Blood Cell Gene Expression Profiling in Subjects With Aggressive Periodontitis and Chronic Arthritis

Sørensen, Lars Korsbæk; Havemose-Poulsen, Anne; Sønder, Søren Ulrik; Bendtzen, Klaus; Holmstrup, Palle

doi:10.1902/jop.2008.070309

Cited by 37 publications

(29 citation statements)

References 50 publications

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“…7 8 Previous studies demonstrate that expression of TLR2 and TLR4 are elevated in RA peripheral blood (PB) monocytes as well as in RA SF and ST macrophages. [9][10][11][12] Further, the data obtained from experimental arthritis models strongly support the role of TLR4 in the pathogenesis of arthritis seen in collagen-induced arthritis (CIA), 13 as well as in IL-1RA−/− model. 13 14 However, little is known about the endosomal TLRs in RA or experimental arthritis models.…”

Section: Introductionmentioning

confidence: 55%

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

et al. 2012

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Objective The aim of the study was to characterize the expression, regulation and pathogenic role of TLR7 and TLR8 in rheumatoid arthritis (RA). Methods Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (ST) employing immunohistochemistry. We next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and TNF-α levels. Further the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF) mediated TNF-α transcription. Results TLR7/TLR8 are predominately expressed in RA ST lining and sublining macrophages. We show that NF-κB and/or PI3K pathways are essential for TLR7/TLR8 induction of proinflammatory factors in RA peripheral blood (PB) differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNF-α levels. In contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNF-α levels. We further demonstrate that RNA from RA SF but not RA or NL plasma could modulate TNF-α transcription from RA monocytes that can be downregulated by antagonizing TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7. Conclusions These results suggest that expression of TLR7 but not TLR8 may be a predictor for RA disease activity and anti-TNF-α responsiveness, and targeting TLR7 may suppress chronic progression of RA.

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Section: Introductionmentioning

confidence: 55%

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

et al. 2012

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“…With regard to periodontal disease, microarray analysis of gingival tissue has been used in an attempt to define subclasses of periodontitis and to evaluate the effect of periodontal therapy [57,58]. In addition, blood cell gene expression profiling has been performed in subjects with aggressive periodontitis [59]. Concerning gingival fibroblasts, microarray studies have been performed on unstimulated cells from healthy and inflamed gingival tissue, and on IL-1β-stimulated immortalized cells [60,61].…”

Section: Discussionmentioning

confidence: 99%

Signal pathways JNK and NF-κB, identified by global gene expression profiling, are involved in regulation of TNFα-induced mPGES-1 and COX-2 expression in gingival fibroblasts

et al. 2010

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BackgroundProstaglandin E2 (PGE2) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor α (TNFα) induces PGE2 synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNFα-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE2-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE2 production.ResultsMicroarray and western blot analyses showed that the mRNA and protein expression of the inflammatory induced microsomal prostaglandin E synthase-1 (mPGES-1) was up-regulated by the cytokine TNFα, accompanied by enhanced expression of COX-2 and increased production of PGE2. In contrast, the expression of the isoenzymes microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFα treatment. Using oligonucleotide microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, differentially expressed genes in response to TNFα treatment were identified. Enrichment analysis of microarray data indicated two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-κB (NF-κB). To evaluate their involvement in the regulation of mPGES-1 and COX-2 expression, we used specific inhibitors as well as phosphorylation analysis. Phosphorylation analysis of JNK (T183/Y185) and NF-κB p65 (S536) showed increased phosphorylation in response to TNFα treatment, which was decreased by specific inhibitors of JNK (SP600125) and NF-κB (Bay 11-7082, Ro 106-9920). Inhibitors of JNK and NF-κB also decreased the TNFα-stimulated up-regulation of mPGES-1 and COX-2 as well as PGE2 production.ConclusionIn the global gene expression profile, the enrichment analysis of microarray data identified the two signal transduction pathways JNK and NF-κB as positively regulated by the cytokine TNFα. Inhibition of these TNFα-activated signal pathways reduced the expression of mPGES-1 and COX-2 as well as their end product PGE2 in gingival fibroblasts. The involvement of the signal pathways JNK and NF-κB in the regulation of PGE2 induced by TNFα may suggest these two pathways as possible attractive targets in the chronic inflammatory disease periodontitis.

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“…Increased expression of TLR2 and TLR4 on peripheral blood monocytes from patients with RA has been demonstrated (3, 4). Utilizing immunohistochemistry, both TLR2 and TLR4, as well as endosomal TLR3 and TLR7 were expressed in RA synovial tissues (3, 5, 6), and TLR3 and TLR4 were highly expressed in early as well as in longstanding RA (7).…”

Section: Introductionmentioning

confidence: 99%

The role of Toll-like receptors in rheumatoid arthritis

Huang

Pope²

2009

Curr Rheumatol Rep

217

163

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An increasing body of data supports the role of the innate immune system in the pathogenesis of rheumatoid arthritis (RA). Toll-like receptors (TLRs) are expressed by cells within the RA joint and a variety of endogenous TLR ligands are present within the inflamed joints of patients with RA. Further, a variety of animal models suggest that TLR signaling is important in the pathogenesis of disease. Overall, the data suggest that activation by endogenous TLR ligands may contribute to the persistent expression of pro-inflammatory cytokines by macrophages and the joint damage to cartilage and bone that occurs in RA. The data supports a potential role for suppression of TLR signaling as a novel therapeutic approach in patients with RA.

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Blood Cell Gene Expression Profiling in Subjects With Aggressive Periodontitis and Chronic Arthritis

Abstract: Several genes upregulated in subjects with LAgP were related to immune responses including TLR2 and myomesin 2.

Cited by 37 publications

References 50 publications

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Signal pathways JNK and NF-κB, identified by global gene expression profiling, are involved in regulation of TNFα-induced mPGES-1 and COX-2 expression in gingival fibroblasts

The role of Toll-like receptors in rheumatoid arthritis

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