Myelosuppressive effects in vivo of purified recombinant murine macrophage inflammatory protein-1 alpha.
Purified recombinant murine macrophage inflammatory protein-1 alpha (rmuMIP-1 alpha), a cytokine with myelopoietic activity in vitro, was assessed in vivo by injection into C3H/HeJ mice for effects on proliferation (percentage of cells in S phase DNA synthesis of the cell cycle) and absolute numbers of granulocyte-macrophage, erythroid, and multipotential progenitor cells in the femur and spleen, and on nucleated cellularity in the bone marrow, spleen, and blood. rmuMIP-1 alpha rapidly decreased cycling rates (at 2 to 10 micrograms/mouse i.v.) and absolute numbers (at 5 to 10 micrograms/mouse i.v.) of myeloid progenitor cells in the marrow and spleen. These effects were dose- and time-dependent and reversible. Suppressive effects were noted within 3 to 24 h for cell cycling and absolute numbers of progenitor cells in the marrow and spleen, and by 48 h for circulating neutrophils. A study comparing the effects of i.v. injection of rmuMIP-1 alpha versus rmuMIP-1 beta, a biochemically similar molecule but with no myelosuppressive effects in vitro, demonstrated myelosuppression in vivo by rmuMIP-1 alpha, but not by rmuMIP-1 beta. The results suggest that rmuMIP-1 alpha has myelosuppressive activity in vivo and offers the possibility that it may be a useful adjunct to treatments involving cytotoxic drugs because of its reversible suppressive effects on normal progenitor cell cycling.
Maze
R
R
Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202.
Sherry
B
B
Kwon
B S
BS
Cerami
A
A
Broxmeyer
H E
HE
D000818:Animals; D001854:Bone Marrow Cells; D002453:Cell Cycle / Q000187:drug effects; D054407:Chemokine CCL4; D016207:Cytokines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D015846:Monokines / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology
D054407:Chemokine CCL4; D016207:Cytokines; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins