title: IL-17R activation of human periodontal ligament fibroblasts induces IL-23 p19 production: Differential involvement of NF-κB versus JNK/AP-1 pathways.
abstract: Interleukin (IL)-23 is an essential cytokine involved in the expansion of a novel CD4(+) T helper subset known as Th17, which has been implicated in the pathogenesis of periodontitis recently. This study hypothesised that Th17 signature cytokine IL-17 may target specialised human periodontal ligament fibroblasts (hPDLFs) for production of IL-23 p19, a key subunit of IL-23. Primary hPDLFs had steady expression of IL-17 receptor (IL-17R) mRNA and surface-bound protein. IL-17 was capable of stimulating the expression of IL-23 p19 mRNA and protein in cultured hPDLFs, which was attenuated by IL-17 or IL-17R neutralising antibodies. In accordance with the enhanced expression of IL-23 p19, IL-17 stimulation resulted in rapid activation of Akt, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK), nuclear factor-kappaB (NF-κB), and activator protein-1 (AP-1) in hPDLFs. Inhibitors of Akt, p38 MAPK, ERK 1/2, or NF-κB significantly suppressed, whereas blocking JNK and AP-1 substantially augmented IL-23 p19 production from IL-17-stimulated hPDLFs. Moreover, IL-17-initiated NF-κB activation was blocked by Akt, p38 MAPK, or ERK 1/2 inhibition, while AP-1 activity was specifically abrogated by JNK inhibition. Thus, these results provide evidence that hPDLFs are a target of Th17, and that IL-17 appears to up-regulate the expression of IL-23 p19 via a homeostatic mechanism involving Akt-, p38 MAPK-, and ERK 1/2-dependent NF-κB signalling versus the JNK/AP-1 pathway. Taken together, our findings suggest that disruption of the interaction between IL-17 and IL-23 may be a potential therapeutic approach in the treatment of periodontitis.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Lingxin
authors.initials: L
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wei
authors.forename: Xin
authors.initials: X
authors.lastname: Xing
authors.forename: Ni
authors.initials: N
authors.lastname: Zhan
authors.forename: Haofei
authors.initials: H
authors.lastname: Xiong
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
mesh_terms: D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010513:Periodontal Ligament / Q000166:cytology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D016328:NF-kappa B; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17; D018808:Transcription Factor AP-1; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases