Production of the Growth Factor Midkine by the Innate Antigen Presenting Cells and Its Functions

Midkine (MK) is a heparin binding growth factor that is involved in development, reproduction, repair, inflammation, innate immunity, control of blood pressure and angiogenesis. MK is strongly expressed during embryogenesis, especially in the mid-gestation period. In adults, significant MK expression is observed only in restricted sites such as the kidney, gut, epidermis of the skin, bronchial epithelium and B-lymphocytes, while MK expression is induced in many tissues after injury. MK enhances tumor progression and its mRNA expression is increased in various human diseases including carcinomas e.g. hepatocellular, esophageal, stomach, colon, breast and pancreatic carcinoma. MK has also been shown to be implicated in vascular endothelial cell and keratinocyte proliferation and survival as well as the survival of hepatocellular carcinoma cells and B cells. MK induces the migration of macrophages and glioblastoma cells and the differentiation of regulatory T cells (Treg). MK has the ability to promote liver regeneration. MK was also shown to be able to inhibit the infection with the Human Immunodeficiency Virus (HIV). Our preliminary results showed for the first time that MK is expressed by antigen presenting cells (APCs) that are differentiated from monocytes, i.e. macrophages and monocyte-derived dendritic cells (MDDCs), upon stimulation with lipopolysaccharides (LPS). Because MK is produced by these APCs and because of the multiple biological implications of MK, we hypothesize that professional innate APCs can induce endothelial cell and keratinocyte proliferation. In this study we aim to understand the function of MK produced by innate APCs. This will be done by: 1.investigating MK expression by the innate APCs (monocytes, macrophages and DCs) upon stimulation with TLR ligands or inflammatory cytokines. MK mRNA and protein will be measured in cells using real time PCR and in the supernatant using ELISA respectively. 2. The function of MK produced by innate APCs will be investigated by studying the effect of MK produced by innate APCs on vascular endothelial cells (HUVEC and HMVEC) and keratinocytes (HaCaT) proliferation, survival and signaling. This will be performed using flow cytometry and immunoblot techniques. Our study will investigate the production of MK by APCs and its function in Omani donors, which has never been done around the world. We will investigate the impact of MK produced by innate APCs on cellular mechanisms that concern ?12.7% of cancer patients in Oman and all patients with major injuries, infections, allergies and autoimmune diseases. Knowledge about the molecular mechanisms related to MK production may help in developing effective treatments against diseases in which MK plays a role.