Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis.
We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple sclerosis (MS), relapsing experimental autoimmune encephalomyelitis (EAE). We describe the effects of ALA and its reduced form, dihydrolipoic acid (DHLA), on the transmigration of human Jurkat T cells across a fibronectin barrier in a transwell system. ALA and DHLA inhibited migration of Jurkat cells in a dose-dependent fashion by 16-75%. ALA and DHLA reduced matrix metalloproteinase-9 (MMP-9) activity by 18-90% in Jurkat cell supernatants. GM6001, a synthetic inhibitor of MMP, reduced Jurkat cell migration, but not as effectively as ALA and DHLA did. Both ALA and DHLA downmodulated the surface expression of the alpha4beta1 integrin (very late activation-4 antigen; VLA-4), which binds fibronectin and its endothelial cell ligand vascular cell adhesion molecule-1 (VCAM-1). Moreover, ALA, but not DHLA, reduced MMP-9-specific mRNA and extracellular MMP-9 from Jurkat cells and their culture supernatants as detected by relative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. ALA and DHLA inhibited Jurkat cell migration and have different mechanisms for inhibiting MMP-9 activity. These data, coupled with its ability to treat relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.
Marracci
Gail H
GH
Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
McKeon
Gabriel P
GP
Marquardt
Whitney E
WE
Winter
Rolf W
RW
Riscoe
Michael K
MK
Bourdette
Dennis N
DN
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002452:Cell Count; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004586:Electrophoresis / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000975:Antioxidants; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D008063:Thioctic Acid; C015144:dihydrolipoic acid; C013091:lipoamide; D020780:Matrix Metalloproteinase 9