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Caveolin‐1 Deficiency May Predispose African Americans to Systemic Sclerosis–Related Interstitial Lung Disease
Author(s) -
Reese Charles,
Perry Beth,
Heywood Jonathan,
Bonner Michael,
Visconti Richard P.,
Lee Rebecca,
Hatfield Corey M.,
Silver Richard M.,
Hoffman Stanley,
Tourkina Elena
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38572
Subject(s) - medicine , caveolin 1 , fibrocyte , interstitial lung disease , immunology , monocyte , cd34 , stromal cell , lung , cancer research , pathology , biology , stem cell , microbiology and biotechnology
Objective Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc; scleroderma). Although SSc‐related ILD is more common and severe in African Americans than in Caucasians, little is known about factors underlying this significant health disparity. The aim of this study was to examine the role that low expression of caveolin‐1 might play in susceptibility to ILD among African Americans. Methods Assays of monocyte migration toward stromal cell–derived factor 1 (SDF‐1) were performed using monocytes from Caucasian and African American healthy donors and patients with SSc. For fibrocyte differentiation studies, total peripheral blood mononuclear cells were incubated on fibronectin‐coated plates. Protein expression was evaluated by immunohistochemistry and Western blotting. Results Monocytes from healthy African American donors and those from patients with SSc had low caveolin‐1 levels, enhanced migration toward the CXCR4 ligand SDF‐1, and enhanced differentiation to fibrocytes. Enhanced migration and differentiation of monocytes from African Americans and patients with SSc appeared to be attributable to the lack of caveolin‐1, because restoring caveolin‐1 function using a caveolin‐1 scaffolding domain peptide inhibited these processes. Although they differed from monocytes from Caucasians, monocytes from both African Americans and patients with SSc were not identical, because SSc monocytes showed major increases from baseline in ERK, JNK, p38, and Smad2/3 activation, while monocytes from African Americans showed only limited ERK activation and no activation of JNK, p38, or Smad2/3. In contrast, SDF‐1 exposure caused no additional ERK activation in SSc monocytes but did cause significant additional activation in monocytes from African Americans. Conclusion African Americans may be predisposed to SSc‐related ILD due to low baseline caveolin‐1 levels in their monocytes, potentially affecting signaling, migration, and fibrocyte differentiation. The monocytes of African Americans may lack caveolin‐1 due to high levels of transforming growth factor β in their blood.