Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells

Schwab, Markus; Reynders, Veerle; Shastri, Yogesh M.; Loitsch, Stefan; Stein, Jürgen M.; Schröder, Oliver

doi:10.1016/j.molimm.2006.09.016

Cited by 56 publications

(33 citation statements)

References 37 publications

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“…Our results are in agreement with the earlier studies that indicated critical involvement of ERK-MAPK in NaB-induced cathelicidin expression in the colon epithelial cells (38). p38 MAPK, on the other hand, has a rather controversial role, and both positive and negative regulation of cathelicidin by this molecule has been reported (38,40). This suggests cell-and stimulus-specific regulation of cathelicidin in response to NaB.…”

Section: Discussionsupporting

confidence: 93%

“…As stated above, vitamin D 3 fails to induce cathelicidin in the colonic epithelial cell line HT-29 (20), but it augments its promoter activity in the presence of NaB, and either of them may induce binding of the Ets family transcription factor PU.1 to the cathelicidin promoter (39). On the other hand, NaB-induced expression of cathelicidin in the Caco-2 cells may require VDR (40). The latter may result from differentiation of the colon epithelial cells by NaB treatment, which leads to major re-programming of gene expression, including significantly elevated cathelicidin levels (22,38,59,60).…”

Section: Discussionmentioning

confidence: 88%

“…Although researchers have described several NaB-responsive elements in the cathelicidin upstream regulatory region, efforts to identify specific trans-acting factors remain largely elusive (39). Recent reports have suggested a role for intracellular signaling molecules like ERK1/2, p38 MAPK, and transforming growth factor-␤1 kinase in NaB-mediated up-regulation of cathelicidin expression (38,40), and it is believed that histone deacetylase inhibition by NaB may also contribute to this effect (21,41). Several pathogenic microorganisms have been demonstrated to either up-or down-regulate cathelicidin in the mucosal ECs (5,22,42), and we have recently reported that bacterial exotoxins markedly suppress cathelicidin expression in the differentiated intestinal ECs in vitro and in vivo in a cAMP-dependent mechanism (43).…”

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confidence: 99%

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response elementbinding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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“…In epithelial cells, a variety of stimuli, including proinflammatory cytokines (17,22), microbial products (35), injury (15), endoplasmic reticulum (ER) stress (39), and butyrate, a short-chain fatty acid produced by resident colonic bacteria (41,44,44), have been shown to increase expression of hCAP18/LL-37. Recent studies also showed that vitamin D is an important regulator of hCAP18/LL-37 expression in epithelial cells and macrophages (56,58).…”

mentioning

confidence: 99%

Interleukin 13 Exposure Enhances Vitamin D-Mediated Expression of the Human Cathelicidin Antimicrobial Peptide 18/LL-37 in Bronchial Epithelial Cells

et al. 2012

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25D 3 ), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D 3 , and expression of hCAP18/LL-37, CYP27B1, the 1,25D 3 -inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D 3 to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D 3 -mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining.In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.T he upper respiratory tract is continuously exposed to pathogens. Epithelial cells function as the front line of host defense in the lung by preventing microbes from entering the bloodstream through the physical barrier provided by the tight junctions (24) and mucociliary clearance (36). Furthermore, epithelial cells secrete antimicrobial peptides and proteins (AMPs), such as lysozyme, lactoferrin and defensins, reactive oxygen and nitrogen species, interferons, and chemokines and cytokines, which eliminate pathogens directly or indirectly via attraction of phagocytic leukocytes (23, 55). In the lung, the AMP human cathelicidin (hCAP18/LL-37) is mainly secreted by neutrophils and epithelial cells, and the active peptide LL-37 displays broad-spectrum antimicrobial activity against bacteria, fungi, and viruses. It also contributes to microbial clearance by other mechanisms, including attraction of phagocytes (21, 48).In epithelial cells, a variety of stimuli, including proinflammatory cytokines (17, 22), microbial products (35), injury (15), endoplasmic reticulum (ER) stress (39), and butyrate, a short-chain fatty acid produced by resident colonic bacteria (41,44,44), have been shown to increase expression of hCAP18/LL-37. Recent studies also showed that vitamin D is an important regulator of hCAP18/LL-37 expression in epithelial cells and macrophages (56,58). Other studies showed that microbial exposures may also increase vitamin D-mediated expression of hCAP18/LL-37 through the induction of 25-hydroxy-vitamin D-1-␣-hydroxylase (CYP27B1), which converts 25-hydroxy-vitamin D 3 (25D 3 ) into the active 1,25(OH) 2 -vitaminD 3 (1,25D 3 ) (25,33).One of the well-established functions of vitamin D is mediating calcium ...

