A novel 1,25-dihydroxyvitamin D-activin A pathway in human alveolar macrophages is dysfunctional in patients with pulmonary alveolar proteinosis (PAP).
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 D(3)) 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 D(3) 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.
Barna
Barbara P
BP
Division of Pulmonary and Critical Care Medicine, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Malur
Anagha
A
Dalrymple
Heidi
H
Karnekar
Reema
R
Culver
Daniel A
DA
Abraham
Susamma
S
Singh
Ravinder J
RJ
Brescia
Donald
D
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D001402:B-Lymphocytes; D002478:Cells, Cultured; D004100:Dihydroxycholecalciferols / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology* / Q000503:physiopathology*
D001323:Autoantibodies; D004100:Dihydroxycholecalciferols; C422405:activin A; D028341:Activins