Abstract
Antibacterial peptides of the innate immune system combat pathogenic microbes, but often have additional roles in promoting inflammation and as growth factors during tissue repair. Midkine (MK) and pleiotrophin (PTN) are the only two members of a family of heparin-binding growth factors. They show restricted expression during embryogenesis and are up-regulated in neoplasia. In addition, MK shows constitutive and inflammation-dependent expression in some non-transformed tissues of the adult. In the present study, we show that both MK and PTN display strong antibacterial activity, present at physiological salt concentrations. Electron microscopy of bacteria and experiments using artificial lipid bilayers suggest that MK and PTN exert their antibacterial action via a membrane disruption mechanism. The predicted structure of PTN, employing the previously solved MK structure as a template, indicates that both molecules consist of two domains, each containing three antiparallel beta-sheets. The antibacterial activity was mapped to the unordered C-terminal tails of both molecules and the last beta-sheets of the N-terminals. Analysis of the highly conserved MK and PTN orthologues from the amphibian Xenopus laevis and the fish Danio rerio suggests that they also harbor antibacterial activity in the corresponding domains. In support of an evolutionary conserved function it was found that the more distant orthologue, insect Miple2 from Drosophila melanogaster, also displays strong antibacterial activity. Taken together, the findings suggest that MK and PTN, in addition to their earlier described activities, may have previously unrealized important roles as innate antibiotics.
Highlights
The innate immune system is an ancient part of host defense and antimicrobial peptides (AMPs)2 are critical to execute its
Human MK and PTN Possess Antibacterial Activity—MK and PTN were investigated for possible antibacterial activity against a panel of pathogenic bacteria, i.e. the Gram-positive bacteria S. pyogenes and S. aureus as well as the Gram-negative bacteria, P. aeruginosa, and E. coli
The antibacterial activity was largely unaffected (Fig. 2A), except in the case of S. aureus incubated with PTN, where a dose-dependent decrease of the antibacterial activity by 23% was seen at 150 mM sodium chloride (Fig. 2B)
Summary
PRESERVED ANTIBACTERIAL ACTIVITY IN A FAMILY OF HEPARIN-BINDING GROWTH FACTORS DURING EVOLUTION*□S. Antibacterial peptides of the innate immune system combat pathogenic microbes, but often have additional roles in promoting inflammation and as growth factors during tissue repair. Midkine (MK) and pleiotrophin (PTN) are the only two members of a family of heparin-binding growth factors They show restricted expression during embryogenesis and are up-regulated in neoplasia. AMPs of the innate immune system serve additional purposes They can act as growth factors to promote tissue repair (e.g. promoting angiogenesis) and they can recruit and activate inflammatory cells [3]. This pluripotency is characteristic of important AMPs such as the cathelicidins, the antibacterial chemokines, and the defensins (4 – 8).
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