O'Sullivan, Sinead, Gasparini, Fabrizio, Mir, Anis Khusro and Dev, Kumlesh (2016) Cytokine mediated liberation of soluble Fractalkine (sCX3CL1) in Human Astrocytes is dependent on ADAM10 and p38/NF-κB signalling. Journal of neuroinflammation, 13. p. 189. ISSN 1742-2094

Abstract

The fractalkine ligand (CX3CL1) is expressed in astrocytes and reported to be neuro-protective. When cleaved from the membrane, soluble fractalkine (sCX3CL1) activates the receptor CX3CR1, which is expressed in neurons and microglia. The membrane bound form of CX3CR1 additionally acts as an adhesion molecule for microglia and infiltrating white blood cells. Here, the mechanisms involved in the up-regulation and cleavage of CX3CL1 from human astrocytes was investigated. A combination of ADAM17 (TACE) and ADAM10 protease inhibitors were found to attenuate IL-1β, TNFα and IFNγ induced sCX3CL1 levels in astrocytes. A specific ADAM10 (but not ADAM17) inhibitor also attenuated these effects, suggesting ADAM10 proteases induce release of sCX3CL1 from stimulated human astrocytes. A p38 MAPK inhibitor also attenuated the levels of sCX3CL1 upon treatment with IL-1β, TNFα or IFNγ. In addition, IKKα and IKKβ inhibitors significantly reduced the levels of sCX3CL1 induced by IL-1β or TNFα in a concentration dependent manner, suggesting a role for the NF-κB pathway. These findings are important for understanding the role of CX3CL1 in healthy and stimulated astrocytes and may benefit our understanding of this pathway in neuro-inflammatory and neurodegenerative diseases.

Item Type:	Article
Date Deposited:	04 Jan 2017 00:45
Last Modified:	04 Jan 2017 00:45
URI:	https://oak.novartis.com/id/eprint/28102