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

被引：82

作者：

Mily, Akhirunnesa ^{[1
]}

Rekha, Rokeya Sultana ^{[1
,2
]}

Kamal, S. M. Mostafa ^{[3
]}

Akhtar, Evana ^{[1
]}

Sarker, Protim ^{[1
,2
]}

Rahim, Zeaur ^{[1
]}

Gudmundsson, Gudmundur H. ^{[4
]}

Agerberth, Birgitta ^{[2
]}

Raqib, Rubhana ^{[1
]}

机构：

[1] Bangladesh Icddr B, Int Ctr Diarrheal Dis Res, Dhaka 1212, Bangladesh

[2] Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden

[3] Natl Inst Dis Chest & Hosp, Dhaka 1212, Bangladesh

[4] Univ Iceland, Inst Biol, IS-101 Reykjavik, Iceland

来源：

BMC PULMONARY MEDICINE | 2013年 / 13卷

基金：

瑞典研究理事会;

关键词：

Innate immunity; Antimicrobial peptides; Monocyte derived macrophages; Mycobacterium; MYCOBACTERIUM-TUBERCULOSIS; ANTIMICROBIAL PEPTIDES; SODIUM-BUTYRATE; DOUBLE-BLIND; EXPRESSION; INDUCTION; AUTOPHAGY; DEFENSINS; DNA;

D O I：

10.1186/1471-2466-13-23

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

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).

引用

页数：8

共 32 条

[1] The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations [J].

Agerberth, B ;

Charo, J ;

Werr, J ;

Olsson, B ;

Idali, F ;

Lindbom, L ;

Kiessling, R ;

Jörnvall, H ;

Wigzell, H ;

Gudmundsson, GH .

BLOOD, 2000, 96 (09) :3086-3093

[2] Neisseria gonorrhoeae downregulates expression of the human antimicrobial peptide LL-37 [J].

Bergman, P ;

Johansson, L ;

Asp, V ;

Plant, L ;

Gudmundsson, GH ;

Jonsson, AB ;

Agerberth, B .

CELLULAR MICROBIOLOGY, 2005, 7 (07) :1009-1017

[3] Multiple drug-resistant tuberculosis [J].

Bradford, WZ ;

Daley, CL .

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA, 1998, 12 (01) :157-+

[4] Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1 [J].

Campbell, Grant R. ;

Spector, Stephen A. .

AUTOPHAGY, 2012, 8 (10) :1523-1525

[5]

DEHAAN JB, 1986, CANCER RES, V46, P713

[6] T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism [J].

Edfeldt, Kristina ;

Liu, Philip T. ;

Chun, Rene ;

Fabri, Mario ;

Schenk, Mirjam ;

Wheelwright, Matthew ;

Keegan, Caroline ;

Krutzik, Stephan R. ;

Adams, John S. ;

Hewison, Martin ;

Modlin, Robert L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (52) :22593-22598

[7] HIV Coinfection in Multidrug- and Extensively Drug-Resistant Tuberculosis Results in High Early Mortality [J].

Gandhi, Neel R. ;

Shah, N. Sarita ;

Andrews, Jason R. ;

Vella, Venanzio ;

Moll, Anthony P. ;

Scott, Michelle ;

Weissman, Darren ;

Marra, Claudio ;

Lalloo, Umesh G. ;

Friedland, Gerald H. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2010, 181 (01) :80-86

[8] Defensins: Antimicrobial peptides of innate immunity [J].

Ganz, T .

NATURE REVIEWS IMMUNOLOGY, 2003, 3 (09) :710-720

[9] Downregulation of bactericidal peptides in enteric infections: A novel immune escape mechanism with bacterial DNA as a potential regulator [J].

Islam, D ;

Bandholtz, L ;

Nilsson, J ;

Wigzell, H ;

Christensson, B ;

Agerberth, B ;

Gudmundsson, GH .

NATURE MEDICINE, 2001, 7 (02) :180-185

[10] The role of the multifunctional peptide LL-37 in host defense [J].

Kai-Larsen, Ylva ;

Agerberth, Birgitta .

FRONTIERS IN BIOSCIENCE, 2008, 13 :3760-3767

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