title: Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis.
abstract: Monocyte-to-macrophage differentiation promotes an inflammatory environment within the arterial vessel wall that causes a mal-adaptive immune response, which contributes to the progression of atheromatous plaque formation. In the current study, we show that resveratrol, a well-known antioxidant, dose-dependently attenuated phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, as measured by cell adhesion, increase in cell size, and scavenger receptor expression in THP-1 monocytes. Also, resveratrol significantly inhibited PMA-induced pro-inflammatory cytokine/chemokine and matrix metalloprotease (MMP-9) production. This inhibitory effect of resveratrol on monocyte differentiation results from its ability to restore intracellular glutathione (GSH) status, as resveratrol in the presence of buthionine sulfoximine (BSO) failed to affect monocyte differentiation. Furthermore, PMA-induced monocyte differentiation and inflammation was greatly inhibited when cells were co-treated with N-Acetyl-l-cysteine (NAC), a GSH precursor, while the presence of BSO aggravated these processes. These results also show that resveratrol mediated up-regulation of GSH is due to AMP-activated protein kinase (AMPK)-α activation, as compound C (AMPK inhibitor) treatment drastically depleted intracellular GSH and exacerbated PMA-induced monocyte differentiation and pro-inflammatory cytokine production. More importantly, chronic administration of resveratrol efficiently prevented monocyte infiltration and markedly diminished angiotensin (Ang)-II-induced atheromatous plaque formation in apolipoprotein-E knockout (ApoE(-/-)) mice. We conclude that, intracellular GSH status plays a critical role in regulating monocyte-to-macrophage differentiation and inflammation and resveratrol, by restoring GSH levels, inhibits these processes. Taken together, these results suggest that resveratrol can attenuate atherosclerosis, at least, in part, by inhibiting monocyte differentiation and pro-inflammatory cytokines production.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai 600113, India.
authors.forename: Sathish Babu
authors.initials: SB
authors.lastname: Vasamsetti
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai 600113, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai 600113, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Gopoju
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai 600113, India.
authors.forename: Paradesi Naidu
authors.initials: PN
authors.lastname: Gollavilli
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
authors.forename: Sai Ram
authors.initials: SR
authors.lastname: Narra
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai 600113, India. Electronic address: giridhar@iict.res.in.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D013267:Stilbenes; D019328:Buthionine Sulfoximine; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol; D000111:Acetylcysteine
keywords: AMPK; Atherosclerosis; GSH; Inflammation; Monocyte differentiation; Resveratrol