Curcumin induces human cathelicidin antimicrobial peptide gene expression through a vitamin D receptor-independent pathway

ArticleinThe Journal of nutritional biochemistry 24(5) · July 2012with82 Reads
DOI: 10.1016/j.jnutbio.2012.04.002 · Source: PubMed
Abstract
The vitamin D receptor (VDR) mediates the pleiotropic biologic effects of 1α,25 dihydroxy-vitamin D(3). Recent in vitro studies suggested that curcumin and polyunsaturated fatty acids (PUFAs) also bind to VDR with low affinity. As potential ligands for the VDR, we hypothesized that curcumin and PUFAs would induce expression of known VDR target genes in cells. In this study, we tested whether these compounds regulated two important VDR target genes - human cathelicidin antimicrobial peptide (CAMP) and 1,25-dihydroxyvitamin D(3) 24-hydroxylase (CYP24A1) - in human monocytic cell line U937, colon cancer cell line HT-29 and keratinocyte cell line HaCaT. We demonstrated that PUFAs failed to induce CAMP or CYP24A1 mRNA expression in all three cell lines, but curcumin up-regulated CAMP mRNA and protein levels in U937 cells. Curcumin treatment induced CAMP promoter activity from a luciferase reporter construct lacking the VDR binding site and did not increase binding of the VDR to the CAMP promoter as determined by chromatin immunoprecipitation assays. These findings indicate that induction of CAMP by curcumin occurs through a vitamin D receptor-independent manner. We conclude that PUFAs and curcumin do not function as ligands for the VDR.
    • "However, high production cost and peptide instability limit direct use of HDPs as effective antibiotics alternatives in animals [1]. Recently, several nutrients have been found to be highly potent in augmenting HDP synthesis and enhancing disease resistance [11][12][13][14][15], suggesting a high-efficiency and low-cost strategy for antimicrobial therapy. Furthermore, because those compounds come from dietary source and have no direct interaction with pathogens they provoke no inflammatory response. "
    [Show abstract] [Hide abstract] ABSTRACT: Host defense peptides (HDPs) play a critical role in innate immunity. Specific modulation of endogenous HDP synthesis by dietary compounds has been regarded as a novel approach to boost immunity and disease resistance in animal production. 1,25-dihydroxy vitamin D3 (1,25D3) is well known as a powerful HDP inducer in humans, but limited information about the effect of 1,25D3 on HDPs in poultry is available. Here, we sought to examine whether 1,25D3 could stimulate avian β-defensin (AvBD) expression in chickens. We used chicken embryo intestinal epithelial cells (CEIEPCs) and peripheral blood mononuclear cells (PBMCs) to study the effect of 1,25D3 on the expression of AvBDs. We observed that 1,25D3 is able to up-regulate the expression of several AvBDs in CEIEPCs and PBMCs, whereas it increased the amounts of AvBD4 mRNA in CEIEPCs only in the presence of lipopolysaccharide (LPS). On the other hand, LPS treatment not only inhibited the expression of CYP24A1 but also altered the expression pattern of VDR in CEIEPCs. Furthermore, AvBDs were not directly regulated by 1,25D3, as cycloheximide completely blocked 1,25D3-induced expression of AvBDs. Our observations suggest that 1,25D3 is capable of inducing AvBD gene expression and is a potential antibiotic alternative through augmentation of host innate immunity as well as disease control in chickens.
    Full-text · Article · May 2016
    • "The gene encoding hCAP-18 contains three vitamin D receptor elements in its promoter region and is under regulation by various signaling pathways where multiple receptors are involved [55,56]. Ligand binding to the vitamin D receptor, triggers complexation with vitamin D receptor elements in the promoter region, initiating transcription of mRNA that translates into hCAP-18 precursor protein [57,58]. LL-37 is up-regulated under inflammatory conditions and is also specifically up-regulated in response to compounds like butyrate and vitamin D3 [59]. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochemical properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics.
    Full-text · Article · Jul 2015
    • "Using a luciferase reporter assay it was observed that induction of cathelicidin by CMN does not require Vitamin D response elements (VDRE). Further, a CHIP assay with CMN-treated U937 cells demonstrated that CMN did not increase VDR binding to cathelicidin promoter suggesting that CMN-induced human LL-37 expression occurs through a VDR-independent mechanism [37]. "
    [Show abstract] [Hide abstract] ABSTRACT: The emergence of antibiotic resistance seriously threatens our ability to treat many common and medically important bacterial infections. Novel therapeutics are needed that can be used alone or in conjunction with antibiotics. Cationic antimicrobial peptides (CAMPs) are important effectors of the host innate defense that exhibit broad-spectrum activity against a wide range of microorganisms. CAMPs are carried within phagocytic granules and are constitutively or inducibly expressed by multiple cell types, including epithelial cells. The role of histone modification enzymes, specifically the histone deacetylases (HDAC), in down-regulating the transcription of CAMP-encoding genes is increasingly appreciated as is the capacity of HDAC inhibitors (HDACi) to block the action of HDACs to increase CAMP expression. The use of synthetic and natural HDACi molecules to increase CAMPs on mucosal surfaces, therefore, has potential therapeutic applications. Here, we review host and pathogen regulation of CAMP expression through the induction of HDACs and assess the therapeutic potential of natural and synthetic HDACi based on evidence from tissue culture systems, animal models, and clinical trials.
    Full-text · Article · Mar 2015
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