title: Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes.
abstract: Phenolic diterpenes present in Rosmarinus officinalis and Salvia officinalis have anti-inflammatory and chemoprotective effects. We investigated the in vitro effects of carnosol (CL), carnosic acid (CA), carnosic acid-12-methylether (CAME), 20-deoxocarnosol and abieta-8,11,13-triene-11,12,20-triol (ABTT) in murine macrophages (RAW264.7 cells) and human chondrocytes. The substances concentration-dependently reduced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in LPS-stimulated macrophages (i.e., acute inflammation). They significantly blunted gene expression levels of iNOS, cytokines/interleukins (IL-1α, IL-6) and chemokines including CCL5/RANTES, CXCL10/IP-10. The substances modulated the expression of catabolic and anabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes that were stimulated by IL-1β (i.e., chronic inflammation In SW1353, catabolic genes like MMP-13 and ADAMTS-4 that contribute to cartilage erosion were down-regulated, while expression of anabolic genes including Col2A1 and aggrecan were shifted towards pre-pathophysiological homeostasis. CL had the strongest overall effect on inflammatory mediators, as well as on macrophage and chondrocyte gene expression. Conversely, CAME mainly affected catabolic gene expression, whereas ABTT had a more selectively altered interleukin and chemokine gene exprssion. CL inhibited the IL-1β induced nuclear translocation of NF-κBp65, suggesting that it primarily regulated via the NF-κB signalling pathway. Collectively, CL had the strongest effects on inflammatory mediators and chondrocyte gene expression. The data show that the phenolic diterpenes altered activity pattern of genes that regulate acute and chronic inflammatory processes. Since the substances affected catabolic and anabolic gene expression in cartilage cells in vitro, they may beneficially act on the aetiology of osteoarthritis.
authors.affiliation: DSM Nutritional Products, Wurmisweg 576, P. O. Box 2676, Basel 4002, Switzerland. jpschwager@gmail.com.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schwager
authors.affiliation: DSM Nutritional Products, Wurmisweg 576, P. O. Box 2676, Basel 4002, Switzerland. Nathalie.Richard@dsm.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Richard
authors.affiliation: DSM Nutritional Products, Wurmisweg 576, P. O. Box 2676, Basel 4002, Switzerland. Ann.Fowler@dsm.com.
authors.forename: Ann
authors.initials: A
authors.lastname: Fowler
authors.affiliation: DSM Nutritional Products, Wurmisweg 576, P. O. Box 2676, Basel 4002, Switzerland. Nicole.Seifert@dsm.com.
authors.forename: Nicole
authors.initials: N
authors.lastname: Seifert
authors.affiliation: DSM Nutritional Products, Wurmisweg 576, P. O. Box 2676, Basel 4002, Switzerland. Daniel.Raederstorff@dsm.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raederstorff
mesh_terms: D045784:Abietanes / Q000008:administration & dosage*; D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D024043:Collagen Type II / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B; D009569:Nitric Oxide / Q000096:biosynthesis; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000008:administration & dosage; D000067996:RAW 264.7 Cells
chemical_list: C469887:20-deoxocarnosol; D045784:Abietanes; C483024:CCL5 protein, human; C499177:COL2A1 protein, human; D018946:Chemokine CCL5; D018925:Chemokines; D024043:Collagen Type II; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D010616:Phenanthrenes; D009569:Nitric Oxide; C068623:carnosol
keywords: NF-κB signaling pathway and nuclear translocation; abietanes; acute inflammation; carnosol; chondrocyte; chronic inflammation; innate immune response; murine macrophages; osteoarthritis