Document Detail


Alveolar macrophage cathelicidin deficiency in severe sarcoidosis.
MedLine Citation:
PMID:  22759465     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Barbara P Barna; Daniel A Culver; Ali Kanchwala; Ravinder J Singh; Isham Huizar; Susamma Abraham; Anagha Malur; Irene Marshall; Mani S Kavuru; Mary Jane Thomassen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2012-07-03
Journal Detail:
Title:  Journal of innate immunity     Volume:  4     ISSN:  1662-8128     ISO Abbreviation:  J Innate Immun     Publication Date:  2012  
Date Detail:
Created Date:  2012-09-05     Completed Date:  2013-01-14     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101469471     Medline TA:  J Innate Immun     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  569-78     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 S. Karger AG, Basel.
Affiliation:
Division of Pulmonary and Critical Care Medicine, East Carolina University, Greenville, NC 27834, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Antimicrobial Cationic Peptides / deficiency*,  genetics,  metabolism
Bronchoalveolar Lavage Fluid / cytology
Female
Humans
Macrophages, Alveolar / metabolism*
Male
Middle Aged
Nuclear Receptor Coactivator 3 / genetics,  metabolism*
Sarcoidosis, Pulmonary / metabolism,  physiopathology*
Severity of Illness Index
Tumor Necrosis Factor-alpha / genetics,  metabolism*,  pharmacology
Vitamin D / analogs & derivatives*,  metabolism
Young Adult
Grant Support
ID/Acronym/Agency:
D52MP02105/MP/OMH OASH HHS; HL-077652/HL/NHLBI NIH HHS; R21 HL077652/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/Tumor Necrosis Factor-alpha; 0/dihydroxy-vitamin D3; 1406-16-2/Vitamin D; 143108-26-3/CAP18 lipopolysaccharide-binding protein; EC 2.3.1.48/NCOA3 protein, human; EC 2.3.1.48/Nuclear Receptor Coactivator 3
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