Vitamin D Induction of the Human Antimicrobial Peptide Cathelicidin in the Urinary Bladder

Hertting, Olof; Holm, Åsa; Lüthje, Petra; Brauner, Hanna; Dyrdak, Robert; Jonasson, Aino Fianu; Wiklund, Peter; Chromek, Milan; Brauner, Annelie

doi:10.1371/journal.pone.0015580

Cited by 121 publications

(131 citation statements)

References 35 publications

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“…Neutrophil release of the peptide ensures a rapid increase in the local concentration upon bacterial presence until epithelial production is increased for further protection (9). Expression can be increased by vitamin D (10). It is known that Camp Ϫ/Ϫ mice, lacking mCRAMP, the mouse homologue of human LL-37, have more E. coli bacteria attached to the bladder than wild-type mice, indicating an important role of this peptide in protection against urinary tract infections (7).…”

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confidence: 99%

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

Nielsen

Dynesen²,

Larsen³

et al. 2014

Infect Immun

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; Haslev Laegecenter, Haslev, Denmark c ; Laegehuset Ellemarksvej, Køge, Denmark d Cathelicidin (LL-37) and human ␤-defensin 1 (hBD-1) are important components of the innate defense in the urinary tract. The aim of this study was to characterize whether these peptides are important for developing uncomplicated Escherichia coli urinary tract infections (UTIs). This was investigated by comparing urinary peptide levels of UTI patients during and after infection to those of controls, as well as characterizing the fecal flora of participants with respect to susceptibility to LL-37 and in vivo virulence. Forty-seven UTI patients and 50 controls who had never had a UTI were included. Participants were otherwise healthy, premenopausal, adult women. LL-37 MIC levels were compared for fecal E. coli clones from patients and controls and were also compared based on phylotypes (A, B1, B2, and D). In vivo virulence was investigated in the murine UTI model by use of selected fecal isolates from patients and controls. On average, UTI patients had significantly more LL-37 in urine during infection than postinfection, and patient LL-37 levels postinfection were significantly lower than those of controls. hBD-1 showed similar urine levels for UTI patients and controls. Fecal E. coli isolates from controls had higher LL-37 susceptibility than fecal and UTI E. coli isolates from UTI patients. In vivo studies showed a high level of virulence of fecal E. coli isolates from both patients and controls and showed no difference in virulence correlated with the LL-37 MIC level. The results indicate that the concentration of LL-37 in the urinary tract and low susceptibility to LL-37 may increase the likelihood of UTI in a complex interplay between host and pathogen attributes.

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confidence: 99%

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

Nielsen

Dynesen²,

Larsen³

et al. 2014

Infect Immun

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“…Recent data show that other extrarenal tissues, such as the skin, prostate, lung, and gastrointestinal tract, but also macrophages and monocytes, express CYP27B1 locally (25,33,42), indicating that vitamin D exerts its actions beyond bone mineralization and could play a role in pathological conditions. In bronchial epithelial cells, 25D 3 is converted by the locally expressed CYP27B1 into its active metabolite, 1,25D 3 , which binds the vitamin D receptor (VDR) (25,28). Subsequently, the 1,25D 3 -VDR complex binds to the retinoic X receptor, moves to the nuclei, and binds to vitamin D response elements present in the promoter regions of genes important for recognition and defense against microbes, such as those encoding hCAP18/LL-37, human ␤-defensins 2 (hBD-2), NGAL, and CD14 (34,43,56).…”

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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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“…Recent studies have indicated that vitamin D plays a vital role in modulating the host immune response to infection. For example, vitamin D can stimulate production of antimicrobial peptides (AMPs) such as α-defensins, β-defensins, and cathelicidin [14,15]. Aside from their direct microbicidal role, AMPs modulate many other immune processes, including mast cell degranulation, cell differentiation, vascular permeability, and the process of antigen presentation [16,17].…”

Section: Discussionmentioning

confidence: 99%

Serum 25-hydroxyvitamin D status in pregnant women with chronic hepatitis B virus infection

Gao

Wang

et al. 2016

J Infect Dev Ctries

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Introduction: Maternal 25-hydroxyvitamin D [25(OH)D] deficiency has a negative influence on the health of the mother and the developing fetus. The aim of this study was to assess serum 25(OH)D status and its relationship to virologic and biochemical parameters in pregnant women with chronic hepatitis B virus (HBV) infection. Methodology: Serum 25(OH)D levels among 142 pregnant women with chronic HBV infection and 251 healthy pregnant women were measured using enzyme-linked immunosorbent assay. Results: The mean ± SD values for serum 25(OH)D levels were 13.63 ± 5.5 ng/mL in healthy pregnant women and 12.05 ± 3.3 ng/mL in pregnant women with chronic HBV infection (p < 0.01). Serum 25(OH)D levels were associated with seasonal variation in healthy pregnant women (p = 0.01); however, similar results were not observed in pregnant women with chronic HBV infection (p = 0.10). Furthermore, multivariate analysis indicated that only ALT level was independently associated with severe vitamin D deficiency (p = 0.01). A significant positive correlation was found between serum 25(OH)D level and ALT level in pregnant women with chronic HBV infection (r = 0.32; p < 0.001). Conclusions: Vitamin D levels were lower in pregnant women with chronic HBV infection compared with healthy pregnant women. Vitamin D supplementation can be routinely recommended for pregnant women in China.

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Vitamin D Induction of the Human Antimicrobial Peptide Cathelicidin in the Urinary Bladder

Cited by 121 publications

References 35 publications

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

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

Serum 25-hydroxyvitamin D status in pregnant women with chronic hepatitis B virus infection

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