title: Involvement of the P2X7 purinergic receptor and c-Jun N-terminal and extracellular signal-regulated kinases in cyclooxygenase-2 and prostaglandin E2 induction by LL-37.
abstract: Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) production. We previously demonstrated that human β-defensin-3 induces COX-2 and PGE(2) in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE(2) synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE(2) in cell-free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X(7) purinergic receptor significantly abrogated COX-2 induction and PGE(2) production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE(2) synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE(2) synthesis via the P2X(7) receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Pareena
authors.initials: P
authors.lastname: Chotjumlong
authors.forename: Jan G
authors.initials: JG
authors.lastname: Bolscher
authors.forename: Kamran
authors.initials: K
authors.lastname: Nazmi
authors.forename: Vichai
authors.initials: V
authors.lastname: Reutrakul
authors.forename: Chayarop
authors.initials: C
authors.lastname: Supanchart
authors.forename: Worakanya
authors.initials: W
authors.lastname: Buranaphatthana
authors.forename: Suttichai
authors.initials: S
authors.lastname: Krisanaprakornkit
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000276:immunology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D005881:Gingiva / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010510:Periodontal Diseases / Q000276:immunology* / Q000382:microbiology; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D058486:Receptors, Purinergic P2X7; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D054804:Cathelicidins