title: An endoplasmic reticulum stress-initiated sphingolipid metabolite, ceramide-1-phosphate, regulates epithelial innate immunity by stimulating β-defensin production.
abstract: Antimicrobial peptides (AMP) are ubiquitous innate immune elements in epithelial tissues. We recently discovered that a signaling lipid, the ceramide metabolite sphingosine-1-phosphate (S1P), regulates production of a major AMP, cathelicidin antimicrobial peptide (CAMP), in response to a subtoxic level of endoplasmic reticulum (ER) stress that can be induced by external perturbants in keratinocytes. We hypothesized that an ER stress-initiated signal could also regulate production of another major class of AMPs: i.e., the human beta-defensins 2 (hBD2) and 3 (hBD3). Keratinocytes stimulated with a pharmacological ER stressor, thapsigargin (Tg), increased hBD2/hBD3 as well as CAMP mRNA expression. While inhibition of sphingosine-1-phosphate production did not alter hBD expression following ER stress, blockade of ceramide-1-phosphate (C1P) suppressed Tg-induced hBD2/hBD3 but not CAMP expression. Exogenous C1P also increased hBD2/hBD3 production, indicating that C1P stimulates hBD expression. We showed further that C1P-induced hBD2/hBD3 expression is regulated by a novel pathway in which C1P stimulates downstream hBD via a cPLA2a→15d-PGJ2→PPARα/PPARβ/δ→Src kinase→STAT1/STAT3 transcriptional mechanism. Finally, conditioned medium from C1P-stimulated keratinocytes showed antimicrobial activity against Staphylococcus aureus. In summary, our present and recent studies discovered two new regulatory mechanisms of key epidermal AMP, hBD2/hBD3 and CAMP. The C1P and S1P pathways both signal to enhance innate immunity in response to ER stress.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA.
authors.forename: Jong Youl
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Radiation Research Division, Korea Atomic Energy Research Institute, Jeongeup, South Korea.
authors.forename: Ho Seong
authors.initials: HS
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Veterans Affairs Medical Center, San Francisco, California, USA Northern California Institute for Research and Education, San Francisco, California, USA uchiday@derm.ucsf.edu.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
mesh_terms: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015603:Keratinocytes / Q000276:immunology*; D008246:Lysophospholipids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D019284:Thapsigargin / Q000276:immunology / Q000494:pharmacology*; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D002518:Ceramides; D017077:Culture Media, Conditioned; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D008246:Lysophospholipids; D023083:beta-Defensins; C065576:ceramide 1-phosphate; C060506:sphingosine 1-phosphate; D019284:Thapsigargin; D013110:Sphingosine