Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling

Zhang, Xiao Liang, Topley, Nicholas, Ito, Takafumi and Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113 2005. Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling. The Journal of Biological Chemistry 280 (13) , pp. 12239-12245. 10.1074/jbc.M413284200

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Abstract

Transforming growth factor (TGF)-1 is a key cytokine involved in the pathogenesis of fibrosis in many organs, whereas interleukin (IL)-6 plays an important role in the regulation of inflammation. Recent reports demonstrate interaction between the two cytokines in disease states. We have assessed the effect of IL-6 on TGF-1 signaling and defined the mechanism by which this occurred. Stimulation of Smad-responsive promoter (SBE)4-Lux activity by TGF-1 was significantly greater in the presence of IL-6 than that induced by TGF-1 alone. Augmented TGF-1 signaling following the addition of IL-6 appeared to be mediated through binding to the cognate IL-6 receptor, the presence of which was confirmed by fluorescence-activated cell sorting and Stat-specific signaling. TGF-1 receptors internalize by both caveolin-1 (Cav-1) lipid raft and early endosome antigen 1 (EEA-1) non-lipid raft pathways, with non-lipid raft-associated internalization increasing TGF-1 signaling. Affinity labeling of TGF-1 receptors demonstrated that IL-6 stimulation resulted in increased partitioning of TGF- receptors to the non-lipid raft fraction. There was no change in expression of Cav-1; however, following IL-6 stimulation, co-immunoprecipitation demonstrated decreased association of IL-6 receptor with Cav-1. Increased TGF-1-dependent Smad signaling by IL-6 was significantly attenuated by inhibition of clathrin-mediated endocytosis and augmented by depletion of membrane cholesterol. These results indicate that IL-6 increased trafficking of TGF-1 receptors to non-lipid raft-associated pools results in augmented TGF-1 Smad signaling.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	1083-351X
Last Modified:	01 Dec 2022 09:43
URI:	https://orca.cardiff.ac.uk/id/eprint/435

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