Abstract
We have shown that activin A, a cytokine implicated in regulating B-cell proliferation, is severely deficient in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP), an autoimmune disorder characterized by surfactant accumulation and neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor. Mechanisms of activin regulation in alveolar macrophages are not well understood. Based on previous gene array results from PAP bronchoalveolar lavage cells suggesting deficiencies in vitamin D target genes, and on recent evidence of vitamin D receptor elements (VDREs) in the human activin A gene promoter, we investigated the effects of 1,25-dihydroxyvitamin D (vitamin D3) on activin A expression in alveolar macrophages from healthy individuals and PAP patients. Activin A expression was stimulated by LPS in cultures of either healthy control or PAP alveolar macrophages; in contrast, vitamin D3 increased activin A only in healthy controls but not in PAP. Compared to healthy controls, freshly obtained (uncultured) PAP alveolar macrophages displayed healthy intrinsic vitamin D receptor expression but deficient expression of vitamin D target genes, cathelicidin and thioredoxin interacting protein. PAP patients also demonstrated a relative insufficiency of circulating vitamin D. Investigation of activin A in murine alveolar macrophages confirmed a lack of functional response to vitamin D as anticipated since murine activin A does not contain VDREs. Results suggest that mechanisms of activin A deficiency in PAP alveolar macrophages may involve dysregulation of a novel species-specific vitamin D-activin A pathway.
Original language | English (US) |
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Pages (from-to) | 56-62 |
Number of pages | 7 |
Journal | Autoimmunity |
Volume | 42 |
Issue number | 1 |
DOIs | |
State | Published - 2009 |
Keywords
- Activin A
- Alveolar macrophage
- Cathelicidin
- Vitamin D
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology