Lipoic acid stimulates cAMP production via the EP2 and EP4 prostanoid receptors and inhibits IFN gamma synthesis and cellular cytotoxicity in NK cells.
The antioxidant lipoic acid (LA) treats and prevents the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In an effort to understand the therapeutic potential of LA in MS, we sought to define the cellular mechanisms that mediate the effects of LA on human natural killer (NK) cells, which are important in innate immunity as the first line of defense against invading pathogens and tumor cells. We discovered that LA stimulates cAMP production in NK cells in a dose-dependent manner. Studies using pharmacological inhibitors and receptor transfection experiments indicate that LA stimulates cAMP production via activation of the EP2 and EP4 prostanoid receptors and adenylyl cyclase. In addition, LA suppressed interleukin (IL)-12/IL-18 induced IFNgamma secretion and cytotoxicity in NK cells. These novel findings suggest that LA may inhibit NK cell function via the cAMP signaling pathway.
Portland Veterans Affairs Medical Center and Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Sonemany
S
Salinthone
Robynn V
RV
Schillace
Gail H
GH
Marracci
Dennis N
DN
Bourdette
Daniel W
DW
Carr
D000975:Antioxidants / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects*; D018078:Receptors, Prostaglandin E / Q000187:drug effects* / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D008063:Thioctic Acid; D007371:Interferon-gamma; D000242:Cyclic AMP