Differential regulation of cell functions by CSD peptide subdomainsReport as inadecuate




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Respiratory Research

, 14:90

First Online: 08 September 2013Received: 05 March 2013Accepted: 02 September 2013

Abstract

BackgroundIn 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.

MethodsMigration 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.

ResultsCav-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.

ConclusionsCav-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.

KeywordsCaveolin-1 Monocytes Fibrocytes Fibroblasts Scleroderma SSc Migration TGFβ AbbreviationsASMAα-smooth muscle actin

CXCL12C-X-C chemokine ligand 12

CXCR4C-X-C Chemokine receptor type 4

eNOSEndothelial Nitric Oxide Synthase

ERKExtracellular signal-regulated kinases

ILDInterstitial lung disease

IPFIdiopathic pulmonary fibrosis

MEKMAPK-ERK kinase

NONitric oxide

SScSystemic sclerosis, scleroderma

TGFβTransforming growth factor β

PIPropidium iodide.

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-14-90 contains supplementary material, which is available to authorized users.

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Author: Charles Reese - Shanice Dyer - Beth Perry - Michael Bonner - James Oates - Ann Hofbauer - William Sessa - Pascal Bernatche

Source: https://link.springer.com/







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