The effects of first-line anti-tuberculosis drugs on the actions of vitamin D in human macrophages

• Type of Material: Article
• Authors: Supavit Chesdachai, Emory University; Susu M Zughaier, Emory University; Li Hao, Emory University School of Medicine; Russell Ryan Kempker, Emory University; Henry Michael Blumberg, Emory University; Thomas R Ziegler, Emory University; Vin Tangpricha, Emory University
• Language: English
• Date: 2016-12-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2016
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcte.2016.08.005
• Title of Journal or Parent Work: Journal of Clinical and Translational Endocrinology
• ISSN: 2214-6237
• Volume: 6
• Start Page: 23
• End Page: 29
• Grant/Funding Information: This work was supported by National Institutes of Health grants K24 DK096574 (to TRZ), D43TW007124 (to HMB), K23 AI103044 (to RRK), UL1 TR000454 (to the Atlanta Clinical and Translational Science Institute) and the Emory University Global Health Institute (to TRZ, VT, HMB).
• Keywords: vitamin D; cathelicidin; tuberculosis; antibiotics
• Research Categories: Health Sciences, General; Health Sciences, Rehabilitation and Therapy

Abstract

Tuberculosis (TB) is a major global health problem. Patients with TB have a high rate of vitamin D deficiency, both at diagnosis and during the course of treatment with anti-tuberculosis drugs. Although data on the efficacy of vitamin D supplementation on Mycobacterium tuberculosis (Mtb) clearance are uncertain from randomized controlled trials (RCTs), vitamin D enhances the expression of the anti-microbial peptide human cathelicidin (hCAP18) in cultured macrophages in vitro. One possible explanation for the mixed (primarily negative) results of RCTs examining vitamin D treatment in TB infection is that anti-TB drugs given to enrolled subjects may impact actions of vitamin D to enhance cathelicidin in macrophages. To address this hypothesis, human macrophage-like monocytic (THP-1) cells were treated with varying doses of first-line anti-tuberculosis drugs in the presence of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The expression of hCAP18 was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 1,25(OH)2D3 strongly induced expression of hCAP18 mRNA in THP-1 cells (fold-change from control). The combination of the standard 4-drug TB therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) in the cultured THP-1 cells demonstrated a significant decrease in hCAP18 mRNA at the dosage of 10 µg/mL. In 31 subjects with newly diagnosed drug-sensitive TB randomized to either high-dose vitamin D3 (1.2 million IU over 8 weeks, n = 13) versus placebo (n = 18), there was no change from baseline to week 8 in hCAP18 mRNA levels in peripheral blood mononuclear cells or in plasma concentrations of LL-37, the protein product of hCAP18. These data suggest that first-line anti-TB drugs may alter the vitamin D-dependent increase in hCAP18 and LL-37 human macrophages.