Signaling pathways involved in the regulation of TNFα-induced toll-like receptor 2 expression in human gingival fibroblasts.
Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFα-induced TLR2 expression. Our results showed that TNFα increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) were involved in the regulation of TNFα-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFα. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.
Department of Dental Medicine, Division of Pediatric Dentistry, Karolinska Institutet, 141 04 Huddinge, Sweden.
Haleh
H
Davanian
Tove
T
Båge
Johan
J
Lindberg
Joakim
J
Lundeberg
Hernan Q
HQ
Concha
Margaret
M
Sällberg Chen
Tülay
T
Yucel-Lindberg
D002648:Child; D002675:Child, Preschool; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D011453:Prostaglandins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases