COOKE, N.E.*; LIEBHABER, S.A.; WHITE, P.: Vitamin D binding Protein in Homone Transport and Host Defense

Vitamin D binding protein (DBP) is serum protein belonging to the albumin, &alpha-fetoprotein, &alpha-albumin/afamin family. Multiple functions have been attributed to DBP: 1. Binding vitamin D metabolites and facilitating their serum transport, 2. Binding G-actin released to serum after cellular damage and cooperating with gelsolin in the “extracellular actin-scavenger system”. 3. DBP acts as a macrophage-activating factor in vitro, 4. DBP participates in leukocyte co-chemotaxis with C5a in vitro. To test the putative functions of DBP in vivo, we interrupted the mouse DBP gene by homologous recombination. Mice were bred to establish a DBP-null model. DBP’s role in vitamin D metabolism was studied. More recently DBP’s putative host defense roles have been studied in a series of experiments: 1. Macrophage-dependent host responses to infections. Two models of intracellular pathogens were used: Leishmania donovani and Toxoplasma gondii. 2. Macrophage and neutrophil recruitment to the sterile inflammatory stimulus of ip thioglycollate broth. 3. Response to systemic inflammatory mediators, iv LPS and interferon-&gamma. 4. Macrophage function in ingestion of fluorescent beads. This battery of comparisons covers aspects of clearance and sequestration of intracellular pathogens, recruitment of macrophages and neutrophils to inflammatory sites, and indices of macrophage activation and function. All of these studies revealed equivalent responses in DBP-null and WT mice. We conclude that DBP does not serve a unique function in the activation and/or recruitment of macrophages in vivo. Rather, we suggest that DBP’s roles are primarily centered on vitamin D metabolite transport and an as yet to be fully assessed role in actin-scavenging and sequestration.