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.
Bernard
Jamie J
JJ
Division of Dermatology, Department of Medicine, University of California San Diego and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA.
Gallo
Richard L
RL
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