Direct and indirect stimulation of megakaryocytopoiesis by TAN-1511 A, a microbial lipopeptide.
TAN-1511 A, a microbial lipopeptide, stimulates granulocytopoiesis through the induction of various hematopoietic cytokines. The ability of synthetic TAN-1511 A to affect megakaryocytopoiesis was examined. TAN-1511. A augmented the activity of acetylcholine esterase (AChE), which is a cell-lineage marker enzyme of megakaryocytes in cultured murine bone marrow cells and enhanced megakaryocyte colony formation in fibrin clot culture. These effects were observed not only in the presence, but also in the absence of IL-3, which is a megakaryocyte colony-stimulating factor. The increase in AChE activity mediated by TAN-1511 A was blocked by anti-IL-6 but not anti-IL-3 or anti-GM-CSF neutralizing antibodies. RT-PCR analysis also showed that the remarkable induction of IL-6 was triggered by treatment with TAN-1511 A, while each message level of c-mpl ligand and c-mpl remained unchanged, suggesting that the IL-6 induced by the lipopeptide plays a role in enhanced megakaryocytopoiesis. TAN-1511 A also stimulated the proliferation of CMK86, a human megakaryoblastic cell line. This promoted growth was partially and additively affected by anti-IL-3, anti-IL-6, and anti-GM-CSF antibodies. TAN-1511 A slightly reduced the expression of GpIb and GpIIb/IL1a in CMK86 cells. The enhanced platelet recovery mediated by TAN-1511 A was also demonstrated in a model of myelosuppressive mice. These results suggest that TAN-1511 A directly affects megakaryocytopoiesis, and indirectly modulates megakaryocytopoiesis through the induction of cytokines such as IL-6.
Nishi
K
K
Discovery Research Laboratories II, Takeda Chemical Industries, Ltd, Ibaraki, Japan.
Horiguchi
T
T
Kawashima
F
F
Tanida
S
S
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004790:Enzyme Induction / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D055666:Lipopeptides; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology*
D005227:Fatty Acids; D007377:Interleukin-3; D055666:Lipopeptides; D009842:Oligopeptides; C095335:TAN 1511 A; D000110:Acetylcholinesterase