Overexpression of human β-defensin-3 in oral dysplasia: Potential role in macrophage trafficking

Kawsar, Hameem I.; Weinberg, Aaron; Hirsch, Stanley; Venizelos, Andrea; Howell, Scott J.; Jiang, Bin; Jin, Ge

doi:10.1016/j.oraloncology.2008.10.016

Cited by 52 publications

(110 citation statements)

References 47 publications

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“…Furthermore, induction of angiogenesis factors by hBD-3 could contribute to tissue repair in some cases and may also exacerbate tumour growth in circumstances where hBD-3 expression may be increased in or near cancerous lesions. 5 Monocytes from HIV + donors display a variety of phenotypic and functional alterations. These cells appear to be activated in HIV disease as indicated by their increased expression of CD69 and HLA-DR 25,26 and are also less capable of responding to type I interferon stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of hBD-3 is observed in inflammatory microenvironments including psoriasis and oral carcinoma. 1,5 Because monocytes are chemoattracted by hBD-3 5,6 and can potentially migrate into inflamed tissues, 7 it is important to consider the functional effects of hBD-3 on these cells. Our previous studies identified Toll-like receptor 1/2 (TLR1/2) -dependent signalling as a mechanism by which hBD-3 could cause activation of these cells.…”

Section: Introductionmentioning

confidence: 99%

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Human β defensin‐3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV‐infected persons

et al. 2013

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Summary Human β defensin‐3 (hBD‐3) is an antimicrobial peptide with diverse functionality. We investigated the capacity of hBD‐3 and, for comparison, Pam3CSK4 and LL‐37 to induce co‐stimulatory molecules and chemokine expression in monocytes. These stimuli differentially induced CD80 and CD86 on the surface of monocytes and each stimulant induced a variety of chemokines including monocyte chemoattractant protein 1 (MCP‐1), Gro‐α, macrophage‐derived chemokine (MDC) and macrophage inflammatory protein 1β (MIP1β), while only hBD‐3 and Pam3CSK4 significantly induced the angiogenesis factor, vascular endothelial growth factor (VEGF). Human BD‐3 induced similar chemokines in monocyte‐derived macrophages and additionally induced expression of Regulated upon activation normal T‐cell expressed and presumably secreted (RANTES) in these cells. Comparison of monocytes from HIV+ and HIV– donors indicated that monocytes from HIV+ donors were more likely to spontaneously express certain chemokines (MIP‐1α, MIP‐1β and MCP‐1) and less able to increase expression of other molecules in response to hBD‐3 (MDC, Gro‐α and VEGF). Chemokine receptor expression (CCR5, CCR2 and CXCR2) was relatively normal in monocytes from HIV+ donors compared with cells from HIV– donors with the exception of diminished expression of the receptor for MDC, CCR4, which was reduced in the patrolling monocyte subset (CD14+ CD16++) of HIV+ donors. These observations implicate chemokine induction by hBD‐3 as a potentially important mechanism for orchestrating cell migration into inflamed tissues. Alterations in chemokine production or their receptors in monocytes of HIV‐infected persons could influence cell migration and modify the effects of hBD‐3 at sites of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human β defensin‐3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV‐infected persons

et al. 2013

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“…In addition to direct microbicidal effects of these polypeptides, it has become evident that certain members of the b-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses by interacting with the CC-chemokine receptor CCR6 (2,3). Furthermore, it has been shown that several b-defensins recruit monocytes and macrophages, which do not express CCR6 (4,5). Recent studies suggest CCR2 as the responsible receptor for CCR6-independent migration of leukocytes (6,7).…”

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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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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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“…[35][36][37]. Under pathological conditions, AMP levels can become upregulated and their overexpression has been correlated with clinical complications such as psoriasis, circulatory derangement in severe infectious diseases, chronic obstructive pulmonary disease, and tumorigenesis (11,(38)(39)(40). However, thus far, not much is known about whether the human host has established mechanisms that can counteract these deleterious side effects.…”

Section: Discussionmentioning

confidence: 99%

“…For example, LL37 and b-defensin 3 were able to lyse endothelial cells and erythrocytes in our experiments, and the addition of p33 was able to prevent this damage. Both AMPs (LL37 in form of its cathelicidin precursor) are stored in blood cells including neutrophils, monocytes, and thrombocytes, and can be released upon stimulation (40,41).…”

Section: Discussionmentioning

confidence: 99%

p33 (gC1q Receptor) Prevents Cell Damage by Blocking the Cytolytic Activity of Antimicrobial Peptides

Westman

Hansen

Olin

et al. 2013

The Journal of Immunology

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The innate immune system is the first line of defense against invading microbes. Its specificity relies a great deal on host pattern recognition molecules that sense pathogen-associated molecular patterns of the invading pathogen. However, full protection is not always guaranteed, and some early defense mechanisms involved in bacterial killing, such as the complement system, can also exert cytolytic activity against host cells. Although these cascades are tightly regulated, the host has to take additional precautions to prevent its cell destruction. In this study, we describe that p33, a negatively charged surface protein found on endothelial cells also known as gC1q receptor, protects host cells from a cytolytic attack by antimicrobial peptides (AMPs), such as LL37 and β-defensin 3. To this end, we characterized the interaction of p33 with AMPs by biochemical and functional means. Our data show that p33 forms a doughnut-shaped trimer that can bind up to three AMPs, and we identified a segment in p33 forming a β-sheet that mediates the binding to all AMPs. Moreover, our results show that p33 abolishes the lytic activity of AMPs at an equimolar ratio, and it protects endothelial cells and erythrocytes from AMP-induced lysis. Taken together, our data suggest a novel protective mechanism of p33 in modulating innate immune response by neutralizing cytotoxic AMPs at the host cell surface.

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Overexpression of human β-defensin-3 in oral dysplasia: Potential role in macrophage trafficking

Cited by 52 publications

References 47 publications

Human β defensin‐3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV‐infected persons

Human β defensin‐3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV‐infected persons

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

p33 (gC1q Receptor) Prevents Cell Damage by Blocking the Cytolytic Activity of Antimicrobial Peptides

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