Every day we encounter many potentially harmful microbes in our environment. The epithelial linings constitute an anatomical barrier protecting us and they also produce antimicrobial polypeptides (AMPs) that act as a chemical barrier. These AMPs are small and positively charged, killing a broad range of microbes rapidly. They can either be constitutively produced or rapidly induced when epithelial cells encounter pathogens or when an injury occurs. Midkine (MK) is a heparin-binding growth factor of 123 amino acids. It is composed of two domains with three anti-parallel β-sheets in each domain and five disulphide bonds stabilize the structure. We found that MK has both antibacterial as well as antifungal properties and exert these activities by disrupting the membranes of the microorganisms, resulting in leakage of intracellular contents. The antibacterial activity of MK is evolutionary conserved, originating in insects. The expression of MK is constitutive in the skin, but during inflammation the expression is increased and the concentrations found in vivo reach levels that are antibacterial. In the large airways, MK expression is also constitutive and may be responsible for a significant part of the antibacterial activity found in the air surface liquid covering the bronchial epithelium of the lungs. In patients with cystic fibrosis, a genetic disorder primarily affecting the ion-transport of the airway epithelium, the expression of MK is increased. These patients suffer from viscous mucus and chronic infections caused by bacteria, not least Pseudomonas aeruginosa. The antibacterial activity of MK was compromised because of the changed environment in the lungs, where both increased salt and a lowered pH decreased its antibacterial activity. Taken together, MK is a potent antimicrobial peptide with activity against several bacterial and fungal species. The expression is constitutive in the skin and the large airways during healthy conditions and during inflammation the expression is increased. Since bacterial resistance against conventional antibiotics is increasing, AMPs such as MK, may provide templates for the development of novel therapeutics strategies to combat disease where microbes are either the primary cause or cause exacerbations of chronic diseases as seen in cystic fibrosis.
Respiratory Medicine and Allergy, Antimicrobial polypeptides, Midkine, antibacterial, antifungal, innate immunity, epithelial surfaces
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Respiratory Medicine and Allergology, Lund University