Glycoprotein 130 and c-kit signals synergistically induce thrombopoietin production by hematopoietic cells.
We have reported that simultaneous activation of glycoprotein (gp) 130 and c-kit signals by interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), and stem cell factor (SCF) promotes proliferation of human hematopoietic progenitor cells and their differentiation into erythroid, myelocytic, and megakaryocytic cells. We recently found that erythropoietin produced by erythroid progenitors stimulates erythropoiesis via gp130 and c-kit signals. Here we examined thrombopoietin (TPO) production by hematopoietic cells cultured with IL-6, sIL-6R, and SCF. Reverse transcription-polymerase chain reaction analysis indicated that hematopoietic cells generated from cord blood CD34+ cells with the 3 factors expressed a minor splice variant of TPO messenger RNA, P1 delta E2, which can be translated to TPO protein more efficiently than regularly spliced isoforms. The reduction in c-mpl, receptors for TPO, by antisense oligodeoxynucleotides suppressed the generation of erythroid, myelocytic, and pluripotent progenitors in suspension culture, plus colony formation of megakaryocytic progenitors in addition to these progenitors in clonal culture of cord blood CD34+ cells with IL-6, sIL-6R, and SCF. The addition of anti-human TPO antibody to the clonal culture also suppressed colony formation. These findings indicate that TPO production by hematopoietic cells stimulated by IL-6, sIL-6R, and SCF is involved in promoting their own growth.
Matsui
A
A
Department of Clinical Oncology, University of Tokyo, Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Sato
T
T
Maekawa
T
T
Asano
S
S
Nakahata
T
T
Tsuji
K
K
D015703:Antigens, CD / Q000494:pharmacology* / Q000502:physiology; D050822:Cytokine Receptor gp130; D004357:Drug Synergism; D005246:Feedback / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000502:physiology; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000494:pharmacology* / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction / Q000187:drug effects; D013926:Thrombopoietin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
D015703:Antigens, CD; C494199:IL6ST protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D050822:Cytokine Receptor gp130; C082218:MPL protein, human; D013926:Thrombopoietin; D019009:Proto-Oncogene Proteins c-kit