title: Cannabinoids decrease the th17 inflammatory autoimmune phenotype.
abstract: Cannabinoids, the Cannabis constituents, are known to possess anti-inflammatory properties but the mechanisms involved are not understood. Here we show that the main psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), and the main nonpsychoactive cannabinoid, cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis. We found that reactivation by MOG35-55 of MOG35-55-specific encephalitogenic T cells (cells that induce Experimental Autoimmune Encephalitis when injected to mice) in the presence of spleen derived antigen presenting cells led to a large increase in IL-17 production and secretion. In addition, we found that the cannabinoids CBD and THC dose-dependently (at 0.1-5 μM) suppressed the production and secretion of this cytokine. Moreover, the mRNA and protein of IL-6, a key factor in Th17 induction, were also decreased. Pretreatment with CBD also resulted in increased levels of the anti-inflammatory cytokine IL-10. Interestingly, CBD and THC did not affect the levels of TNFα and IFNγ. The downregulation of IL-17 secretion by these cannabinoids does not seem to involve the CB1, CB2, PPARγ, 5-HT1A or TRPV1 receptors. In conclusion, the results show a unique cannabinoid modulation of the autoimmune cytokine milieu combining suppression of the pathogenic IL-17 and IL-6 cytokines along with boosting the expression of the anti-inflammatory cytokine IL-10.
authors.affiliation: The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, ewa.kozela@weizmann.ac.il.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kozela
authors.forename: Ana
authors.initials: A
authors.lastname: Juknat
authors.forename: Nathali
authors.initials: N
authors.lastname: Kaushansky
authors.forename: Neta
authors.initials: N
authors.lastname: Rimmerman
authors.forename: Avraham
authors.initials: A
authors.lastname: Ben-Nun
authors.forename: Zvi
authors.initials: Z
authors.lastname: Vogel
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002185:Cannabidiol / Q000494:pharmacology*; D002460:Cell Line; D018920:Coculture Techniques; D013759:Dronabinol / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D002185:Cannabidiol; D013759:Dronabinol; D007371:Interferon-gamma
references.citation: PLoS One. 2013 Apr 24;8(4):e61462
references.pmid: 23637839
references.citation: Nat Med. 2007 Oct;13(10):1173-5
references.pmid: 17828272
references.citation: J Immunoassay Immunochem. 2008;29(4):370-89
references.pmid: 18821411
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9561-6
references.pmid: 10920191
references.citation: J Immunol. 2006 Jul 1;177(1):566-73
references.pmid: 16785554
references.citation: PLoS One. 2011;6(12):e28432
references.pmid: 22163016
references.citation: Immunobiology. 2010 Aug;215(8):588-97
references.pmid: 20153077
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5172-6
references.pmid: 18362339
references.citation: Life Sci. 2005 Feb 4;76(12):1307-24
references.pmid: 15670612
references.citation: Cell Mol Neurobiol. 2011 Aug;31(6):921-30
references.pmid: 21533611
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: Nat Med. 2007 Apr;13(4):492-7
references.pmid: 17401376
references.citation: Glia. 2000 Jan 1;29(1):58-69
references.pmid: 10594923
references.citation: Curr Opin Pharmacol. 2011 Feb;11(1):29-33
references.pmid: 21393060
references.citation: J Neuroimmunol. 2000 Nov 1;111(1-2):55-63
references.pmid: 11063821
references.citation: Mult Scler. 1999 Apr;5(2):101-4
references.pmid: 10335518
references.citation: J Neurosci. 2007 Feb 28;27(9):2396-402
references.pmid: 17329437
references.citation: Br J Pharmacol. 2011 Aug;163(7):1507-19
references.pmid: 21449980
references.citation: Mult Scler. 2000 Feb;6(1):19-23
references.pmid: 10694841
references.citation: Trends Pharmacol Sci. 2009 Oct;30(10):515-27
references.pmid: 19729208
references.citation: J Immunol. 2009 May 15;182(10):5929-37
references.pmid: 19414744
references.citation: Neurology. 1999 Aug 11;53(3):457-65
