Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1 alpha.
Macrophage inflammatory protein (MIP)-1 alpha has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that > 99.7% of recombinant murine (rm) MIP-1 alpha polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1 alpha that is active in vitro as a myelosuppressive factor. Polymerized MIP-1 alpha is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1 alpha. MIP-1 alpha could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1 alpha necessary for myelosuppression in vivo. C3H/HeJ mice were injected intravenously (i.v.) with monomeric rmMIP-1 alpha or control diluent and effects were evaluated on progenitor cells--multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)--as described in previous studies in which MIP-1 alpha concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1 alpha rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1 alpha than we previously reported, were dose-dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1 alpha was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1 alpha in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1 alpha as a myelosuppressive/myeloprotective agent.
Cooper
S
S
Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202-5121.
Mantel
C
C
Broxmeyer
H E
HE
D000818:Animals; D001854:Bone Marrow Cells; D002452:Cell Count; D002453:Cell Cycle; D054407:Chemokine CCL4; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D015672:Erythroid Precursor Cells / Q000166:cytology; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008809:Mice, Inbred C3H; D015846:Monokines / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
D054407:Chemokine CCL4; D016207:Cytokines; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins