Alveolar macrophage cathelicidin deficiency in severe sarcoidosis

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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)569-578
Number of pages10
JournalJournal of Innate Immunity
Volume4
Issue number5-6
DOIs
StatePublished - Aug 2012

Keywords

  • Alveolar macrophage
  • Cathelicidin
  • Cytokines
  • Sarcoidosis
  • Steroid receptor coactivators
  • Vitamin D

ASJC Scopus subject areas

  • Immunology and Allergy

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