Open AccessInvolvement of the P2X<sub>7</sub> Purinergic Receptor and c-Jun N-Terminal and Extracellular Signal-Regulated Kinases in Cyclooxygenase-2 and Prostaglandin E<sub>2</sub> Induction by LL-37
Author(s) -
Pareena Chotjumlong,
Jan G. M. Bolscher,
Kamran Nazmi,
Vichai Reutrakul,
Chayarop Supanchart,
Worakanya Buranaphatthana,
Suttichai Krisanaprakornkit
Publication year - 2012
Publication title -
journal of innate immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.078
H-Index - 64
eISSN - 1662-8128
pISSN - 1662-811X
DOI - 10.1159/000342928
Subject(s) - prostaglandin e , cyclooxygenase , kinase , prostaglandin , mapk/erk pathway , extracellular , purinergic receptor , microbiology and biotechnology , protein kinase c , endocrinology , medicine , chemistry , biology , biochemistry , enzyme
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.