GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR PRODUCED IN LESIONEDPERIPHERAL-NERVES INDUCES THE UP-REGULATION OF CELL-SURFACE EXPRESSION OF MAC-2 BY MACROPHAGES AND SCHWANN-CELLS

Peripheral nerve injury is followed by Wallerian degeneration which is characterized by cellular and molecular events that turn the degenera ting nerve into a tissue that supports nerve regeneration. One of thes e is the removal, by phagocytosis, of myelin that contains molecules w hich inhibit regeneration. We have recently documented that the scaven ger macrophage and Schwann cells express the galactose-specific lectin MAC-2 which is significant to myelin phagocytosis. In the present stu dy we provide evidence for a mechanism leading to the augmented expres sion of cell surface MAC-2. Nerve lesion causes nonneuronal cells, pri marily fibroblasts, to produce the cytokine granulocyte macrophage-col ony stimulating factor (GM-CSF). In turn, GM-CSF induces Schwann cells and macrophages to up-regulate surface expression of MAC-2. The propo sed mechanism is based on the following novel observations. GM-CSF mRN A was detected by PCR in in vitro and in vivo degenerating nerves, but not in intact nerves. The GM-CSF molecule was detected by ELISA in me dium conditioned by in vitro and in vivo degenerating peripheral nerve s as of the 4th h after injury. GMCSF activity was demonstrated by two independent bioassays, and repressed by activity blocking antibodies. Significant levels of GM-CSF were produced by nerve derived fibroblas ts, but neither by Schwann cells nor by nerve derived macrophages. Mou se rGM-CSF enhanced MAC-2 production in nerve explants, and up-regulat ed cell surface expression of MAC-2 by Schwann cells and macrophages, Interleukin-1 beta up-regulated GM-CSF production thus suggesting that injury induced GM-CSF production may be mediated by interleukin-1 bet a. Our findings highlight the fact that fibroblasts, by producing GM-C SF and thereby affecting macrophage and Schwann function, play a signi ficant role in the cascade of molecular events and cellular interactio ns of Wallerian degeneration.