Phenylbutyrate Induces Antimicrobial Peptide Expression

Steinmann, Jonas; Halldórsson, Skarphéðinn; Agerberth, Birgitta; Guðmundsson, Guðmundur H.

doi:10.1128/aac.00818-09

Cited by 123 publications

(140 citation statements)

References 45 publications

(47 reference statements)

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“…16 Histone deacetylase inhibitors, such as butyrate and suberoylanilide hydroxamic acid/SAHA, induce autophagy in several human cancer cell lines. 28 We have recently demonstrated that oral administration of PBA alone or in combination with vitamin D, enhanced LL-37 expression and significantly improved the capacity to inhibit the growth of Mtb in MDMs obtained from healthy human volunteers.…”

Section: Discussionmentioning

confidence: 99%

“…15 Our findings have further established that 4-phenylbutyrate (PBA) can induce LL-37 expression at both mRNA and protein levels in a synergistic manner with the active form of vitamin D 3 , 1,25(OH) 2 D 3 , in lung epithelial cells. 16 Accordingly, LL-37 expression is induced in human monocyte derived macrophages (MDMs) upon oral administration of PBA and vitamin D 3 to healthy individuals. 17 Interestingly, Yuk et al showed that 1,25(OH) 2 D 3 activates autophagy in human macrophages via an LL-37-dependent mechanism, which results in reduced intracellular survival of Mtb.…”

Section: Introductionmentioning

confidence: 99%

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Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

et al. 2015

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These authors contributed equally to this work.Keywords: antimicrobial peptides, cathelicidin, innate immunity, P2RX7, tuberculosis, vitamin D Abbreviations: 1,25(OH) 2 D 3 , 1,25-dihydroxy vitamin D 3 ; AMPK, adenosine monophosphate-activated protein kinase; AMPs, antimicrobial peptides; ATG, autophagy related; BECN1, Beclin 1, autophagy related; CAMP, cathelicidin antimicrobial peptide; CFUs, colony-forming units; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MDMs, monocyte-derived macrophages; Mtb, Mycobacterium tuberculosis; P2RX7, purinergic receptor P2X, ligand gated ion channel, 7; PBA, 4-phenylbutyrate; PBS, phosphate-buffered saline; PtdIns3K, phosphatidylinositol 3-kinase; RNA18S/18S rRNA, RNA 18S ribosomal; SQSTM1, sequestosome 1; TB, tuberculosis LL-37 is a human antimicrobial peptide (AMP) of the cathelicidin family with multiple activities including a mediator of vitamin D-induced autophagy in human macrophages, resulting in intracellular killing of Mycobacterium tuberculosis (Mtb). In a previous trial in healthy volunteers, we have shown that LL-37 expression and subsequent Mtb-killing can be further enhanced by 4-phenylbutyrate (PBA), also an inducer of LL-37 expression. Here, we explore a potential mechanism(s) behind PBA and LL-37-induced autophagy and intracellular killing of Mtb. Mtb infection of macrophages downregulated the expression of both the CAMP transcript and LL-37 peptide as well as certain autophagy-related genes (BECN1 and ATG5) at both the mRNA and protein levels. In addition, activation of LC3-II in primary macrophages and THP-1 cells was not detected. PBA and the active form of vitamin D 3 (1,25[OH] 2 D 3 ), separately or particularly in combination, were able to overcome Mtb-induced suppression of LL-37 expression. Notably, reactivation of autophagy occurred by stimulation of macrophages with PBA and promoted colocalization of LL-37 and LC3-II in autophagosomes. Importantly, PBA treatment failed to induce autophagy in Mtb-infected THP-1 cells, when the expression of LL-37 was silenced. However, PBA-induced autophagy was restored when the LL-37 knockdown cells were supplemented with synthetic LL-37. Interestingly, we have found that LL-37-induced autophagy was mediated via P2RX7 receptor followed by enhanced cytosolic free Ca 2C , and activation of AMPK and PtdIns3K pathways. Altogether, these results suggest a novel activity for PBA as an inducer of autophagy, which is LL-37-dependent and promotes intracellular killing of Mtb in human macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

et al. 2015

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“…LL-37 is an AMP which induces autophagy in M. tuberculosis infected human macrophages. 143,144 Increased production of LL-37 could potentially enhance killing of both extra-cellular and intra-cellular bacteria as reported earlier. There is no significant clinical or microbiological data of the effects of treatment with these drugs.…”

Section: The Promising Molecules and Natural Productsmentioning

confidence: 76%

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

et al. 2016

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To say that tuberculosis (TB) has regained a strong foothold in the global human health and wellbeing scenario would be an understatement. Ranking alongside HIV/AIDS as the top reason for mortality due to a single infectious disease, the impact of TB extends far into socio-economic context worldwide. As global efforts led by experts and political bodies converge to mitigate the predicted outcome of growing antimicrobial resistance, the academic community of students, practitioners and researchers have mobilised to develop integrated, inter-disciplinary programmes to bring the plans of the former to fruition. Enabling this crucial requirement for unimpeded dissemination of scientific discovery was the TB Summit 2016, held in London, United Kingdom. This report critically discusses the recent breakthroughs made in diagnostics and treatment while bringing to light the major hurdles in the control of the disease as discussed in the course of the 3-day international event. Conferences and symposia such as these are the breeding grounds for successful local and global collaborations and therefore must be supported to expand the understanding and outreach of basic science research.

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“…Enhanced acetylation of histones by histone deacetylase inhibitors (HDACi), e.g., butyrate, phenylbutyrate, and trichostatin A (TSA), has been proposed to mediate the transcriptional induction of LL-37 (26)(27)(28). A panel of HDACi that are analogues of butyrate or phenylbutyrate also induced LL-37 in the MN8CampLuc reporter cell line (18).…”

Section: Discussionmentioning

confidence: 99%

Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

Sarker

Banik

Strömberg

et al. 2017

Antimicrob Agents Chemother

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We have shown previously that oral treatment with sodium butyrate or phenylbutyrate in an experimental model of shigellosis improves clinical outcomes and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we found that entinostat, an aroylated phenylenediamine compound, has similar therapeutic potential against shigellosis. In this study, we aimed to evaluate entinostat as a potential candidate for host-directed therapy against cholera in an experimental model. Vibrio cholerae-infected rabbits were treated with two different dose regimens of entinostat: either 0.5 mg twice daily for 2 days or 1 mg once daily for 2 days. The effects of treatment on clinical outcomes and V. cholerae shedding (CFU count in stool) were observed. Immunohistochemical analysis was carried out to assess CAP-18 expression in ileal and jejunal mucosae. The serum zonulin level was measured by an enzyme-linked immunosorbent assay (ELISA) to evaluate gut permeability. Infection of rabbits with V. cholerae downregulated CAP-18 expression in the ileal epithelium; the expression was replenished by oral treatment with entinostat at either dose regimen. The level of zonulin, a marker of gut permeability, in serum was upregulated after infection, and this upregulation was counteracted after treatment with entinostat. Entinostat treatment also led to recovery from cholera and a decline in the V. cholerae count in stool. In conclusion, the improved clinical outcome of cholera for rabbits treated with entinostat is associated with the induction of CAP-18 and the reduction of gut epithelial permeability.

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Phenylbutyrate Induces Antimicrobial Peptide Expression

Cited by 123 publications

References 45 publications

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

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