title: Caveolin-1 deficiency may predispose African Americans to systemic sclerosis-related interstitial lung disease.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical University of South Carolina, Charleston.
authors.forename: Charles
authors.initials: C
authors.lastname: Reese
authors.forename: Beth
authors.initials: B
authors.lastname: Perry
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heywood
authors.forename: Michael
authors.initials: M
authors.lastname: Bonner
authors.forename: Richard P
authors.initials: RP
authors.lastname: Visconti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lee
authors.forename: Corey M
authors.initials: CM
authors.lastname: Hatfield
authors.forename: Richard M
authors.initials: RM
authors.lastname: Silver
authors.forename: Stanley
authors.initials: S
authors.lastname: Hoffman
authors.forename: Elena
authors.initials: E
authors.lastname: Tourkina
mesh_terms: D001741:Black or African American; D051242:Caveolin 1 / Q000172:deficiency* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003599:Cytoskeleton / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D017563:Lung Diseases, Interstitial / Q000208:ethnology / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D019718:Receptors, CXCR4 / Q000378:metabolism; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000208:ethnology / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D044465:White People
chemical_list: C527276:CXCR4 protein, human; D051242:Caveolin 1; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta