Abstract
The immune system of humans can be viewed as two parallel and communicating units, i.e. innate and adaptive immunity. Innate immunity provides a readily available, sometimes inducible, and less specific defense against potentially harmful pathogens of the environment. Adaptive immunity is slower, highly specific via production of immunoglobulins, and has an immunologic memory (e.g. as seen in vaccination). The mechanisms and functions of innate immunity have caught increasing attention in recent years. An important part, executing antimicrobial activity of innate immunity, is antimicrobial polypeptides (AMPs). Midkine shares several features with AMPs, including cationicity at physiological pH, heparin-binding properties, domains containing anti-parallel β-sheets (similar to the classical AMPs β-defensins), and expression by epithelial cells. In addition, midkine recruits and activates neutrophils, and acts as a growth factor, features shared with many AMPs. Recently, midkine was shown to have strong bactericidal activity against both gram-positive and gram-negative bacteria in vitro, an activity exerted through membrane-disrupting properties. Bactericidal activity was also found in the early midkine-orthologue Miple2 of Drosophila melanogaster, indicating conserved antibacterial activity in this small family of molecules during evolution. In this review, we discuss midkine in the context of innate immunity in general and particularly as an AMP.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ganz T (2003) The role of antimicrobial peptides in innate immunity. Integr Comp Biol 43:300–304
Diamond G, Beckloff N, Weinberg A et al (2009) The roles of antimicrobial peptides in innate host defense. Curr Pharm Des 15:2377–2392
Bernard JJ, Gallo RL (2011) Protecting the boundary: the sentinel role of host defense peptides in the skin. Cell Mol life Sci CMLS 68:2189–2199
Boman HG (2003) Antibacterial peptides: basic facts and emerging concepts. J Intern Med 254:197–215
Bulet P, Stocklin R, Menin L (2004) Anti-microbial peptides: from invertebrates to vertebrates. Immunol Rev 198:169–184
Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216
Elsbach P (2003) What is the real role of antimicrobial polypeptides that can mediate several other inflammatory responses? J Clin Invest 111:1643–1645
Lai Y, Gallo RL (2009) AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol 30:131–141
Niyonsaba F, Nagaoka I, Ogawa H et al (2009) Multifunctional antimicrobial proteins and peptides: natural activators of immune systems. Curr Pharm Des 15:2393–2413
Andersson E, Rydengard V, Sonesson A et al (2004) Antimicrobial activities of heparin-binding peptides. Eur J Biochem 271:1219–1226
Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250
Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–395
Harder J, Glaser R, Schroder JM (2007) Human antimicrobial proteins effectors of innate immunity. J Endotoxin Res 13:317–338
Cudic M, Otvos L Jr (2002) Intracellular targets of antibacterial peptides. Curr Drug Targets 3:101–106
Peschel A, Sahl HG (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol 4:529–536
Frick IM, Akesson P, Rasmussen M et al (2003) SIC, a secreted protein of Streptococcus pyogenes that inactivates antibacterial peptides. J Biol Chem 2278:16561–16566
Karlsson C, Eliasson M, Olin AI et al (2009) SufA of the opportunistic pathogen finegoldia magna modulates actions of the antibacterial chemokine MIG/CXCL9, promoting bacterial survival during epithelial inflammation. J Biol Chem 284:29499–29508
Muramatsu T (2002) Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem 132:359–371
Svensson SL, Pasupuleti M, Walse B et al (2010) Midkine and pleiotrophin have bactericidal properties: preserved antibacterial activity in a family of heparin-binding growth factors during evolution. J Biol Chem 285:16105–16115
Palmer RH, Vernersson E, Grabbe C et al (2009) Anaplastic lymphoma kinase: signalling in development and disease. Biochem J 420:345–361
Takada T, Toriyama K, Muramatsu H et al (1997) Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses: chemotactic activity to neutrophils and association with inflammatory synovitis. J Biochem 122:453–458
Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3:710–720
Iwasaki W, Nagata K, Hatanaka H et al (1997) Solution structure of midkine, a new heparin-binding growth factor. EMBO J 16:6936–6946
Goldman MJ, Anderson GM, Stolzenberg ED et al (1997) Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553–560
Englund C, Birve A, Falileeva L et al (2006) Miple1 and miple2 encode a family of MK/PTN homologues in Drosophila melanogaster. Dev Genes Evol 216:10–18
De Y, Chen Q, Schmidt AP et al (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192:1069–1074
Hoover DM, Boulegue C, Yang D et al (2002) The structure of human macrophage inflammatory protein-3alpha/CCL20. Linking antimicrobial and CC chemokine receptor-6-binding activities with human beta-defensins. J Biol Chem 277:37647–37654
Yang D, Chen Q, Hoover DM et al (2003) Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 74:448–455
Takada T, Kinkori T, Muramatsu H et al (1997) Midkine, a retinoic acid-inducible heparin-binding cytokine, is a novel regulator of intracellular calcium in human neutrophils. Biochem Biophys Res Commun 241:756–761
Maruyama K, Muramatsu H, Ishiguro N et al (2004) Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 50:1420–1429
You Z, Dong Y, Kong X et al (2008) Midkine is a NF-kappaB-inducible gene that supports prostate cancer cell survival. BMC Med Genomics 1:6
Krzystek-Korpacka M, Mierzchala M, Neubauer K (2011) Midkine, a multifunctional cytokine, in patients with severe sepsis and septic shock: a pilot study. Shock 35:471–477
Reynolds PR, Mucenski ML, Le Cras TD et al (2004) Midkine is regulated by hypoxia and causes pulmonary vascular remodeling. J Biol Chem 279:37124–37132
Peyssonnaux C, Cejudo-Martin P, Doedens A et al (2007) Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178:7516–7519
Rius J, Guma M, Schachtrup C et al (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453:807–811
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Funding: The work was supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Government Funds for Clinical Research (ALF), the foundations of Bergh, Greta & Johan Kock, and Alfred Österlund.
Conflict of interest: The authors have a patent application concerning the antimicrobial activity of midkine.
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Nordin, S.L., Egesten, A. (2012). Midkine: A Player in Innate Immunity. In: Ergüven, M., Muramatsu, T., Bilir, A. (eds) Midkine: From Embryogenesis to Pathogenesis and Therapy. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4234-5_3
Download citation
DOI: https://doi.org/10.1007/978-94-007-4234-5_3
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-4233-8
Online ISBN: 978-94-007-4234-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)