references.pmid: 10449104
references.citation: PLoS One. 2011 Apr 01;6(4):e18281
references.pmid: 21483776
references.citation: Future Med Chem. 2009 Oct;1(7):1333-49
references.pmid: 20191092
references.citation: J Neuroimmunol. 1989 Jun;23(1):73-81
references.pmid: 2542370
references.citation: PLoS One. 2010 Jan 14;5(1):e8688
references.pmid: 20098669
references.citation: Immunol Rev. 2008 Dec;226:87-102
references.pmid: 19161418
references.citation: Nat Immunol. 2007 Sep;8(9):967-74
references.pmid: 17581537
references.citation: Eur Cytokine Netw. 2000 Sep;11(3):346-53
references.pmid: 11022117
references.citation: Immunobiology. 2010 Aug;215(8):611-6
references.pmid: 19833407
references.citation: Autoimmunity. 2006 Mar;39(2):143-51
references.pmid: 16698671
references.citation: Brain Behav Immun. 2011 May;25(4):736-49
references.pmid: 21310228
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):1054-61
references.pmid: 21238581
references.citation: PLoS One. 2011;6(12):e28159
references.pmid: 22163000
references.citation: Neurology. 1987 Jul;37(7):1097-102
references.pmid: 3110648
references.citation: J Immunol. 1998 Dec 15;161(12):6480-6
references.pmid: 9862671
references.citation: Nat Med. 2007 Feb;13(2):139-45
references.pmid: 17290272
references.citation: Annu Rev Immunol. 2005;23:683-747
references.pmid: 15771584
references.citation: J Biol Chem. 2010 Jan 15;285(3):1616-26
references.pmid: 19910459
references.citation: J Autoimmun. 2001 Aug;17(1):17-25
references.pmid: 11488634
references.citation: Stroke. 2005 May;36(5):1077-82
references.pmid: 15845890
references.citation: Ann Neurol. 2000 Jun;47(6):707-17
references.pmid: 10852536
references.citation: J Pharmacol Exp Ther. 2006 Sep;318(3):1375-87
references.pmid: 16728591
references.citation: J Immunol. 1996 Oct 15;157(8):3223-7
references.pmid: 8871615
references.citation: Immunity. 2010 Sep 24;33(3):424-36
references.pmid: 20870176
references.citation: J Immunol. 2010 Jul 15;185(2):791-4
references.pmid: 20601610
references.citation: Neuropharmacology. 2013 Aug;71:282-91
references.pmid: 23587650
references.citation: Nat Rev Immunol. 2012 Nov;12(11):799-804
references.pmid: 23059426
references.citation: Mult Scler. 1998 Feb;4(1):12-5
references.pmid: 9532586
references.citation: Neurogastroenterol Motil. 2008 Aug;20(8):919-27
references.pmid: 18373655
references.citation: Nat Med. 1998 Jan;4(1):78-83
references.pmid: 9427610
references.citation: Am J Pathol. 2006 Jan;168(1):235-44
references.pmid: 16400026
references.citation: J Pharmacol Exp Ther. 1985 Mar;232(3):579-88
references.pmid: 2983062
references.citation: Eur J Immunol. 1994 Jun;24(6):1434-40
references.pmid: 7515815
references.citation: Nat Med. 1999 Feb;5(2):153-4
references.pmid: 9930860
references.citation: Handb Exp Pharmacol. 2005;(168):299-325
references.pmid: 16596779
references.citation: Immunobiology. 2010 Aug;215(8):598-605
references.pmid: 19457575
references.citation: J Mol Med (Berl). 2009 Mar;87(3):273-86
references.pmid: 19050840
references.citation: J Exp Med. 2012 May 7;209(5):1001-10
references.pmid: 22547654
references.citation: Am J Pathol. 2012 Jul;181(1):8-18
references.pmid: 22640807
references.citation: J Immunol. 1988 Mar 1;140(5):1506-10
references.pmid: 3126227
references.citation: J Immunol. 1982 Jul;129(1):303-8
references.pmid: 6177753
references.citation: J Pharmacol Exp Ther. 2003 Sep;306(3):1077-85
references.pmid: 12805480
references.citation: J Immunol. 1996 Jan 1;156(1):5-7
references.pmid: 8598493
references.citation: J Neuroimmunol. 2009 Oct 30;215(1-2):10-24
references.pmid: 19692128
references.citation: Adv Exp Med Biol. 1998;437:207-14
references.pmid: 9666273
references.citation: J Immunol. 2005 Jul 1;175(1):69-81
references.pmid: 15972633
references.citation: J Pharmacol Exp Ther. 1996 Sep;278(3):989-99
references.pmid: 8819477
references.citation: PLoS One. 2011;6(12):e28668
references.pmid: 22163051
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070