Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

Journal of Clinical Investigation

Volumn 124, Issue 9, 2014, Pages 3713-3724

  Oláh, Attila ^a   Tóth, Balázs I ^a,b   Borbíró, István ^a   Sugawara, Koji ^c,d   Szöllõsi, Attila G ^a   Czifra, Gabriella ^a   Pál, Balázs ^a   Ambrus, Lídia ^a   Kloepper, Jennifer ^d   Camera, Emanuela ^e   Ludovici, Matteo ^e   Picardo, Mauro ^e   Voets, Thomas ^b   Zouboulis, Christos C ^f   Paus, Ralf ^d,g   Bíró, Tamás ^a  

^a UNIVERSITY OF DEBRECEN   (Hungary)

^b LABORATORY OF MOLECULAR AND CELLULAR SIGNALING   (Belgium)

^c OSAKA CITY UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^d UNIVERSITY OF LÜBECK   (Germany)

^e SAN GALLICANO DERMATOLOGICAL INSTITUTE   (Italy)

^f DESSAU MEDICAL CENTER   (Germany)

^g UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE A2 RECEPTOR; ARACHIDONIC ACID; CANNABIDIOL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LINOLEIC ACID; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; RECEPTOR INTERACTING PROTEIN 140; TESTOSTERONE; VANILLOID RECEPTOR 4; ANTIINFLAMMATORY AGENT; TRPV4 PROTEIN, HUMAN; VANILLOID RECEPTOR;

ANTIINFLAMMATORY ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; CELL CULTURE; CELL PROLIFERATION; CONTROLLED STUDY; DOWN REGULATION; DRUG MECHANISM; GLUCOSE METABOLISM; HUMAN; HUMAN CELL; LIPID METABOLISM; LIPOGENESIS; SEBACEOUS CELL; SIGNAL TRANSDUCTION; SKIN CULTURE; UPREGULATION; ACNE VULGARIS; CYTOLOGY; DRUG EFFECTS; PATHOLOGY; PHYSIOLOGY; SEBACEOUS GLAND; SEBUM;

ACNE VULGARIS; ANTI-INFLAMMATORY AGENTS; CANNABIDIOL; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; HUMANS; LIPOGENESIS; SEBACEOUS GLANDS; SEBUM; TRPV CATION CHANNELS;

EID: 84907010601     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI64628     Document Type: Article

References (80)

