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

Schrumpf, Jasmijn A.; Sterkenburg, M. A. J. A. Van; Verhoosel, Renate M.; Zuyderduyn, Suzanne; Hiemstra, Pieter S.

doi:10.1128/iai.06224-11

Cited by 50 publications

(42 citation statements)

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“…In this respect, at least four mechanisms are known to regulate 1, 25[OH] 2 D activity. These are production of the active 1α-hydroxylated hormone by CYP27B1 [11,31,36], generation of relatively inactive 24α-hydroxylated metabolites by the action of CYP24A1 [31], sequestration by vitamin D-binding protein (VDBP) [37] and expression levels of the VDR [38]. We were interested in the regulation of vitamin D modulation of DC function.…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, at least four mechanisms are known to regulate 1,25[OH] 2 D activity. These are production of the active 1α-hydroxylated hormone by CYP27B1 [11,31,36] concentrations required to induce cellular responses, but the concentration of VDBP that may operate at the level of tissue-resident macrophages or DCs is not known, and data from VDBP-null mice suggests that the presence or absence of VDBP does not appear to modulate vitamin D activity in vivo [39]. Therefore, we did not investigate the role VDBP in the present model, which requires further consideration in future studies.…”

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confidence: 99%

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Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

et al. 2014

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Keywords: CYP27B1 r CYP24A1 r DCs r Macrophages r Vitamin D Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe capacity of vitamin D metabolites to modulate macrophage and DC function has been subject to extensive research interest in light of the association of vitamin D deficiency with a broad spectrum of immunological and infectious diseases. This gives Correspondence: Dr. Mahdad Noursadeghi e-mail: m.noursadeghi@ucl.ac.uk way to the potential for vitamin D supplementation [1][2][3][4] or ex vivo conditioning of DCs with vitamin D for cell therapy strategies [5]. Vitamin D is synthesized from 7-dehydrocholesterol in the skin following exposure to ultraviolet B radiation and thermal isomerisation, or replenished by dietary intake. It is 25-hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D), which is in * These authors contributed equally to this work. Results 25[OH]D is not functionally activated during monocyte differentiation to immature DCsWe first compared the activation of 25[OH]D during monocyte differentiation into macrophages and immature DCs. Conventional cell culture media in this model are vitamin D deficient (Fig. 1A) (Fig. 1B). This was also associated with upregulation of the prototypic vitamin D-inducible gene cathelicidin (CAMP) in macrophages (Fig. 1C) (Fig. 1C). Importantly, upregulation of DC-SIGN during monocyte differentiation to DCs was not affected by the presence of 1,25[OH] 2 D (Fig. 1D) DCs show time-dependent increase in activation of 25[OH]D independent of CYP27B1 expression levelsWe confirmed previous observations [16] that expression of the vitamin D-activating hydroxylase CYP27B1 is significantly lower in DCs compared with MDMs at both transcript and protein levels ( Fig. 2A and B). In contrast, vitamin D receptor (VDR) expression was higher in DCs than MDMs ( Fig. 2A). Taken together, these data further support the hypothesis that 25[OH]D has no effect on DCs in the experiments described above, because of a failure to generate 1,25[OH] 2 D rather than an inability to respond to 1,25[OH] 2 D. We also confirmed that 24-h stimulation of DCs with LPS significantly increases transcript and protein levels of CYP27B1 ( Fig. 2B and C (Fig. 2D). However, there was no concomitant upregulation of CAMP (Fig. 2C) . Monocytes are typically differentiated to DCs over 4-7 days, therefore we considered the possibility that time in culture may confound comparisons between different studies. Interestingly, we did find 25[OH]D-dependent upregulation of CAMP gene expression in DCs that increased with time after at least 6 days in culture (Fig. 2E). This was not associated with any significant time-dependent increase in CYP27B1 expression ( DCs express truncated CYP27B1 transcriptsWe found that LPS stimulation was able to upregulate DC expression of CYP27B1 transcript to levels higher than that in MDMs ( Figs. 2A and C). However, the expression of CYP27B1 protein remains much lower in DCs compared with ...

