Effect of narrow spectrum versus selective kinase inhibitors on the intestinal proinflammatory immune tesponse in ulcerative colitis
Autor: | Thomas T. MacDonald, Claire A. Walshe, Paolo Biancheri, Yemisi Solanke, Eleanor Wood, Matthew C. Fyfe, Martyn R Foster, Adele Rowley, Steve Webber, Sameer Sirohi |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Niacinamide medicine.drug_class Biopsy Primary Cell Culture Dasatinib Original Basic Science Articles Syk Pharmacology Naphthalenes Fostamatinib Mitogen-Activated Protein Kinase 14 03 medical and health sciences 0302 clinical medicine medicine Immunology and Allergy Humans Syk Kinase Protein kinase A Myofibroblasts narrow spectrum kinase inhibitor Protein Kinase Inhibitors ulcerative colitis business.industry Kinase Macrophages Interleukin-8 TOP1210 Gastroenterology Protein kinase inhibitor 030104 developmental biology Pyrimidines src-Family Kinases Benzamides Leukocytes Mononuclear Cytokines Pyrazoles 030211 gastroenterology & hepatology Colitis Ulcerative Signal transduction Janus kinase business HT29 Cells medicine.drug |
Zdroj: | Inflammatory Bowel Diseases |
Popis: | Article first published online 22 April 2016. Background: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. Methods: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC). Effects on recombinant P38α, Src, and Syk kinase activities were assessed using Z-lyte assays (Invitrogen, Paisley, United Kingdom). Anti-inflammatory effects were assessed by measurement of proinflammatory cytokine release from peripheral blood mononuclear cells, primary macrophages, HT29 cells, inflamed colonic UC biopsies, and myofibroblasts isolated from inflamed colonic UC mucosa. Results: TOP1210 potently inhibits P38α, Src, and Syk kinase activities. Similarly, TOP1210 demonstrates potent inhibitory activity against proinflammatory cytokine release in each of the cellular assays and the inflamed colonic UC biopsies and myofibroblasts isolated from inflamed colonic UC mucosa. Generally, the selective kinase inhibitors showed limited and weaker activity in the cellular assays compared with the broad inhibitory profile of TOP1210. However, combination of the selective inhibitors led to improved efficacy and potency in both cellular and UC biopsy assays. Conclusions: Targeted, multikinase inhibition with TOP1210 leads to a broad efficacy profile in both the innate and adaptive immune responses, with significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in inflammatory bowel disease. |
Databáze: | OpenAIRE |
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