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

J Innate Immun. 2013;5(1):72-83. doi: 10.1159/000342928. Epub 2012 Oct 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sulfonamides / pharmacology

Substances

  • Antimicrobial Cationic Peptides
  • Cyclooxygenase Inhibitors
  • Nitrobenzenes
  • Receptors, Purinergic P2X7
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • ropocamptide
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Dinoprostone