title: Alveolar macrophage cathelicidin deficiency in severe sarcoidosis.
abstract: BACKGROUND
  Dysfunctional immune responses characterize sarcoidosis, but the status of cathelicidin, a potent immunoregulatory and antimicrobial molecule, has not been established in clinical disease activity.
  
  
  METHODS
  Alveolar macrophage cathelicidin expression was determined in biopsy-proven sarcoidosis patients classified clinically as 'severe' (requiring systemic treatment) or 'non-severe' (never requiring treatment). Bronchoalveolar lavage (BAL) cells from sarcoidosis patients and healthy controls were analyzed for mRNA expression of cathelicidin, vitamin D receptor (VDR) and the VDR coactivator steroid receptor coactivator-3 (SRC3) by quantitative PCR. Cathelicidin-derived peptide LL-37 was determined by immunocytochemistry. Serum calcidiol (25-hydroxyvitamin D2; vitD2) and calcitriol (1,25-dihydroxyvitamin D3; vitD3) were quantified.
  
  
  RESULTS
  The results indicated reduced BAL cell expression of cathelicidin and SRC3 in severe but not non-severe sarcoidosis compared to controls. Serum levels of biologically active vitD3 in both severe and non-severe patients were within the control range even though vitD2 levels in both groups were below the recommended level (30 ng/ml). Sarcoidosis and control alveolar macrophages were studied in vitro to determine cathelicidin responses to vitD3 and tumor necrosis factor-α (TNFα), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNFα, which also repressed SRC3.
  
  
  CONCLUSIONS
  These findings suggest that TNFα-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. Deficiency of cathelicidin, a multifunctional regulator of immune cells and proinflammatory cytokines, may impede resolution of inflammation in the lungs of patients with severe sarcoidosis.
authors: Division of Pulmonary and Critical Care Medicine, East Carolina University, Greenville, NC 27834, USA.
authors: Barbara P
authors: BP
authors: Barna
authors: Daniel A
authors: DA
authors: Culver
authors: Ali
authors: A
authors: Kanchwala
authors: Ravinder J
authors: RJ
authors: Singh
authors: Isham
authors: I
authors: Huizar
authors: Susamma
authors: S
authors: Abraham
authors: Anagha
authors: A
authors: Malur
authors: Irene
authors: I
authors: Marshall
authors: Mani S
authors: MS
authors: Kavuru
authors: Mary Jane
authors: MJ
authors: Thomassen
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005260:Female; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D017565:Sarcoidosis, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism; D055815:Young Adult; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D014409:Tumor Necrosis Factor-alpha; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D054804:Cathelicidins