Beta-defensin 14 (Mus musculus)

Background: β-defensins are an excellent antimicrobial peptide against microbial infection in which dendritic cells (DCs) play a crucial role by improving the innate and adaptive immune defense. However, it is unclear whether BDs affect DC maturation. This work aimed to study the effects of mouse β-defensin-14 (MBD-14) on DC maturation. Methods: Via in vitro using mouse bone marrow DCs, the maturation of DCs was evaluated by cell morphological staining, flow cytometry, endocytosis assay, and allogeneic mixed lymphocyte reaction, respectively. And it was also assessed by in vivo establishing a mouse air-pouch model for flow cytometric determination, cytokine analysis, and histological staining. Additionally, CLI-095, an inhibitor of Toll-like receptor-4 (TLR-4), was used to determine whether TLR-4 is possibly involved in DC maturation. Results: It was found MBD-14 promoted DCs to form more filopodia and lamellipodia, increased the expression of DC maturation markers (CD40 and MHC-II), decreased their endocytic capacity, and enhanced T-cell proliferation. The analyses of the air-pouch exudates were consistent with the in vitro results of MBD-14 activating DCs. And when CLI-095 was applied, DC maturation was inhibited partly. Conclusions: This work demonstrates that MBD-14 can promote the maturation of DCs in which TLR-4 is possibly involved.

Searching the database for mouse homologs of the antimicrobial peptide human beta-defensin-3 (hBD-3) revealed highest identity (69%) to mouse beta-defensin-14 (mBD-14). Recombinant mBD-14 exhibited broad-spectrum, nanomolar microbicidal activity. Treatment of keratinocytes with gamma interferon or transforming growth factor alpha increased mBD-14 gene expression. These data suggest that mBD-14 is the functional ortholog of hBD-3.

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.