1. Zouboulis CC, et al. What is the pathogenesis of acne? Exp Dermatol. 2005;14(2):143-152.
2. Kurokawa I, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18(10):821-832.
3. Demuth DG, Molleman A. Cannabinoid signaling. Life Sci. 2006;78(6):549-563.
4. Abood ME, Sorensen RG, Stella N, eds. endo- CANNABINOIDS. New York, New York, USA: Springer Science+Business Media New York; 2013.
5. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008;7(5):438-455.
6. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.
7. Bíró T, et al. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009;30(8):411-420.
8. Kupczyk P, Reich A, Szepietowski JC. Cannabinoid system in the skin - a possible target for future therapies in dermatology. Exp Dermatol. 2009;18(8):669-679.
9. Telek A, et al. Inhibition of human hair follicle growth by endo- and exocannabinoids. FASEB J. 2007;21(13):3534-3541.
10. Tóth BI, et al. Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid- 1. J Invest Dermatol. 2011;131(5):1095-1104.
11. Karsak M, et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science. 2007;316(5830):1494-1497.
12. Dobrosi N, et al. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling. FASEB J. 2008;22(10):3685-3695.
13. Zuardi AW, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006;39(4):421-429.
14. Zuardi AW, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20(5):683-686.
15. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.
16. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006; 147(suppl 1):S163-S171.
17. NIH. Clinical Trials.gov. NIH Web site. http://clinicaltrials.gov/ct2/results?term=cannabidiol. Accessed July 8, 2013.
18. Mirshahpanah P, Maibach HI. Models in acnegenesis. Cutan Ocul Toxicol. 2007;26(3):195-202.
19. Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol. 1999;113(6):1011-1020.
20. Lu Z, Hasse S, Bodó E, Rose C, Funk W, Paus R. Towards the development of a simplified longterm organ culture method for human scalp skin and its appendages under serum-free conditions. Exp Dermatol. 2007;16(1):37-44.
21. Wróbel A, et al. Differentiation and apoptosis in human immortalized sebocytes. J Invest Dermatol. 2003;120(2):175-181.
22. Makrantonaki E, Zouboulis CC. Testosterone metabolism to 5α-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes. Br J Dermatol. 2007;156(3):428-432.
23. Rey AA, Purrio M, Viveros M-P, Lutz B. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology. 2012;37(12):2624-2634.
24. Melnik BC, Schmitz G. Role of insulin, insulinlike growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18(10):833-841.
25. Zouboulis CC, Jourdan E, Picardo M. Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions. J Eur Acad Dermatol Venereol. 2014;28(5):527-532.
26. Zouboulis CC, et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139(5):668-670.
27. Schneider MR, Paus R. Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion. Int J Biochem Cell Biol. 2010;42(2):181-185.
28. Layton AM. Disorders of the sebaceous glands. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook's Textbook of Dermatology. 8th ed. Oxford, United Kingdom: Wiley-Blackwell; 2010:42.1-42.89.
29. Shirakawa M, Uramoto K, Harada FA. Treatment of acne conglobata with in?iximab. J Am Acad Dermatol. 2006;55(2):344-346.
30. Szabó K, Kemény L. Studying the genetic predisposing factors in the pathogenesis of acne vulgaris. Hum Immunol. 2011;72(9):766-773.
31. Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med. 2011;51(5):1054-1061.
32. Akopian AN, Ruparel NB, Jeske NA, Patwardhan A, Hargreaves KM. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci. 2008;30(2):79-84.
33. De Petrocellis L, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008;325(3):1007-1015.
34. De Petrocellis L, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494.
35. Bisogno T, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852.
36. Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM. TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci. 2008;28(24):6231-6238.
37. De Petrocellis L, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf). 2012;204(2):255-266.
38. Tóth BI, et al. Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology. J Invest Dermatol. 2009;129(2):329-339.
39. Clapham DE. Transient Receptor Potential (TRP) channels. In: Squire LR, ed. Encyclopedia Of Neuroscience. Vol. 9. Oxford, United Kingdom: Oxford Academic Press; 2009:1109-1133.
40. Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550.
41. Mootha VK, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267-273.
42. Broad Institute. Gene Set Enrichment Analysis. http://www.broadinstitute.org/gsea/index.jsp. Broad Institute Web site. Updated January 23, 2014. Accessed June 16, 2014.
43. Melnik BC, Schmitz G. Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? Exp Dermatol. 2013;22(7):502-504.
44. The Gene Ontology Consortium. The Gene Ontology Database. The Gene Ontology Web site. homepage. http://www.geneontology.org/. Accessed June 16, 2014.
45. Gene Ontology Consortium. The Sequence Ontology Project homepage. The Sequence Ontology Web site. http://www.sequenceontology.org/. Accessed June 16, 2014.
46. Ang BK, et al. ArhGAP9, a novel MAP kinase docking protein, inhibits Erk and p38 activation through WW domain binding. J Mol Signal. 2007;2:1.
47. Roskoski R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66(2):105-143.
48. Leonardsson G, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A. 2004;101(22):8437-8442.
49. Lee D-Y, et al. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes. J Invest Dermatol. 2008;128(7):1863-1866.
50. Wu M, Xu LG, Zhai Z, Shu HB. SINK is a p65-interacting negative regulator of NF-κB-dependent transcription. J Biol Chem. 2003;278(29):27072-27079.
51. Kozela E, et al. Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-κB and interferon-β/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem. 2010;285(3):1616-1626.
52. Zou T, et al. TRB3 mediates homocysteine-induced inhibition of endothelial cell proliferation. J Cell Physiol. 2011;226(11):2782-2789.
53. Ribeiro A, et al. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor. Eur J Pharmacol. 2012;678(1-3):78-85.
54. Wilkinson JD, Wiliamson EM. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatol Sci. 2007;45(2):87-92.
55. Appendino G, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008;71(8):1427-1430.
56. Ananthapadmanabhan KP, Mukherjee S, Chandar P. Stratum corneum fatty acids: their critical role in preserving barrier integrity during cleansing. Int J Cosmet Sci. 2013;35(4):337-345.
57. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043.
58. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(5):354-361.
59. Rimmerman N, et al. Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid- induced cell death. Cell Death Dis. 2013;4:e949.
60. Ross RA. The enigmatic pharmacology of GPR55. Trends Pharmacol Sci. 2009;30(3):156-163.
61. Shi H, Halvorsen YD, Ellis PN, Wilkison WO, Zemel MB. Role of intracellular calcium in human adipocyte differentiation. Physiol Genomics. 2000;3(2):75-82.
62. Zhang LL, et al. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 2007;100(7):1063-1070.
63. Takahashi Y, et al. TRB3 suppresses adipocytes differentiation by negatively regulating PPARγ transcriptional activity. J Lipid Res. 2008;49(4):880-892.
64. Salazar M, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 2009;119(5):1359-1372.
65. Salazar M, et al. The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta. 2013;1831(10):1573-1578.
66. Juknat A, et al. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid- mediated modulation of LPS-induced activation of BV-2 microglial cells. PLoS One. 2013;8(4):e61462.
67. Mungrue IN, et al. CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 2009;182(1):466-476.
68. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 2006;103(20):7895-7900.
69. Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol. 2001;45(5):S150-S157.
70. Rigopoulos D, Larios G, Katsambas AD. The role of isotretinoin in acne therapy: why not as first-line therapy? facts and controversies. Clin Dermatol. 2010;28(1):24-30.
71. Kintz P, Cirimele V, Mangin P. Testing human hair for cannabis. II. Identification of THCCOOH by GC-MS-NCI as a unique proof. J Forensic Sci. 1995;40(4):619-622.
72. Skopp G, Strohbeck-Kuehner P, Mann K, Hermann D. Deposition of cannabinoids in hair after long-term use of cannabis. Forensic Sci Int. 2007;170(1):46-50.
73. Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57(1):66-75.
74. Lodzki M, et al. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release. 2003;93(3):377-387.
75. Tubaro A, et al. Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia. 2010;81(7):816-819.
76. Hueber F, Wepierre J, Schaefer H. Role of transepidermal and transfollicular routes in percutaneous absorption of hydrocortisone and testosterone: in vivo study in the hairless rat. Skin Pharmacol. 1992;5(2):99-107.
77. Togsverd-Bo K, et al. Porphyrin biodistribution in UV-exposed murine skin after methyl- and hexyl-aminolevulinate incubation. Exp Dermatol. 2012;21(4):260-264.
78. Camera E, et al. Comprehensive analysis of the major lipid classes in sebum by rapid resolutionhigh-performance liquid chromatography and electrospray mass spectrometry. J Lipid Res. 2010;51(11):3377-3388.
79. Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207-210.
80. Borbíró I, et al. Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J Invest Dermatol. 2011;131(8):1605-1614.