Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection

Sawamura, Daisuke; Goto, Maki; Shibaki, Akihiko; Akiyama, Masashi; McMillan, James R.; Abiko, Yoshihiro; Shimizu, Hiroshi

doi:10.1038/sj.gt.3302472

Cited by 49 publications

(48 citation statements)

References 19 publications

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“…To date, no report has shown that non-HBD-3-expressing cells (mammalian system) produce HBD-3 after gene transduction. Only HBD-3-expressing cells (skin epithelial cell line HaCaT) have been transduced with HBD-3 and secrete functional HBD-3 reported by Carretero et al [7] and Sawamura et al [8]. However, it is not clear in those reports what the levels of HBD-3 production per unit number of cells per time period are.…”

Section: Discussionmentioning

confidence: 69%

“…NIH-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].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 69%

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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“…22 A similar study using a human b-defensin-3 (HBD-3) plasmid construct has demonstrated significant antimicrobial activity in patients when transfected skin ulcers were analyzed. 23 Biopsies from transplanted epidermal sheets showed 2.5-times higher levels of HBD-3 transcripts than those of control skin. 23 In mouse models of wound healing, electroporation has been successfully introduced to enhance transfection.…”

Section: Suitable Animal Models Have Demonstrated Proof Of Concept Fomentioning

confidence: 99%

“…23 Biopsies from transplanted epidermal sheets showed 2.5-times higher levels of HBD-3 transcripts than those of control skin. 23 In mouse models of wound healing, electroporation has been successfully introduced to enhance transfection. In a recent study, keratinocyte growth factor (KGF) has been delivered to an excisional wound model via naked DNA injection with subsequent electroporation.…”

Section: Suitable Animal Models Have Demonstrated Proof Of Concept Fomentioning

confidence: 99%

Gene therapy progress and prospects: the skin – easily accessible, but still far away

Hengge

2006

Gene Ther

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Significant progress has been made in corrective gene therapy of inherited skin diseases. This includes advances in vector technology, targeted gene expression, gene replacement, and the availability of appropriate animal models for a variety of candidate diseases. In addition, an increased understanding of the uptake and trafficking mechanisms inside keratinocytes has evolved. Topical application facilitates DNA vaccination through the skin, albeit clinical benefits have not yet materialized. However, the translation into clinical trials has only been partially mastered. The latter and the control of immune responses represent challenges for the research community.

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“…HBD-3 was further detected in many other tissues such as heart, liver, fetal thymus, and placenta cells (103,105,106). In skin, hBD-3 is stored like hBD-2 in lamellar bodies of keratinocytes (107). TNF-α, transforming growth factor (TGF)-α, insulin-like growth factor 1 (IGF-1), Toll-like receptor 5, IL-1β, IFN-γ, TGF-α, and IGF-1 as well as various bacteria play an important role in activation of the synthesis of hBD-3 (103,108).…”

Section: Host Defense (Antimicrobial) Peptidesmentioning

confidence: 99%

Host Defense Peptides in Wound Healing

Steinstraesser

Koehler

Jacobsen

et al. 2008

Mol Med

141

112

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Host defense peptides are effector molecules of the innate immune system. They show broad antimicrobial action against gram-positive and -negative bacteria, and they likely play a key role in activating and mediating the innate as well as adaptive immune response in infection and inflammation. These features make them of high interest for wound healing research. Nonhealing and infected wounds are a major problem in patient care and health care spending. Increasing infection rates, growing bacterial resistance to common antibiotics, and the lack of effective therapeutic options for the treatment of problematic wounds emphasize the need for new approaches in therapy and pathophysiologic understanding. This review focuses on the current knowledge of host defense peptides affecting wound healing and infection. We discuss the current data and highlight the potential future developments in this field of research.

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Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection

Cited by 49 publications

References 19 publications

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

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

Gene therapy progress and prospects: the skin – easily accessible, but still far away

Host Defense Peptides in Wound Healing

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