A semi-synthetic natural product blocks collagen induced arthritis by preferentially suppressing the production of IL-6.
Int Immunopharmacol
; 33: 63-9, 2016 Apr.
Article
em En
| MEDLINE
| ID: mdl-26869203
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Polienos
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Artrite Experimental
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Artrite Reumatoide
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Monócitos
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Interleucina-6
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Actinobacteria
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Antirreumáticos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article