title: Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression.
abstract: Various sebum free fatty acids (FFAs) have shown antibacterial activity against a broad range of gram-positive bacteria, resulting in the suggestion that they are accountable, at least partially, for the direct antimicrobial activity of the skin surface. In this study, we examined the effects of sebum FFAs on the antimicrobial peptide (AMP)-mediated innate immune defense of human sebocytes. Incubation of lauric acid, palmitic acid, or oleic acid (OA) with human sebocytes dramatically enhanced their expression of human beta-defensin (hBD)-2, one of the predominant AMPs found in the skin, whereas remarkable increases in hBD-1, hBD-3, and human cathelicidin LL-37 were not observed. Secreted hBD-2 was detectable by western blotting in the supernatant of sebocyte culture incubated with each FFA, but not with a vehicle control. The supernatant of FFA-incubated sebocyte culture showed antimicrobial activity against Propionibacterium acnes, whereas the enhanced antimicrobial activity of human sebocytes was neutralized by anti-hBD-2 IgG. In addition, the FFA-induced hBD-2 expression was suppressed by blocking the cluster of differentiation (CD)36 fatty acid translocase on the surface of sebocytes with anti-human CD36 IgG or blocking the NF-kappaB signaling pathway with BMS-345541, a highly selective inhibitor of inhibitory kappaB kinase. These data suggest that sebum FFAs upregulate the expression of hBD-2 in human sebocytes, which may enhance the disinfecting activity of the human sebaceous gland. The FFA-induced upregulation of hBD-2 is facilitated by CD36-mediated FFA uptake and NF-kappaB-mediated transactivation. The upregulation of mouse beta-defensin 4, a mouse ortholog for hBD-2, was also observed in the hair follicle sebaceous glands of mouse ear skin after an epicutaneous application of OA, the most hBD-2-inducible FFA tested. This report highlights the potential of using FFAs as a multifunctional antimicrobial therapy agent for acne vulgaris treatment; FFAs may provide direct antibacterial activities against P. acnes and enhance the skin's innate antibacterial defense by inducing the expression of hBD-2 in sebocytes as well.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California 92161, USA.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Nakatsuji
authors.forename: Mandy C
authors.initials: MC
authors.lastname: Kao
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Huang
mesh_terms: D000152:Acne Vulgaris / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D000818:Animals; D018955:CD36 Antigens / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D005230:Fatty Acids, Nonesterified / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000276:immunology; D018859:Hair Follicle / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007850:Lauric Acids / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D019301:Oleic Acid / Q000276:immunology / Q000494:pharmacology; D019308:Palmitic Acid / Q000276:immunology / Q000494:pharmacology; D011425:Propionibacterium acnes / Q000187:drug effects / Q000276:immunology; D012627:Sebaceous Glands / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D012629:Sebum / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000502:physiology; D023083:beta-Defensins / Q000276:immunology / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; C106641:DEFB4A protein, human; C513975:Defb4 protein, mouse; D005230:Fatty Acids, Nonesterified; D007074:Immunoglobulin G; D007850:Lauric Acids; D016328:NF-kappa B; D023083:beta-Defensins; C030358:lauric acid; D019301:Oleic Acid; D019308:Palmitic Acid