Wikén
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.forename: Jan
authors.initials: J
authors.lastname: Wahlström
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D008024:Ligands; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D012507:Sarcoidosis / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008024:Ligands; D055666:Lipopeptides; D008070:Lipopolysaccharides; D053473:Nod2 Signaling Adaptor Protein; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
references.citation: J Invest Dermatol. 2005 May;124(5):931-8
references.pmid: 15854033
references.citation: Lancet. 2002 Aug 10;360(9331):465-6
references.pmid: 12241724
references.citation: J Leukoc Biol. 2006 Apr;79(4):860-6
references.pmid: 16461743
references.citation: Lancet. 1992 Apr 25;339(8800):1012-5
references.pmid: 1349051
references.citation: Clin Exp Immunol. 2001 Oct;126(1):151-6
references.pmid: 11678912
references.citation: PLoS Pathog. 2005 Nov;1(3):279-85
references.pmid: 16322770
references.citation: Nat Genet. 2001 Sep;29(1):19-20
references.pmid: 11528384
references.citation: Clin Exp Immunol. 2008 Jun;152(3):423-31
references.pmid: 18422738
references.citation: Biochim Biophys Acta. 2006 Sep;1762(9):794-801
references.pmid: 16935475
references.citation: Immunobiology. 1996-1997;196(5):522-34
references.pmid: 9145330
references.citation: Semin Immunol. 2004 Feb;16(1):35-41
references.pmid: 14751762
references.citation: J Endocrinol. 2007 Jun;193(3):323-30
references.pmid: 17535871
references.citation: Clin Exp Immunol. 2006 Aug;145(2):215-8
references.pmid: 16879239
references.citation: Sarcoidosis Vasc Diffuse Lung Dis. 2006 Mar;23(1):23-9
references.pmid: 16933467
references.citation: Clin Exp Immunol. 2007 Sep;149(3):453-62
references.pmid: 17565608
references.citation: Blood. 2005 Feb 1;105(3):1195-7
references.pmid: 15459013
references.citation: Cell Microbiol. 2005 Jan;7(1):53-61
references.pmid: 15617523
references.citation: Thorax. 1988 Jul;43(7):516-24
references.pmid: 2850637
references.citation: Arthritis Rheum. 2004 May;50(5):1457-67
references.pmid: 15146415
references.citation: Nature. 2001 May 31;411(6837):603-6
references.pmid: 11385577
references.citation: Acta Med Scand. 1952 Mar 19;142(4):265-73
references.pmid: 14932794
references.citation: Am J Respir Crit Care Med. 1999 Aug;160(2):736-55
references.pmid: 10430755
references.citation: J Immunol. 2005 May 15;174(10):6518-23
references.pmid: 15879155
references.citation: Mol Immunol. 2004 Nov;41(11):1099-108
references.pmid: 15476921
references.citation: Proc Am Thorac Soc. 2007 Aug 15;4(5):457-60
references.pmid: 17684289
references.citation: Int Arch Allergy Appl Immunol. 1991;96(1):68-75
references.pmid: 1752698
references.citation: Respir Res. 2005 Jul 08;6:68
references.pmid: 16004610
references.citation: Zentralbl Bakteriol Mikrobiol Hyg A. 1984 Apr;256(4):541-7
references.pmid: 6377763
references.citation: Am J Respir Cell Mol Biol. 2004 Oct;31(4):463-9
references.pmid: 15242847
references.citation: J Exp Med. 2005 Mar 7;201(5):755-67
references.pmid: 15753209
references.citation: Cell Death Differ. 2006 May;13(5):798-815
references.pmid: 16528382
references.citation: Eur J Immunol. 1990 Aug;20(8):1661-7
references.pmid: 1976520
references.citation: J Leukoc Biol. 2001 Jun;69(6):1036-44
references.pmid: 11404392
references.citation: Am J Respir Crit Care Med. 1997 Nov;156(5):1601-5
references.pmid: 9372682
references.citation: Nat Immunol. 2004 Aug;5(8):800-8
references.pmid: 15220916
references.citation: Am J Ophthalmol. 2003 Nov;136(5):933-5
references.pmid: 14597055
references.citation: Clin Chest Med. 1997 Dec;18(4):681-94
references.pmid: 9413652
references.citation: Eur Respir J. 2006 Mar;27(3):451-9
references.pmid: 16507843
references.citation: Thorax. 1987 Jun;42(6):420-6
references.pmid: 3660300
references.citation: Blood. 2002 May 1;99(9):3427-31
references.pmid: 11964313
references.citation: Biochim Biophys Acta. 1998 Mar 13;1396(3):320-35
references.pmid: 9545592
references.citation: J Biol Chem. 2003 Feb 21;278(8):5509-12
references.pmid: 12514169