Differential regulation of cell functions by CSD peptide subdomains

Respiratory Research

Elena Tourkina⁵  Stanley Hoffman²  Richard M Silver⁴  Corey M Hatfield⁴  Jing Zhang²  Richard P Visconti²  Pascal Bernatchez¹  William Sessa³  Ann Hofbauer⁴  James Oates⁴  Michael Bonner⁴  Beth Perry⁴  Shanice Dyer⁴  Charles Reese⁴ 

[1] Department of Anesthesiology, The James Hogg Research Centre, Heart and Lung Institute at St. Paul’s Hospital, Pharmacology and Therapeutics, University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada;Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA;Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA;Department of Medicine/Division of Rheumatology and Immunology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA;Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912 MSC 637, Charleston, SC 29425, USA

关键词: TGFβ;    Migration;    Scleroderma (SSc);    Fibroblasts;    Fibrocytes;    Monocytes;    Caveolin-1;   

Others  :  792819
DOI  :  10.1186/1465-9921-14-90

 received in 2013-03-05, accepted in 2013-09-02,  发布年份 2013

【 摘 要 】

Background

In fibrotic lung diseases, expression of caveolin-1 is decreased in fibroblasts and monocytes. The effects of this deficiency are reversed by treating cells or animals with the caveolin-1 scaffolding domain peptide (CSD, amino acids 82–101 of caveolin-1) which compensates for the lack of caveolin-1. Here we compare the function of CSD subdomains (Cav-A, Cav-B, Cav-C, Cav-AB, and Cav-BC) and mutated versions of CSD (F92A and T90A/T91A/F92A).

Methods

Migration toward the chemokine CXCL12 and the associated expression of F-actin, CXCR4, and pSmad 2/3 were studied in monocytes from healthy donors and SSc patients. Fibrocyte differentiation was studied using PBMC from healthy donors and SSc patients. Collagen I secretion and signaling were studied in fibroblasts derived from the lung tissue of healthy subjects and SSc patients.

Results

Cav-BC and CSD at concentrations as low as 0.01 μM inhibited the hypermigration of SSc monocytes and TGFβ-activated Normal monocytes and the differentiation into fibrocytes of SSc and Normal monocytes. While CSD also inhibited the migration of poorly migrating Normal monocytes, Cav-A (and other subdomains to a lesser extent) promoted the migration of Normal monocytes while inhibiting the hypermigration of TGFβ-activated Normal monocytes. The effects of versions of CSD on migration may be mediated in part via their effects on CXCR4, F-actin, and pSmad 2/3 expression. Cav-BC was as effective as CSD in inhibiting fibroblast collagen I and ASMA expression and MEK/ERK signaling. Cav-C and Cav-AB also inhibited collagen I expression, but in many cases did not affect ASMA or MEK/ERK. Cav-A increased collagen I expression in scleroderma lung fibroblasts. Full effects on fibroblasts of versions of CSD required 5 μM peptide.

Conclusions

Cav-BC retains most of the anti-fibrotic functions of CSD; Cav-A exhibits certain pro-fibrotic functions. Results obtained with subdomains and mutated versions of CSD further suggest that the critical functional residues in CSD depend on the cell type and readout being studied. Monocytes may be more sensitive to versions of CSD than fibroblasts and endothelial cells because the baseline level of caveolin-1 in monocytes is much lower than in these other cell types.

【 授权许可】

   
2013 Reese et al.; licensee BioMed Central Ltd.

【 图 表 】

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