Midkine in inflammation

Abstract

The 13 kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology.

Keywords: Leukocytes; cytokines; immunity..

Figure 1

Protein structure of MK. (a) MK protein structure is shown. MK consists of two domains with similar size connected by an interdomain (white box). Numbers indicate amino acid position within the protein. The heparin-binding sites consisting of basic amino acids are located in the C-terminal domain (green boxes) [20]. (b) Tertiary structure of the C-terminal domain of MK protein “taken from the protein data bank PDB via http://www.rcsb.org/pdb/explore.do?structureId=1MKC.” The C-terminal domain contains three β-strands (yellow structure). Heparin binding clusters consisting of basic amino acids (cluster 1: K79, R81, K102; cluster 2: K86, K87, R89 in human MK) are displayed as green dots. C62, C72, C94, and C104 represent highly conserved cysteine residues forming disulfide bonds (black lines) [20].

Figure 2

Sequence homologies of MK and PTN. (a) Amino acid sequence of human MK and murine MK as well as human MK and human PTN. Human and murine MK show 87% amino acid sequence identity; human MK and PTN share 50% sequence homology. ⋆ = residues identical in both sequences [–40]. (b) Web logos displaying sequence homology of human MK, murine MK, chicken MK, miple1, and human PTN in information bits [50]. A large overall height indicates strong conservation of the corresponding amino acid in that position; the height within the stack shows the relative frequency of the amino acid at that position. Cysteine residues (black circle) and basic amino acids (green circle) are highly conserved within different species of the MK family.