title: A semi-synthetic natural product blocks collagen induced arthritis by preferentially suppressing the production of IL-6.
abstract: Rheumatoid arthritis (RA), an autoimmune-inflammatory disease is characterized by dysregulation of signal transduction pathways, increased production of pro-inflammatory cytokines, enhanced leukocyte infiltration into synovial microvascular endothelium, extensive formation of hyper proliferative pannus, degradation of cartilage and bone erosion. Several compounds that abrogate cytokine production demonstrate a therapeutic effect in experimental models of arthritis. In this study, we report that a novel semi-synthetic natural product (Compound A) being a preferential IL-6 inhibitor, is efficacious in a murine model of arthritis. In vitro evaluations of pro-inflammatory cytokine production reveal that Compound A preferentially inhibits induced production of IL-6 and not TNF-α from THP-1 cells and isolated human monocytes. Furthermore, Compound A robustly inhibits the spontaneous production of IL-6 from pathologically relevant synovial tissue cells isolated from patients with active RA. In a physiologically relevant assay, Compound A selectively inhibits the activated T cell contact-mediated production of IL-6 from human monocytes. Compound A, at pharmacologically efficacious concentrations, does not significantly curtail the LPS-induced activation of p38 MAPKs. In the collagen-induced arthritis (CIA) mouse model (i) macroscopic observations demonstrate that Compound A, administered subcutaneously in a therapeutic regimen, significantly and dose-dependently inhibits disease associated increases in articular index and paw thickness; (ii) histological analyses of paw tissues reveal that Compound A prominently diminishes joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide direct evidence that Compound A, a novel preferential IL-6 inhibitor, suppresses collagen-induced arthritis, and may be a potential therapeutic for treating patients with active RA.
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India. Electronic address: asha_almeida@yahoo.co.in.
authors: Asha
authors: A
authors: Kulkarni-Almeida
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Meet
authors: M
authors: Shah
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Mahesh
authors: M
authors: Jadhav
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Bindu
authors: B
authors: Hegde
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Jacqueline
authors: J
authors: Trivedi
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Prabhu D
authors: PD
authors: Mishra
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Girish B
authors: GB
authors: Mahajan
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Shruta
authors: S
authors: Dadarkar
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Ravindra
authors: R
authors: Gupte
authors: Piramal Enterprises Ltd., NCE Research Division, Mumbai, India.
authors: Nilesh
authors: N
authors: Dagia
mesh_terms: D039903:Actinobacteria / Q000276:immunology*; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D011090:Polyenes / Q000138:chemical synthesis / Q000627:therapeutic use*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018501:Antirheumatic Agents; D011090:Polyenes; D000093242:Interleukin-6 Inhibitors; C000595534:(3Z,5E,7E,9E,11E,13Z,15E,17E)-18-methyl-19-oxoicosa-3,5,7,9,11,13,15,17-octaenoic acid
keywords: CIA; IL-6; Inflammation; Rheumatoid arthritis