[Note: The full text of this article is available free online. Trophoblasts are cells that form the outer layer of the blastocyst membrane, which surrounds and feeds the embryo during the first stage of pregnancy, then forms part of the placenta. “Intracrine” refers to a hormone that acts inside a cell.]
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) is a potent inducer of the antimicrobial protein cathelicidin, CAMP (LL37). In macrophages this response is dependent on intracrine synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D (25OHD), catalyzed by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). [“Macrophages” are a type of white blood cell that surrounds and kills infectious microorganisms & tumor cells and stimulates other immune cells.]
In view of the fact that trophoblastic cells also express abundant CYP27B1, we postulated a similar intracrine pathway for induction of CAMP in the placenta.
Analysis of placenta explants, primary cultures of human trophoblast, and the 3A trophoblastic cell line treated with 1,25(OH)2D (1-100 nM) revealed dose-dependent induction of CAMP similar to that observed with primary cultures of human macrophages. Also consistent with macrophages, induction of trophoblastic CAMP was enhanced via intracrine conversion of 25OHD to 1,25(OH)2D. However, in contrast to macrophages, induction of CAMP by vitamin D in trophoblasts was not enhanced by co-stimulation with toll-like receptor ligands such as lipopolysaccharide.
Despite this, exposure to vitamin D metabolites significantly enhanced antibacterial responses in trophoblastic cells: 3A cells infected with Escherichia coli (E. coli) showed decreased numbers of bacterial colony-forming units compared to vehicle-treated controls when treated with 25OHD (49.6 +/- 10.9 %) or 1,25(OH)2D (45.4 +/- 9.2 %), both P < 0.001.
Treatment with 25OHD (1-100 nM) or 1,25(OH)2D (0.1-10 nM) also protected 3A cells against cell death following infection with E. coli (13.6-26.9 and 22.3-40.2% protection respectively). These observations indicate that 1,25(OH)2D can function as an intracrine regulator of CAMP in trophoblasts, and may thus provide a novel mechanism for activation of innate immune responses in the placenta.
Source: Biology of Reproduction, Nov 12, 2008. E-pub ahead of print. PMID: 19005165, by Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O, Hewison M. David Geffen School of Medicine, UCLA; Cedars-Sinai Medical Center, Los Angeles, USA. [E-mail: Martin Hewison firstname.lastname@example.org]