Maria Wikén1, Johan Grunewald, Anders Eklund, Jan Wahlström. 1. 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
Abstract
INTRODUCTION: 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. MATERIALS AND 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. CONCLUSION: Increased TLR expression and enhanced secretion of pro-inflammatory cytokines after combined TLR2 and NOD2 stimulation may be related to the pathogenesis of sarcoidosis.
INTRODUCTION: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. MATERIALS AND METHODS: Blood mononuclear cells from sarcoidosispatients (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. CONCLUSION: 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: Naohiro Inohara; Yasunori Ogura; Ana Fontalba; Olga Gutierrez; Fernando Pons; Javier Crespo; Koichi Fukase; Seiichi Inamura; Shoichi Kusumoto; Masahito Hashimoto; Simon J Foster; Anthony P Moran; Jose L Fernandez-Luna; Gabriel Nuñez Journal: J Biol Chem Date: 2003-01-04 Impact factor: 5.157
Authors: Gerben Ferwerda; Stephen E Girardin; Bart-Jan Kullberg; Lionel Le Bourhis; Dirk J de Jong; Dennis M L Langenberg; Reinout van Crevel; Gosse J Adema; Tom H M Ottenhoff; Jos W M Van der Meer; Mihai G Netea Journal: PLoS Pathog Date: 2005-11-25 Impact factor: 6.823
Authors: L Mentlein; G E Thorlacius; L Meneghel; L A Aqrawi; J I Ramírez Sepúlveda; J Grunewald; A Espinosa; M Wahren-Herlenius Journal: Clin Exp Immunol Date: 2018-05-16 Impact factor: 4.330
Authors: Giorgos A Margaritopoulos; Katerina M Antoniou; Kostas Karagiannis; Katerina D Samara; Ismini Lasithiotaki; Evi Vassalou; Rena Lymbouridou; Helen Koutala; Nikos M Siafakas Journal: Fibrogenesis Tissue Repair Date: 2010-10-11
Authors: H L Rosenzweig; M M Jann; T T Glant; T M Martin; S R Planck; W van Eden; P J S van Kooten; R A Flavell; K S Kobayashi; J T Rosenbaum; M P Davey Journal: J Leukoc Biol Date: 2009-01-07 Impact factor: 4.962