Expression of the Antimicrobial Peptide, Human β-defensin 1, in Duct Cells of Minor Salivary Glands and Detection in Saliva

Sahasrabudhe, K.S.; Kimball, Janet R.; Morton, Thomas Hellman; Weinberg, Aaron; Dale, Beverly A.

doi:10.1177/00220345000790090601

Cited by 105 publications

(93 citation statements)

References 35 publications

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“…[7][8][9][10] Constitutive expression of antimicrobial peptides has previously been detected in various exocrine glands such as the human cathelicidin LL-37 in sweat glands, the cathelicidin CRAMP in murine salivary glands and ␤-defensins in human salivary glands. [21][22][23] Expression of human ␤-defensin-2 (hBD-2) mRNA in mammary glands was reported by Bals et al 24 in 1998 and recently other groups have found constitutive hBD-1 expression in mammary glandular tissue of nonlactating women as well as in breast tissue during lactation and in breast milk. 25,26 Our finding that hCAP18/LL-37 is expressed in breast cancer cells is novel.…”

Section: Discussionmentioning

confidence: 92%

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

Heilborn

Nilsson

Jimenez

et al. 2005

Intl Journal of Cancer

111

110

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Human cathelicidin antimicrobial protein hCAP18/LL-37 is an effector molecule of the nonspecific innate immune system. hCAP18/LL-37 is present in leukocytes and is expressed in skin and other epithelia, where it is upregulated in association with inflammation and injury. In addition, antimicrobial proteins including cathelicidins have been proposed to play a role in the nonspecific defense against tumors. To assess its potential role in tumor host defense, we investigated the expression of hCAP18/ LL-37 in a series of breast carcinomas. Unexpectedly, we found that hCAP18/LL-37 was strongly expressed in the tumor cells and not in the adjacent stroma. To test the hypothesis that hCAP18/ LL-37 may provide a growth advantage for the tumor cells, we treated human epithelial cell lines with synthetic biologically active LL-37 peptide and found a significant increase in cell proliferation. In addition, transgenic expression of hCAP18 in 2 different human epithelial cell lines resulted in increased proliferation of both cell types. These findings do not support the hypothesis that LL-37 has an antitumor effect, but rather suggest that hCAP18/LL-37 may promote tumor cell growth in breast cancer.

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Section: Discussionmentioning

confidence: 92%

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

Heilborn

Nilsson

Jimenez

et al. 2005

Intl Journal of Cancer

111

110

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“…hBD-2 was not detected in human parotid glands [24,34]. In contrast, hBD-1 mRNA is expressed in all human salivary glands and its peptides in duct cells of minor salivary glands as well as in saliva [34,35]. Since hBD-2 is more potent than hBD-1, overexpressing hBD-2 in human saliva appears to be a logical approach for oral infection control.…”

Section: Discussionmentioning

confidence: 99%

Mouse salivary glands and human β-defensin-2 as a study model for antimicrobial gene therapy: technical considerations

Yin¹,

Dang

Gazor³

et al. 2006

International Journal of Antimicrobial Agents

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Transduction of salivary glands with antimicrobial peptide genes has great potential for oral infection control. Our ultimate goal is to introduce antimicrobial peptide genes into salivary glands that secrete these peptides into saliva to control bacterial/fungal infection in the oral cavity. However, an animal study model to test this potential has not been established. Therefore, we determined to test (i) whether the potent antimicrobial peptide human β-defensin-2 (hBD-2) can be overexpressed in saliva after transduction of salivary glands and (ii) whether oral fungal infection can be developed in a NOD/SCID murine model. Lentiviral vector SIN18cPPTRhMLV bearing hBD-2 cDNA was introduced into SCID mouse submandibular glands via cannulation. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry or enzyme-linked immunosorbent assay (ELISA) were performed to detect hBD-2 expression in glands or in saliva. Candida albicans 613p was inoculated orally into SCID mice to establish oral candidiasis. Whilst expression of hBD-2 was detected in mouse salivary glands by RT-PCR and immunohistochemistry 1 day or 1 week following delivery of lentivirus, hBD-2 was not detected in saliva. There was recoverable C. albicans from the oral cavity and gastrointestinal tract 4 days to 4 weeks after infection, but there was no establishment of observable oral candidiasis in SCID mice under a stereomicroscope. Our data indicate that lentiviral vectors transduce mouse salivary glands, but not at a sufficient level to allow hBD-2 detection in saliva. Other vectors for gene transduction and additional treatment of SCID mice to establish oral candidiasis are needed in order to utilise mouse salivary glands to test antimicrobial gene therapy.

