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

Barbara P. Barna, Anagha Malur, Heidi Dalrymple, Reema Karnekar, Daniel A. Culver, Susamma Abraham, Ravinder J. Singh, Donald Brescia, Mani S. Kavuru, Mary Jane Thomassen

Research output: Contribution to journalArticle

8 Scopus citations

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 languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalAutoimmunity
Volume42
Issue number1
DOIs
StatePublished - Jan 19 2009

Keywords

  • Activin A
  • Alveolar macrophage
  • Cathelicidin
  • Vitamin D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'A novel 1,25-dihydroxyvitamin D - Activin A pathway in human alveolar macrophages is dysfunctional in patients with pulmonary alveolar proteinosis (PAP)'. Together they form a unique fingerprint.

  • Cite this

    Barna, B. P., Malur, A., Dalrymple, H., Karnekar, R., Culver, D. A., Abraham, S., Singh, R. J., Brescia, D., Kavuru, M. S., & Thomassen, M. J. (2009). A novel 1,25-dihydroxyvitamin D - Activin A pathway in human alveolar macrophages is dysfunctional in patients with pulmonary alveolar proteinosis (PAP). Autoimmunity, 42(1), 56-62. https://doi.org/10.1080/08916930802316277