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Background  We earlier showed that 4-phenylbutyrate (PB) can induce cathelicidin LL-37 expression synergistically with 1,25-dihydroxyvitamin D 3  in a lung epithelial cell line. We aimed to evaluate a therapeutic dose of PB alone or in combination with vitamin D 3  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 D 3  {5000 IU once daily (o.d.)}, PB (500 mg b.d.) (Group-IV) or vitamin D 3  (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 D 3  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 D 3  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).

bmc pulmonary medicine

Oral intake of phenylbutyrate with or without vitamin D3upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis