Defensins as Anti-Inflammatory Compounds and Mucosal Adjuvants

Abstract

Human neutrophil peptide α-defensins and human β-defensins are small, well-characterized peptides with broad antimicrobial activities. In mixtures with microbial antigens, defensins attenuate proinflammatory cytokine responses by dendritic cells in culture, attenuate proinflammatory cytokine responses in the nasal fluids of exposed mice and enhance antibody responses in the serum of vaccinated mice. Although the exact mechanisms are unknown, defensins first start by binding to microbial antigens and adhesins, often attenuating toxic or inflammatory-inducing capacities. Binding is not generic; it appears to be both defensin-specific and antigen-specific with high affinities. Binding of defensins to antigens may, in turn, alter the interaction of antigens with epithelial cells and antigen-presenting cells attenuating the production of proinflammatory cytokines. The binding of defensins to antigens may also facilitate the delivery of bound antigen to antigenpresenting cells in some cases via specific receptors. These interactions enhance the immunogenicity of the bound antigen in an adjuvant-like fashion. Future research will determine the extent to which defensins can suppress early events in inflammation and enhance systemic antibody responses, a very recent and exciting concept that could be exploited to develop therapeutics to prevent or treat a variety of oral mucosal infections, particularly where inflammation plays a role in the pathogenesis of disease and its long-term sequelae.

Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1

“…Significantly hypermethylated genes in PD patients compared to controls were detected only in putamen but not in cortex DNA ("Online resource 2"): Defensin alpha 1 (DEFA1) and the checkpoint with forkhead-associated domain and RING-finger domain (CHFR) gene, coding for a mitotic checkpoint protein with tumor-suppressor functions [7,8]. In PD putamen, DEFA1 messenger RNA (mRNA) appeared down-regulated, but not significantly (mean±SD: …”

Human Defensins Facilitate Local Unfolding of Thermodynamically Unstable Regions of Bacterial Protein Toxins

“…Consequently, it should be considered that precipitation might arise from the defensin-potentiated exposure of otherwise hidden hydrophobic residues of the affected proteins followed by self-aggregation due to a hydrophobic effect. Therefore, it is plausible that various mechanisms of toxin inactivation by defensins can be derived from the ability of these peptides to promote local unfolding of the affected toxins, rendering them more immunogenic (Kohlgraf et al, 2010), more susceptible to proteolysis (present study), and more prone to aggregation (Lehrer et al, 2009) whether with itself or with hydrophobic surfaces of serum proteins. The latter is a possible mechanism of inactivation of nanomolar quantities of LF N ACD and LF N RID toxins complexed with PA in the presence of serum when toxins’ concentration (5 nM) is four orders of magnitude lower than the serum albumin concentration (~50–80 μM).…”

Human β-Defensin 2 Induces Extracellular Accumulation of Adenosine in Escherichia coli

“…Moreover, in addition to their antimicrobial activity, manifold immunomodulatory properties of defensins have been reported, and many of these reports describe direct effects on immune cells and cytokine expression (13-15). In some cases, the interaction of peptides with bacterial components is implicated in their immunomodulatory effects (16,17). In this context, the present study hypothesized that hBD-2 activity on E. coli could result in the generation of extracellular mediators with relevance for immunomodulation.…”