An endoplasmic reticulum stress-initiated sphingolipid metabolite, ceramide-1-phosphate, regulates epithelial innate immunity by stimulating β-defensin production

Mol Cell Biol. 2014 Dec;34(24):4368-78. doi: 10.1128/MCB.00599-14. Epub 2014 Oct 13.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimicrobial Cationic Peptides
  • Cathelicidins / genetics
  • Cells, Cultured
  • Ceramides / pharmacology*
  • Culture Media, Conditioned / pharmacology
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / immunology
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Immunity, Innate / drug effects*
  • Keratinocytes / immunology*
  • Lysophospholipids / pharmacology*
  • Signal Transduction / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Staphylococcus aureus / drug effects
  • Thapsigargin / immunology
  • Thapsigargin / pharmacology*
  • beta-Defensins / genetics
  • beta-Defensins / metabolism


  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • Ceramides
  • Culture Media, Conditioned
  • DEFB103A protein, human
  • DEFB4A protein, human
  • Lysophospholipids
  • beta-Defensins
  • ceramide 1-phosphate
  • sphingosine 1-phosphate
  • Thapsigargin
  • Sphingosine