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“…Rivas-Santiago et al [83] reports that L-isoleucine upregulates HBD3 and HBD4 in mice. Furthermore, according to a study of Schwab et al [84], butyrate upregulates LL-37 mRNA. Estrogen can also increase AMPs including HBD1-3, LL-37, and RNase 7 in the urinary tract [85].…”

Section: Current and Potential Applications Of Amps In Utismentioning

confidence: 97%

Molecular Defense Mechanisms during Urinary Tract Infection

Choi

Chang

2015

Urogenit Tract Infect

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The urinary tract is a common site of infection. The complete mechanisms of urinary tract infection (UTI) are still unknown. In general, the strategies of the uropathogenic Escherichia coli are adherence, motility, iron acquisition, toxin, and evasion of host immunity. Host immune responses play a significant part in defense of UTI. Various antimicrobial peptides (AMPs) including defensins, cathelicidin, hepcidin, ribonuclease 7, lactoferrin, lipocalin, Tamm-Horsfall protein, and secretory leukocyte proteinase inhibitor help to prevent UTI by modulation of innate and adaptive immunity. Toll-like receptors (TLRs) play an important role of microorganism identification in innate immunity. Stimulation of TLRs on the cell membrane by ligand of bacteria triggers production of inflammatory chemokines, cytokines, and AMPs. These mechanisms are an attempt to defend the urinary tract against UTI. Keywords: Urinary tract infections; Molecular biology INTRODUCTIONUrinary tract infections (UTIs) are one of the most common infections that lead to out-patient and in-patient hospital visits. About 50% of women suffer from a UTI during their lifetime [1]. About 8 million female patients are treated annually for UTI alone in the United States and UTI recurs in about 30% of those who have normal function and anatomy of urinary tract [2]. UTI comprises acute uncomplicated cystitis and acute uncomplicated pyelonephritis. Acute uncomplicated cystitis results in dysuria, frequency, or urgency in healthy and non-pregnant women [3]. The diagnosis is aided by the presence of pyuria in voided urine and positive urine culture of at least 10 3 CFU/ml [3]. Acute uncomplicated pyelonephritis results in fever, costovertebral angle tenderness and flank pain in healthy and non-pregnant women and is similar to cystitis in lower urinary tract symptoms and laboratory analyses [4]. UTIs are commonly classified as uncomplicated and complicated. Complicated UTI occurs in patients with co-morbid illness or anatomic malformations of the urinary tract that can aggravate the risk of infection or therapeutic failure [5]. Complicating factors, for example, include the presence of catheter, obstructive uropathy, pregnancy, urinary stones, diabetes, and male gender. Most of them are main causes of pathogenesis in the host. Meanwhile, bacterial factors in UTI have been studied worldwide for decades with the main focus on Escherichia coli that is the most common pathogen in community acquired UTI [6]. Eighty percent to ninety percent of acute uncomplicated cystitis or acute uncomplicated pyelonephritis correspond to E. coli and the similar explanation applies to most complicated UTIs [7]. E. coli are classified into intestinal E. coli and extraintestinal E. coli. Most in vivo and clinical studies on extraintestinal E. coli related to UTI show that the specific adaptations of uropathogenic E. coli (UPEC)

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Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells

Cited by 56 publications

References 37 publications

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Interleukin 13 Exposure Enhances Vitamin D-Mediated Expression of the Human Cathelicidin Antimicrobial Peptide 18/LL-37 in Bronchial Epithelial Cells

Molecular Defense Mechanisms during Urinary Tract Infection

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