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“…Bacteria and cytokines IL-1 and TNFα upregulate HBD-2 expression in lung and skin epithelial cells [10,28] and induction of HBDs by these stimuli is differentially regulated involving multiple mechanisms [29]. Expression of HBDs in oral tissues has also been extensively studied [23,[30][31][32][33][34][35][36][37][38][39][40]. In gingival epithelium, variable expression levels of HBD-1, -2 or -3 are found in either healthy or diseased gingival tissues [41,42] Previously, we transduced a number of non-HBD-2-expressing cell lines to produce HBD-2 with the notion that these cells may become part of the innate defense mechanisms against infection [6,49].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Capacity of human β-defensin expression in gene-transduced and cytokine-induced cells

Yin¹,

Dang²,

Zhang³

et al. 2006

Biochemical and Biophysical Research Communications

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The purpose of this study was to determine the capacity of cells transduced with human β-defensins (HBDs) to express antimicrobial peptides, since sufficient expression level is required for effective antimicrobial activity. Retroviral vector pBabeNeo and lentiviral vector SIN18cPPTRhMLV (SIN18) carrying HBDs were utilized to transduce non-HBD-expressing cells such as fibroblasts or HBD-producing oral epithelial cells. We found that HBD-3 gene transfer to fibroblasts was possible not via retrovirus but by direct vector transfection. SIN18 had high transduction efficiencies (80.9-99.9%) and transduced cells expressed higher amounts of HBD-2 than those by pBabe-Neo. Primary human gingival epithelial cells (HGECs) expressed greater amounts of HBD-2 than primary fibroblasts after lentiviral transduction. Additionally, HBD-2 secretion from transduced HGECs cells was further increased when stimulated with IL-1 or TNFα. Our data indicate that while HBD-2 expression is limited in primary fibroblasts, its expression in HGECs may be maximized by gene transduction plus cytokine induction. KeywordsHBD-2; HBD-3; Lentiviral vectors; Retroviral vectors; IL-1; TNFα; Gingival epithelial cells Natural antimicrobial peptides have been considered as an alternative option for infection control due to the increasing resistance of microbes to conventional antibiotics. Because some potent antimicrobial peptides are encoded by single genes, the possibility of artificially delivering these genes into tissues/organs to augment innate immunity against infection or creating transgenic animals to produce antimicrobial peptides has been explored [1][2][3][4][5]. Subsequently, the term antimicrobial gene therapy has emerged [6] and engineered skin NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript models have been used to test the concept of antimicrobial gene therapy both in vitro and in vivo [7,8]. Human β-defensins (HBDs or DEFB) and cathelicidin LL37 are being actively used as study models for their potent ability to kill a broad spectrum of bacteria and fungi [6,7,[9][10][11][12][13], as well as to inhibit viral infections [14,15]. HBDs are expressed mostly in epithelia [11,12,[16][17][18][19][20][21][22][23][24]. Besides the cloned, sequenced, and well-characterized HBD-1, -2, -3, and -4, there appears to be at least 28 more HBDs existing based on the genomic surveys using computational search strategy [25][26][27]. Fourteen HBDs or DEFB gene transcripts (DEFB-1, -4, and DEFB-103 to -114) were investigated using reverse transcriptionpolymerase chain reaction (RT-PCR) to detect their expression in gingival keratinocytes and a selected few have been classified as constitutive or inducible [27].HBDs are considered to play an important role in epithelial defense mechanism and the regulation of their expression in diseased conditions is being actively investigated. Bacteria and cytokines IL-1 and TNFα upregulate HBD-2 expression in lung and skin epithelial cells [10,28] and induction of HBDs by these stimuli is...

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Expression of the Antimicrobial Peptide, Human β-defensin 1, in Duct Cells of Minor Salivary Glands and Detection in Saliva

Cited by 105 publications

References 35 publications

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

Mouse salivary glands and human β-defensin-2 as a study model for antimicrobial gene therapy: technical considerations

Capacity of human β-defensin expression in gene-transduced and cytokine-induced cells

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