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

• Published in: Journal of innate immunity 2013-01, Vol.5 (1), p.72-83
• Main Authors: Chotjumlong, Pareena, Bolscher, Jan G., Nazmi, Kamran, Reutrakul, Vichai, Supanchart, Chayarop, Buranaphatthana, Worakanya, Krisanaprakornkit, Suttichai
• Format: Article
• Language: English
• Subjects: Antimicrobial Cationic Peptides - immunology; Cells, Cultured; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - microbiology; Fibroblasts - pathology; Gingiva - drug effects; Gingiva - microbiology; Gingiva - pathology; Humans; Immunity, Mucosal - drug effects; JNK Mitogen-Activated Protein Kinases - metabolism; Nitrobenzenes - pharmacology; Periodontal Diseases - immunology; Periodontal Diseases - microbiology; Receptors, Purinergic P2X7 - metabolism; Research Article; Signal Transduction - drug effects; Signal Transduction - immunology; Sulfonamides - pharmacology
• ISSN: 1662-811X; 1662-8128
• DOI: 10.1159/000342928

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.