Cyclooxygenase-2 enhances antimicrobial peptide expression and killing of Staphylococcus aureus.
Antimicrobial peptides such as human β-defensins (hBDs) and cathelicidins are critical for protection against infection and can be induced by activation of TLRs, a pathway that also activates cyclooxygenase(Cox)-2 expression. We hypothesized that Cox-2 is induced by TLR activation and is necessary for optimal AMP production, and that inhibitors of Cox-2 may therefore inhibit antimicrobial action. Normal human keratinocytes (NHEKs) stimulated with a TLR2/6 ligand, macrophage-activating lipopeptide-2, or a TLR3 ligand, polyinosinic-polycytidylic acid, increased Cox-2 mRNA and protein and increased PGE(2), a product of Cox-2. Treatment with a Cox-2 selective inhibitor (SC-58125) or Cox-2 small interfering RNA attenuated hBD2 and hBD3 production in NHEKs when stimulated with macrophage-activating lipopeptide-2, polyinosinic-polycytidylic acid, or UVB (15 mJ/cm(2)), but it did not attenuate vitamin D3-induced cathelicidin. SC-58125 also inhibited TLR-dependent NF-κB activation. Conversely, treatment with Cox-derived prostanoids PGD(2) or 15-deoxy-Δ(12,14)-PGJ(2) induced hBD3 or hBD2 and hBD3, respectively. The functional significance of these observations was seen in NHEKs that showed reduced anti-staphylococcal activity when treated with a Cox-2 inhibitor. These findings demonstrate a critical role for Cox-2 in hBD production and suggest that the use of Cox-2 inhibitors may adversely influence the risk for bacterial infection.
Division of Dermatology, Department of Medicine, University of California San Diego and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA.
Jamie J
JJ
Bernard
Richard L
RL
Gallo
D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008024:Ligands; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D051216:Toll-Like Receptor 6 / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D023083:beta-Defensins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051216:Toll-Like Receptor 6; D023083:beta-Defensins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human