Abstract
Defensins are important molecules in the innate immune system that eliminate infectious microbes. They also exhibit cytotoxicity against host cells in higher concentrations. The mechanisms by which hosts protect their own cells from cytotoxicity of defensins have been poorly understood. We found that the cytotoxicity of human β-defensin 3 (hBD3) against lung epithelial cells was dose-dependently attenuated by pulmonary surfactant protein A (SP-A), a collectin implicated in host defense and regulation of inflammatory responses in the lung. The direct interaction between SP-A and hBD3 may be an important factor in decreasing this cytotoxicity because preincubation of epithelial cells with SP-A did not affect the cytotoxicity. Consistent with in vitro analysis, intratracheal administration of hBD3 to SP-A(-/-) mice resulted in more severe tissue damage compared with that in WT mice. These data indicate that SP-A protects lung epithelium from tissue injury caused by hBD3. Furthermore, we found that the functional region of SP-A lies within Tyr(161)-Lys(201). Synthetic peptide corresponding to this region, tentatively called SP-A Y161-G200, also inhibited cytotoxicity of hBD3 in a dose-dependent manner. The SP-A Y161-G200 is a candidate as a therapeutic reagent that prevents tissue injury during inflammation.
Highlights
The mechanisms by which hosts protect their own cells from cytotoxicity of defensins have been poorly understood
We found that the cytotoxicity of human -defensin 3 against lung epithelial cells was dose-dependently attenuated by pulmonary surfactant protein A (SP-A), a collectin implicated in host defense and regulation of inflammatory responses in the lung
The important roles of Antimicrobial peptides (AMPs) in host defense have been reported in many studies, molecular mechanisms underlying the negative regulation to prevent overamplification of inflammation and tissue injury by AMPs are poorly understood
Summary
The mechanisms by which hosts protect their own cells from cytotoxicity of defensins have been poorly understood. Defensins are important molecules in the innate immune system that eliminate infectious microbes They exhibit cytotoxicity against host cells in higher concentrations. We found that the cytotoxicity of human -defensin 3 (hBD3) against lung epithelial cells was dose-dependently attenuated by pulmonary surfactant protein A (SP-A), a collectin implicated in host defense and regulation of inflammatory responses in the lung. In addition to microbicidal activities, these peptides play important roles in innate immune responses and wound healing. Understanding the mechanisms by which the host prevents tissue injury caused by AMPs will result in greater recognition of the therapeutic use of AMPs. Defensins are cationic AMPs displaying broad spectrum microbicidal activity against both bacteria and fungi. We focused on the effects of pulmonary collectins on the cytotoxic activity of defensins against lung epithelial cells. We report the protective role of SP-A against cytotoxicity of hBD3
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