A semi-synthetic natural product blocks collagen induced arthritis by preferentially suppressing the production of IL-6
| Autor: | Ravindra Dattatraya Gupte, Mahesh G. Jadhav, Prabhu Dutt Mishra, Asha Kulkarni-Almeida, Bindu Hegde, Shruta Dadarkar, Meet Shah, Girish B Mahajan, Nilesh M Dagia, Jacqueline Trivedi |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment T cell Immunology Arthritis Pannus Inflammation Polyenes Monocytes Cell Line Arthritis Rheumatoid Mice 03 medical and health sciences 0302 clinical medicine Pannus Formation medicine Animals Humans Immunology and Allergy Interleukin 6 Pharmacology biology Interleukin-6 Chemistry medicine.disease Arthritis Experimental Actinobacteria Disease Models Animal 030104 developmental biology Cytokine medicine.anatomical_structure Mice Inbred DBA Antirheumatic Agents biology.protein Cancer research Tumor necrosis factor alpha medicine.symptom 030215 immunology |
| Zdroj: | International Immunopharmacology. 33:63-69 |
| ISSN: | 1567-5769 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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