A novel 1,25-dihydroxyvitamin D-activin A pathway in human alveolar macrophages is dysfunctional in patients with pulmonary alveolar proteinosis (PAP)

作者：Barna Barbara P; Malur Anagha; Dalrymple Heidi; Karnekar Reema; Culver Daniel A; Abraham Susamma; Singh Ravinder J; Brescia Donald; Kavuru Mani S; Thomassen Mary Jane^*

来源：Autoimmunity, 2009, 42(1): 56-62.

DOI：10.1080/08916930802316277

• Activin A
• vitamin D
• alveolar macrophage
• cathelicidin

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.

• 出版日期2009