Significance of macrophage inflammatory protein-1 alpha (MIP-1alpha) in multiple myeloma.
Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a member of the CC chemokine family and is primarily associated with cell adhesion and migration. It is produced by myeloma (MM) cells and directly stimulates osteoclast formation and differentiation in a dose dependent way. MIP-1alpha protein levels were elevated in the bone marrow plasma of MM patients and correlated with disease stage and activity. MIP-1alpha was also elevated in the serum of myeloma patients with severe bone disease and correlated positively with bone resorption markers providing evidence for a causal role of MIP-1alpha in the development of lytic bone lesions in MM. MIP-1alpha has also been found to stimulate proliferation, migration and survival of plasma cells. Mice, which were inoculated with myeloma cells and treated with a monoclonal rat anti-mouse MIP-1alpha antibody, showed a reduction of both paraprotein and lytic lesions. In addition, MIP-1alpha enhanced adhesive interactions between myeloma and marrow stromal cells, increasing the expression of RANKL and IL-6, which further increased bone destruction and tumor burden. Myeloma patients with high MIP-1alpha serum levels have poor prognosis. The positive correlation between MIP-1alpha and beta(2)-microglobulin that has been observed in MM patients at diagnosis further supports the notion that MIP-1alpha is not only a chemokine with osteoclast activity function but is also implicated in myeloma growth and survival. Therefore, MIP-1alpha pathway may serve as a target for the development of novel anti-myeloma therapies.
Terpos
Evangelos
E
Department of Hematology, 251 General Airforce Hospital, Athens, Greece. e.terpos@imperial.ac.uk
Politou
Marianna
M
Viniou
Nora
N
Rahemtulla
Amin
A
D000818:Animals; D001847:Bone Diseases / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000097:blood / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D016019:Survival Analysis
D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse