From top to bottom: midkine and pleiotrophin as emerging players in immune regulation

Abstract

Cytokines are pivotal in the generation and resolution of the inflammatory response. The midkine/pleiotrophin (MK/PTN) family of cytokines, composed of just two members, was discovered as heparin-binding neurite outgrowth-promoting factors. Since their discovery, expression of this cytokine family has been reported in a wide array of inflammatory diseases and cancer. In this minireview, we will discuss the emerging appreciation of the functions of the MK/PTN family in the immune system, which include promoting lymphocyte survival, sculpting myeloid cell phenotype, driving immune cell chemotaxis, and maintaining hematopoiesis.

Keywords: cytokines; hematopoiesis; lymphoid cells; myeloid cells.

Figure 1.. Known functions of MK/PTN signaling through their receptors.

Syndecans: Although MK/PTN binds to Sdc 1, 2, and 4, the downstream effectors are unknown. PTN binding to Sdc3 promotes neurite outgrowth and migration [37, 38]. RPTP-β: MK/PTN binding to RPTP-β promotes B cell survival, hematopoiesis, neurite outgrowth, and migration [39, 42]. Integrins: MK can directly interact with α4β1 and α6β1 integrins [50], whereas PTN interacts with αvβ3 [51]; those interactions promote cell migration [50, 51, 58]. Lrp1: MK interacts with α4β1 and α6β1, whereas PTN interacts with αvβ3. Lrp1 drives macrophage/neutrophil haptotaxis [140]. Nucleolin: MK/PTN interaction with nucleolin promotes MK/PTN nuclear localization, cell migration, and survival [58, 67, 68].