Macrophage inflammatory protein-1 alpha mediated growth inhibition in a haemopoietic stem cell line is associated with inositol 1,4,5 triphosphate 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 1L-3 stimulated cell cycling (assessed using the [3H]-thymidine "suicide" assay). Furthermore, MIP-1 alpha can inhibit 1L-3-stimulated [3H]-thymidine incorporation in FDCP-Mix cells, with half maximal inhibition observed at 3 ng/ml MIP-1 alpha. Prostaglandin E2, but not MIP-1 alpha was able to elevate cyclic AMP levels in FDCP-Mix A4 cells although both agents can cause growth inhibition. However, MIP-1 alpha addition resulted in a pertussis-toxin-insensitive increase in the level of the second messenger inositol 1,4,5 triphosphate (Ins 1,4,5P3). This response was both rapid (maximal at 5 seconds) and transient. A half maximal effect was observed at 5 ng/ml MIP-1 alpha and the dose dependency correlated with that for MIP-1 alpha mediated growth inhibition. A rapid increase in cytosolic Ca2+ levels was also observed in response to 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.
Heyworth
C M
CM
Department of Experimental Haematology, Paterson Institute, Manchester, UK.
Pearson
M A
MA
Dexter
T M
TM
Wark
G
G
Owen-Lynch
P J
PJ
Whetton
A D
AD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D054407:Chemokine CCL4; D003114:Colony-Forming Units Assay; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D015846:Monokines / Q000494:pharmacology*; D037342:Pertussis Toxin; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D054407:Chemokine CCL4; D006131:Growth Inhibitors; D007377:Interleukin-3; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D010566:Virulence Factors, Bordetella; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA; D000242:Cyclic AMP; D037342:Pertussis Toxin; D015232:Dinoprostone; D002118:Calcium; D013936:Thymidine