Regulation of colony-stimulating activity production from bone marrow stromal cells by the hematoregulatory peptide, HP-5.
It has been reported that the granulocyte-derived hematoregulatory pentapeptide, HP-5, and its dimer (HP-5b) have potent hematoregulatory properties. The proposed mechanism of action for HP-5b is synergy with colony-stimulating activity (CSA) resulting in enhanced myeloid colony formation in vitro. We now demonstrate that the effects of HP-5b on enhanced colony formation are indirect and mediated by an effect on CSA production by bone marrow stromal cells. Bone marrow stromal cell culture systems from mice, rats, and humans were used as target cells for the action of HP-5 monomer and dimer. Cell-free supernatants from these cultures were assayed for CSA in a murine granulocyte-macrophage colony-forming unit (CFU-GM) assay. Supernatants from stromal cell cultures pulsed for 1 h with HP-5b resulted in increased murine CFU-GM colony proliferation with an estimated half-maximal effective concentration (EC50) of 1-5 ng/ml. This increase in CFU-GM proliferation was neutralized by anti-macrophage colony-stimulating factor (anti-M-CSF) antibodies. The HP-5 monomer was without effect on constitutive CSA production by stromal cells, but it antagonized HP-5b-induced CSA production in a dose-responsive manner with an estimated half-maximal inhibitory concentration (IC50) of 0.2-0.4 ng/ml. The ability of HP-5 monomer to antagonize HP-5b induction of CSA appears specific in that HP-5 monomer failed to alter interleukin 1 (IL-1) or lipopolysaccharide (LPS)-induced stromal cell CSA production.
King
A G
AG
Department of Anti-Infectives, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Talmadge
J E
JE
Badger
A M
AM
Pelus
L M
LM
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006098:Granulocytes / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D011917:Rats, Inbred Lew
D003115:Colony-Stimulating Factors; D006131:Growth Inhibitors; D009842:Oligopeptides; C040758:hemoregulatory peptide 5b; D011761:Pyrrolidonecarboxylic Acid