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Clinical Trial
. 2013 Apr 16:13:23.
doi: 10.1186/1471-2466-13-23.

Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis

Akhirunnesa Mily  1 , Rokeya Sultana Rekha, S M Mostafa Kamal, Evana Akhtar, Protim Sarker, Zeaur Rahim, Gudmundur H Gudmundsson, Birgitta Agerberth, Rubhana Raqib
Affiliations
Clinical Trial

Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis

Akhirunnesa Mily et al. BMC Pulm Med. .

Abstract

Background: We earlier showed that 4-phenylbutyrate (PB) can induce cathelicidin LL-37 expression synergistically with 1,25-dihydroxyvitamin D3 in a lung epithelial cell line. We aimed to evaluate a therapeutic dose of PB alone or in combination with vitamin D3 for induction of LL-37 expression in immune cells and enhancement of antimycobacterial activity in monocyte-derived macrophages (MDM).

Methods: Healthy volunteers were enrolled in an 8-days open trial with three doses of PB [250 mg (Group-I), 500 mg (Group-II) or 1000 mg (Group-III)] twice daily (b.d.) together with vitamin D3 {5000 IU once daily (o.d.)}, PB (500 mg b.d.) (Group-IV) or vitamin D3 (5000 IU o.d.) (Group-V), given orally for 4 days. Blood was collected on day-0, day-4 and day-8; plasma was separated, peripheral blood mononuclear cells (PBMC), non-adherent lymphocytes (NAL) and MDM were cultured. LL-37 transcript in cells and peptide concentrations in supernatant were determined by qPCR and ELISA, respectively. In plasma, 25-hydorxyvitamin D3 levels were determined by ELISA. MDM-mediated killing of Mycobacterium tuberculosis (Mtb) (H37Rv) was performed by conventional culture method.

Results: MDM from Group-II had increased concentration of LL-37 peptide and transcript at day-4, while Group-I showed increased transcript at day-4 and day-8 compared to day-0 (p < 0.05). Both Group-I and -II exhibited higher levels of transcript on day-4 compared to Group-III and Group-V (p < 0.035). Increased induction of peptide was observed in lymphocytes from Group-II on day-4 compared to Group-I and Group-IV (p < 0.05), while Group-IV showed increased levels on day-8 compared to Group-I and Group-III (p < 0.04). Intracellular killing of Mtb on day-4 was significantly increased compared to day-0 in Group-I, -II and -V (p < 0.05).

Conclusion: The results demonstrate that 500 mg b.d. PB with 5000 IU o.d. vitamin D3 is the optimal dose for the induction of LL-37 in macrophages and lymphocytes and intracellular killing of Mtb by macrophages. Hence, this dose has potential application in the treatment of TB and is now being used in a clinical trial of adults with active pulmonary TB (NCT01580007).

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Figures

Figure 1
Figure 1
Plasma 25-hydroxyvitamin D3 concentration in healthy adults before and after supplementation. Group-I: 250 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-II: 500 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-III: 1000 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-IV: 500 mg PB b.d.; Group-V: 5000 IU vitamin D3 o.d. PB: Phenylbutyrate. b.d.: twice daily. o.d. : once daily. Data were analyzed by One-way ANOVA.
Figure 2
Figure 2
Viable Mtb CFU count in Monocyte derived macrophages (MDM). MDM from different group of volunteers were incubated with Mtb H37Rv strain for 2 h, after that extracellular bacteria were removed and cultured for 3 days, cells were lysed and plated for variable colony (CFU) count. Group-I: 250 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-II: 500 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-III: 1000 mg PB b.d. + 5000 IU vitamin D3 o.d.; Group-IV: 500 mg PB b.d.; Group-V: 5000 IU vitamin D3 o.d.. PB: Phenylbutyrate. b.d.: twice daily. o.d. : once daily. The straight horizontal line indicates means. Data were analyzed by two-way (treatment and time) repeated measures ANOVA. * p < 0.05, and *** p < 0.001.
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