THE CYTOKINE NETWORK OF WALLERIAN DEGENERATION - IL-10 AND GM-CSF

Wallerian degeneration (WD) is the inflammatory response of peripheral nerves to injury. Evidence is provided that granulocyte macrophage co lony stimulating factor (GM-CSF) contributes to the initiation and pro gression of WD by activating macrophages and Schwann, whereas IL-10 do wn-regulates WD by inhibiting GM-CSF production. A significant role of activated macrophages and Schwann for future regeneration is myelin r emoval by phagocytosis and degradation. We studied the timing and magn itude of GM-CSF and IL-10 production, macrophage and Schwann activatio n, and myelin degradation in C57BL/6NHSD and C57BL/6-WLD/OLA/NHSD mice that display normal rapid-WD and abnormal slow-WD, respectively. We o bserved the following events in rapid-WD. The onset of GM-CSF producti on is within 5 h after injury. Production is steadily augmented during the first 3 days, but is attenuated thereafter. The onset of producti on of the macrophage and Schwann activation marker Galectin-3/MAC-2 su cceeds that of GM-CSF. Galectin-3/MAC-2 production is up-regulated dur ing the first 6 days, but is down-regulated thereafter. The onset of m yelin degradation succeeds that of Galectin-3/MAG-2, and is almost com plete within 1 week. IL-10 production displays two phases. An immediat e low followed by a. high that begins on the fourth day, reaching high est levels on the seventh. The timing and magnitude of GM-CSF producti on thus enable the rapid activation of macrophages and Schwann that co nsequently phagocytose and degrade myelin. The timing and magnitude of IL-10 production suggest a role in down-regulating WD after myelin is removed. In contrast, slow-WD nerves produce low inefficient levels o f GM-CSF and IL-10 throughout. Therefore, deficient IL-10 levels canno t account for inefficient GM-CSF production, whereas deficient GM-CSF levels may account, in part, for slow-WD.