Mouse Beta-Defensin-14, an Antimicrobial Ortholog of Human Beta-Defensin-3

Hinrichsen, Kerstin; Podschun, Rainer; Schubert, Sabine; Schröder, Jens-Michael; Harder, Jürgen; Proksch, Ehrhardt

doi:10.1128/aac.01308-07

Cited by 52 publications

(56 citation statements)

References 19 publications

(27 reference statements)

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“…b-defensins like mBD14 are typically expressed by epithelial cells, but have also been detected in keratinocytes and cells of the myeloid lineage (8,22). Expression is either constitutive or regulated in response to bacterial challenge and proinflammatory cytokines in a tissue-specific manner (1,23).…”

Section: Discussionmentioning

confidence: 99%

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Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner

Röhrl

Huber

Koehl

et al. 2012

The Journal of Immunology

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β-defensins are known for their antimicrobial activity and belong to the molecular barrier of the innate immune system against invading pathogens. In addition, it has been shown that some members of the β-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses, mediated in part by the interaction with CCR6. We found that mouse β-defensin 14 (mBD14, Defb14), a newly identified member of the mouse β-defensin superfamily, is expressed in mouse fibrosarcoma tumor tissue. Tumor cells overexpressing mBD14 demonstrated enhanced solid tumor growth in syngeneic C57BL/6 mice concomitant with increased vascularization of these tumors. Furthermore, mBD14-overexpressing tumors demonstrated increased expression of proangiogenic MIP-2 (CXCL2) ex vivo. In contrast, vascular endothelial growth factor expression was not affected. Cellular analysis of tumor-infiltrating leukocytes revealed a significant increase of CCR6+ B220+ lymphocytes in solid tumors derived from mBD14-overexpressing tumor cells. Enhanced tumor growth of mBD14-overexpressing fibrosarcomas was abolished in CCR6-deficient mice, which was paralleled by decreased infiltration of CCR6+ B220+ lymphocytes, indicating the requirement of CCR6 expression on host cells. Previously, the interaction of activated, LTαβ+, lymphocytes with lymphotoxin β-receptor–expressing fibrosarcoma tumor cells has been identified as a new CXCL2-dependent proangiogenic pathway. Coexpression of a soluble lymphotoxin β-receptor:Ig fusion protein, an inhibitor of CXCL2-dependent angiogenesis, in mBD14-overexpressing fibrosarcoma tumor cells abolished enhanced solid tumor growth. Thus, we conclude that mBD14 expression by tumor-infiltrating host cells results in the chemoattraction of CCR6+ B220+ lymphocytes, which in turn initiates a proangiogenic pathway leading to enhanced angiogenesis and organized tumor tissue development.

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Section: Discussionmentioning

confidence: 99%

“…on the back of mice. Tumor area was measured by caliper from day 3 through day 22 after inoculation.…”

Section: Tumor Cellsmentioning

confidence: 99%

Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner

Röhrl

Huber

Koehl

et al. 2012

The Journal of Immunology

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“…To study what impact AMPs might have on the adaptive immune response, we selected mBD-14, the murine ortholog of hBD-3, sharing 69% identity (18). Human AMPs were recently found to be induced by UVR (6).…”

Section: T Cellsmentioning

confidence: 99%

Induction of Regulatory T Cells by a Murine β-Defensin

Navid

Boniotto

Walker

et al. 2012

The Journal of Immunology

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β-Defensins are antimicrobial peptides of the innate immune system produced in the skin by various stimuli, including proinflammatory cytokines, bacterial infection, and exposure to UV radiation (UVR). In this study we demonstrate that the UVR-inducible antimicrobial peptide murine β-defensin-14 (mBD-14) switches CD4+CD25− T cells into a regulatory phenotype by inducing the expression of specific markers like Foxp3 and CTLA-4. This is functionally relevant because mBD-14–treated T cells inhibit sensitization upon adoptive transfer into naive C57BL/6 mice. Accordingly, injection of mBD-14, comparable to UVR, suppresses the induction of contact hypersensitivity and induces Ag-specific regulatory T cells (Tregs). Further evidence for the ability of mBD-14 to induce Foxp3+ T cells is provided using DEREG (depletion of Tregs) mice in which Foxp3-expressing cells can be depleted by injecting diphtheria toxin. mBD-14 does not suppress sensitization in IL-10 knockout mice, suggesting involvement of IL-10 in mBD-14–mediated immunosuppression. However, unlike UVR, mBD-14 does not appear to mediate its immunosuppressive effects by affecting dendritic cells. Accordingly, UVR-induced immunosuppression is not abrogated in mBD-14 knockout mice. Together, these data suggest that mBD-14, like UVR, has the capacity to induce Tregs but does not appear to play a major role in UVR-induced immunosuppression. Through this capacity, mBD-14 may protect the host from microbial attacks on the one hand, but tame T cell-driven reactions on the other hand, thereby enabling an antimicrobial defense without collateral damage by the adaptive immune system.

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“…Analogous to LL-37, neutrophil-derived CRAMP displays effective S. aureus killing (19). Mouse ␤-defensin-3 and -14 correspond to human ␤-defensin-2 and -3, respectively (20,21). S. aureus cells treated with recombinant mBD-3 showed growth inhibition and morphological and structural changes, including delamination and perforation of the peripheral cell walls, porosity, and release of the cytoplasmic contents (22,23).…”

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confidence: 99%

Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

et al. 2016

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g Approximately 20% of the population is persistently colonized by Staphylococcus aureus in the nares. Th17-like immune responses mediated by the interleukin-17 (IL-17) family of cytokines and neutrophils are becoming recognized as relevant host defense mechanisms for resolution of S. aureus mucocutaneous infections. Since antimicrobial peptides are regulated by the IL-17 cytokines, we sought to determine the role of IL-17 cytokines in production of antimicrobial peptides in a murine model of S. aureus nasal carriage. We discovered that nasal tissue supernatants have antistaphylococcal activity, and mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus nasal colonization. IL-17A was found to be sufficient for nasal mBD-3 production ex vivo and was required for CRAMP, mBD-3, and mBD-14 expression in response to S. aureus colonization in vivo. These data were confirmed in a clinical study of nasal secretions in which elevated levels of the human forms of these antimicrobial peptides were found in nasal secretions from healthy human subjects when they were colonized with S. aureus but not in secretions from noncolonized subjects. Together, these data provide evidence for the importance of IL-17A regulation of antimicrobial peptides and IL-17F in the clearance of S. aureus nasal carriage.

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Mouse Beta-Defensin-14, an Antimicrobial Ortholog of Human Beta-Defensin-3

Cited by 52 publications

References 19 publications

Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner

Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner

Induction of Regulatory T Cells by a Murine β-Defensin

Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

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