Neural regenerative mechanism of granulocyte-macrophage colony stimulating factor (GM-CSF)

초록

Abstract: Granulocyte macrophage colony stimulating factor (GM-CSF) is a potent hematopoietic cytokine that stimulates stem cell proliferation in the bone marrow and inhibits apoptotic cell death in leukocytes. However, GM-CSF has recently been reported to play a role in the nervous system. In our previous studies, GM-CSF induced proliferation of neural progenitor cells in vitro and improved behavioral recovery and histological regeneration of neural tissues in spinal cord injury (SCI) or brain ischemic injury model of rats. In other study, GM-CSF has been also reported to show neurotropic activity. This study investigated if GM-CSF has neural regenerative activity by directly activating the regenerative signals and inducing the expression of related genes. PC12 cells were cultured in RPMI medium and treated with GMCSF at PBS. In the phase contrast images and immunohistochemical staining for neurofilament (NF), GM-CSF was shown to induce axonal sprouting of PC12 cells. GM-CSF also increased the expression of regeneration-related genes such as GAP43, SPRR1A and NF-M in RT-PCR and Western blot analyses. Their expression was also observed to increase in a rat SCI model using a vascular clip (T8~10 levels) by intraperitoneal injection of GM-CSF (once, 20 ug). When signal transduction pathways involved was also analyzed in PC12 cells, Jak2-STAT3 and Jak2-PKACREB pathways were shown to be responsible for the GM-CSF effect. Cooperative effect of STAT3 and CREB on the expression of the regeneration-related genes was also revealed by the reporter analysis and EMSA. This study demonstrated that GM-CSF has a potential to induce axonal regeneration by activating STAT3 and CREB signal pathways. To our knowledge, this is the first report to show the neural regeneration activity and underlying molecular mechanism of GM-CSF.