Alveolar Macrophage Cathelicidin Deficiency in Severe Sarcoidosis

作者：Barna Barbara R; Culver Daniel A; Kanchwala Ali; Singh Ravinder J; Huizar Isham; Abraham Susamma; Malur Anagha; Marshall Irene; Kavuru Mani S; Thomassen Mary Jane^*

来源：Journal of Innate Immunity, 2012, 4(5-6): 569-578.

DOI：10.1159/000339149

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

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 %26apos;severe%26apos; (requiring systemic treatment) or %26apos;non-severe%26apos; (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-alpha (TNF alpha), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNF alpha, which also repressed SRC3. Conclusions: These findings suggest that TNF alpha-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.

• 出版日期2012