MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA MEDIATED GROWTH-INHIBITION INA HEMATOPOIETIC STEM-CELL LINE IS ASSOCIATED WITH INOSITOL 1,4,5-TRISPHOSPHATE GENERATION

Macrophage Inflammatory Protein-1 alpha (MIP-1 alpha) can inhibit the proliferation of multipotent haemopoietic cells. Using the FDCP-Mix A4 multipotent stem cell line, MIP-1 alpha was shown to inhibit IL-3 sti mulated cell cycling (assessed using the [H-3]-thymidine ''suicide'' a ssay). Furthermore MIP-1 alpha can inhibit IL-3-stimulated [H-3]-thymi dine incorporation in FDGP-Mix cells, with half maximal inhibition obs erved at 3 ng/ml MIP-1 alpha. Prostaglandin E(2), but not MIP-1 alpha was able to elevate cyclic AMP levels in FDCP-Mix A4 cells although bo th agents can cause growth inhibition. However, MIP-1 alpha addition r esulted in a pertussis-toxinin-sensitive increase in the level of the second messenger inositol 1,4,5 trisphosphate (Ins 1,4,5P(3)). This re sponse was both rapid (maximal at 5 seconds) and transient. A half max imal effect was observed at 5 ng/ml MIP-1 alpha and the dose dependenc y correlated with that for MIP-1 alpha mediated growth inhibition. A r apid increase in cytosolic Ca2+ levels was also observed in response t o MIP-1 alpha. Inositol lipid hydrolysis and an increase in cytosolic Ca2+ (signals normally associated with proliferation) may therefore be implicated in growth inhibitory mechanisms in multipotent cells.