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Section: Discussionmentioning

confidence: 99%

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Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

et al. 2014

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“…On the other hand, the Th2 cytokine IL-4 induces CYP24A1 expression which leads to the catabolism of 25(OH)D 3 and downregulation of CAMP expression (Edfeldt et al 2010 ). In contrast, the Th2 cytokine IL-13 enhances CAMP expression by 25(OH)D 3 due to increased CYP27B1 expression and synthesis of 1,25(OH) 2 D 3 (Schrumpf et al 2012 ). No effect is observed with IL-17 in monocytes, but in the presence of 1,25(OH) 2 D 3 , IL-17 enhances CAMP expression in human keratinocytes via activation of the Act1 and MEK/ERK pathway (Peric et al 2008 ).…”

Section: Cooperative Induction Of Antimicrobial Peptide Gene Expressimentioning

confidence: 99%

Antimicrobial Peptides

2016

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“…More than 100 years ago, it was also observed that sun exposure was an effective treatment for cutaneous tuberculosis (Niels Finsen received the Nobel Prize in 1903 for this discovery), which was later explained by the requirement of sun exposure for the synthesis of vitamin D . More recent discoveries have elucidated that vitamin D exerts many of its protective functions by increasing the secretion of LL‐37 . LL‐37 has a defined vitamin D dependent mechanism, in that adequate circulating concentrations of its hydroxylated form 25(OH)D are required for optimal cathelicidin production by macrophages, and costimulation of 25(OH)D and TLR ligands leads to the induction of cathelicidin and killing of intracellular pathogens .…”

Section: Relevance For Human Diseasementioning

confidence: 99%

The immediate protective response to microbial challenge

González‐Navajas

Corr

2014

Eur J Immunol

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The innate immune system detects infection and tissue injury through different families of pattern-recognition receptors (PRRs), such as Toll-like receptors. Most PRR-mediated responses initiate elaborate processes of signaling, transcription, translation, and secretion of effector mediators, which together require time to achieve. Therefore, PRRmediated processes are not active in the early phases of infection. These considerations raise the question of how the host limits microbial replication and invasion during this critical period. Here, we examine the crucial defense mechanisms, such as antimicrobial peptides or extracellular traps, typically activated within minutes of the initial infection phase, which we term the "immediate protective response". Deficiencies in different components of the immediate protective response are often associated with severe and recurrent infectious diseases in humans, highlighting their physiologic importance. Keywords: Antimicrobial response r Infection r Innate immunity IntroductionInfection activates the innate immune response through different families of germline-encoded pattern-recognition receptors (PRRs), among which the Toll-like receptors (TLRs) are the most studied. These PRRs are expressed on the cell membranes or in the cytosol of immune and other cells and respond to microbial signature compounds, known as pathogen-associated molecular patterns (PAMPs). As a result, an acute inflammatory/defense response is initiated that is able to target a wide range of microbial agents and/or infected cells.Interestingly, tissue injury caused by sterile insults, such as trauma or hypoxia, activates a similar early inflammatory response. One potential evolutionary explanation for these similarities is that tissue injury usually results in the disruption of physiological barriers followed by microbial invasion. Another possibility is that microbes can also cause cell necrosis, so responding to tissue injury may be an indirect way of detecting microbial invasion. Thus, the mammalian host has developed a system Correspondence: Dr. José M. González-Navajas e-mail: gonzalez_josnav@gva.es of endogenous warning signals that are constitutively available and are rapidly activated in the very early phase of both sterile and nonsterile inflammation. These warning signals are provoked by alarmins or danger-associated molecular patterns. Alarmins are multifunctional endogenous molecules of structural heterogeneity, such as ATP, high-mobility group protein B1, or heat shock proteins, that are passively released following nonapoptotic cell death or actively secreted by leukocytes and epithelial cells [1]. As potent inducers of inflammatory responses, alarmins contribute to the defense against pathogens and promote tissue repair, but excessive alarmin secretion is also associated with acute and chronic inflammatory conditions [2].Stimulation of immune cells by endogenous alarmins or microbial derived PAMPs evokes similar signaling cascades and activates similar transcription factors [3] that c...

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

Cited by 50 publications

References 60 publications

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

Antimicrobial Peptides

The immediate protective response to microbial challenge

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