Tumour necrosis factor-stimulated gene (TSG)-6-mediated interactions with the inter-alpha-inhibitor heavy chain 5 facilitate TGF beta1-dependent fibroblast to myofibroblast differentiation.

Martin, John, Midgley, Adam, Meran, Soma ORCID: https://orcid.org/0000-0003-3408-3978, Woods, Emma, Bowen, Timothy ORCID: https://orcid.org/0000-0001-6050-0435, Phillips, Aled O. ORCID: https://orcid.org/0000-0001-9744-7113 and Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496 2016. Tumour necrosis factor-stimulated gene (TSG)-6-mediated interactions with the inter-alpha-inhibitor heavy chain 5 facilitate TGF beta1-dependent fibroblast to myofibroblast differentiation. Journal of Biological Chemistry 291 , pp. 13789-13801. 10.1074/jbc.M115.670521

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Abstract

Fibroblasts are central to wound healing and fibrosis through Transforming Growth Factor-beta (TGF-beta1)-triggered differentiation into contractile, alpha_smooth muscle actin (alpha_sma)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localisation of CD44 with the Epidermal Growth Factor Receptor (EGFR). Interactions of HA with hyaladherins, such as Inter-alpha-Inhibitor (IalphaI) and Tumour Necrosis Factor-stimulated gene_6 (TSG_6) are also essential for differentiation. This study investigated the mechanisms involved. TSG6 and alpha_sma had different kinetics of induction by TGFbeta1, with TSG6 peaking before alphasma. siCD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing IalphaI heavy chain [HC] transfer), HA-oligosaccharides, Cobalt, or siBikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG6/IalphaI HC interaction was necessary for the effect of TSG-6 and that HC-stabilisation of HA initiated the CD44/EGF-R association. The newly-described HC5 was shown to be the principal HC expressed and its cell surface expression was prevented by siRNA inhibition of TSG6 or Bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knock down by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly-described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGFbeta1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > Q Science (General) R Medicine > RZ Other systems of medicine
Additional Information:	PDF uploaded in accordance with publisher OA policy at http://www.sherpa.ac.uk/romeo/issn/0021-9258/ [accessed 18/05/16]
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	13 May 2016
Date of Acceptance:	20 April 2016
Last Modified:	06 Nov 2024 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/90877

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