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Biologic and structural differences of thrombopoietic growth factors

SEMINARS IN HEMATOLOGY 2000年第2期37卷 19-27页

作者： Begley, CG Basser, RL Western Australian Inst Med Res Perth WA 6000 Australia Ctr Dev Canc Therapeut Parkville Vic Australia Royal Melbourne Hosp Dept Clin Haematol & Med Oncol Melbourne Vic Australia Royal Melbourne Hosp Rotary Bone Marrow Res Labs Melbourne Vic Australia Walter & Eliza Hall Inst Med Res Parkville Vic Australia Ludwig Inst Canc Res CH-1066 Epalinges Switzerland

The search for a thrombopoietic agent has resulted in the identification of numerous cytokines and growth factors with thrombopoietic activity. However, with the exception of interleukin (IL)-11 and thrombopoietin (TPO), the megakaryopoietic activity of most of these molecules has not produced clearly identifiable clinical benefits. Despite the relatively modest effect of IL-11 on megakaryocyte and platelet production in vitro and in vivo, it does reduce the need for platelet transfusions in specialized clinical settings. In contrast, the c-Mpl ligand TPO has been shown to be a potent stimulator of megakaryocyte and platelet production both in vitro and in vivo. Clinical studies are being conducted with two different preparations of the c-Mpl ligand: recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). A recombinant form of the complete human molecule, rhTPO is glycosylated and produced in mammalian cells. PEG-rHuMGDF consists of only the receptor-binding domain linked to a polyethylene glycol (PEG) moiety and is generated in Escherichia coli. Although c-Mpl ligands are still being evaluated, preliminary evidence indicates that these molecules can elevate platelet counts and may be useful in a range of clinical contexts. This report discusses aspects of the biology behind the clinical actions of IL-11 and the c-Mpl ligands.

关键词：血小板/细胞学血小板/药物作用细胞因子类/血液细胞因子类/药理学细胞因子类/生理学生长物质/血液生长物质/药理学生长物质/生理学血细胞生成/药物作用白细胞介素11/血液白细胞介素11/药理学白细胞介素11/生理学巨核细胞/细胞学巨核细胞/药物作用血小板生成素/血液血小板生成素/药理学血小板生成素/生理学动物人类

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Dose-dependent effects of recombinant human interleukin-11 on contractile properties in rabbit 2,4,6-trinitrobenzene sulfonic acid colitis

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 983-990页

作者： Depoortere, I Thijs, T Van Assche, G Keith, JC Peeters, TL Univ Leuven Dept Pathophysiol Ctr Gastroenterol Res Louvain Belgium Genet Inst Inc Andover MA USA

We studied the effect of recombinant human interleukin-11 (rhIL-11), a cytokine with protective effects against injury to the intestinal mucosa, on inflammatory changes in the muscle layers of the gut, in rabbits with colitis. A single dose of rhIL-11 (4, 40, or 720 mu g/kg) was given 1 h before colitis was induced with 135 mg/kg 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a continuous s.c. administration of 4, 40, or 720 mu g/kg . day rhIL-11 or saline for 5 days. Colitis affected mucosal architecture, general mechanical properties (passive tension increased with 12.3 g/mm(2), optimal stretch decreased with 26%), and collagen content (decreased from 366 +/- 25 to 237 +/- 13 mu g/mg of protein). Changes in passive tension and collagen content were normalized by the highest and lowest dose of rhIL-11, respectively, but neither dose could normalize the optimal stretch. Colitis also decreased maximal contractile tension in response to acetylcholine (ACh), motilin, substance P (SP), K+, and prostaglandin E-2 but this was normalized with 40 mu g/ kg day (motilin, SP) and 720 mu g/kg . day (ACh, K+) rhIL-11 but not for prostaglandin E-2. For motilin and SP, receptor density was decreased in colitis and normalized in treated rabbits. Colitis also increased the contractile potency toward ACh, an effect already reversed by rhIL-11, 4 mu g/kg . day. In conclusion, rhIL-11 partially normalizes disturbed tension generation in experimental colitis. The use of this cytokine in the treatment of irritable bowel disease may contribute to the restoration of motor dysfunction.

关键词：乙酰胆碱/药理学结肠炎/化学诱导结肠炎/病理学结肠炎/病理生理学结肠/药物作用结肠/病理学结肠/病理生理学地诺前列酮/药理学剂量效应关系药物白细胞介素11/药理学促胃动素/药理学肌收缩/药物作用肌平滑/药物作用氯化钾/药理学受体胃肠激素/代谢受体神经激肽1/代谢受体神经肽/代谢重组蛋白质类/药理学逆转录聚合酶链反应 P物质/药理学拉伸强度三硝基苯磺酸动物女(雌)性男(雄)性兔

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Recombinant human interleukin-11 synergizes with steel factor and interleukin-3 to promote directly the early stages of murine megakaryocyte development in vitro

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BLOOD 2000年第2期95卷 503-509页

作者： Weich, NS Fitzgerald, M Wang, AL Calvetti, J Yetz-Aldape, J Neben, S Turner, KJ Genet Inst Dept Tissue Growth & Repair Cambridge MA 02140 USA Genet Inst Dept Immunol Cambridge MA 02140 USA

The authors studied the role that interleukin (IL)-11 plays during the early stages of megakaryocyte (MK) development by investigating its in vitro effects on cell subpopulations enriched for bone marrow primitive progenitor cells and early and late committed progenitor cells. Progenitor subpopulations were isolated from bone marrow of normal or 5-fluorouracil (5FU)-treated mice and separated by sorting based on the surface antigens Sca-1, c-kit, and CD34. Functional analysis of the cell subpopulations, 5FU Lin(-)Sca-1(+)c-kit(+) or normal bone marrow (NBM) Lin(-)Sca-1(+)c-kit(+)CD34(-)cells, indicated that exposure of these cells to recombinant human (rh)IL-11 in combination with steel factor (SF) stimulates the formation of colonies in methylcellulose and their proliferation in single cell-containing liquid cultures. Kinetic studies of MK progenitor generation, in response to SF and rhIL-11, demonstrated that a significant number of the progenitors produced are committed to the MK lineage. RhlL-11 also synergized with both SF and IL-3 to stimulate MK colony growth from NBM Lin(-)Sca-1(+)c-kit(+) cells (early progenitors) and NBM Lin(-)Sca-1(-)c-kit(+) cells (committed late progenitors). In the presence of IL-3, NBM, Lin(-)Sca-1(-)c-kit(+) cells responded more strongly to rhIL-11 than SF. Consistent with these results is the observation that IL-11 receptor alpha chain mRNA is present in all the progenitor cells from which the MKs are derived. This cell culture and RNA analysis suggest that murine bone marrow primitive progenitor cells and early and late progenitor cells are direct targets of rhIL-11 and that rhIL-11 has the potential to promote megakaryocyte development at several very early stages. (Blood, 2000;95:503-509) (C) 2000 by The American Society of Hematology.

关键词：抗原 CD34/分析抗原 Ly/分析骨髓细胞/细胞学细胞分化/药物作用细胞分离/方法细胞培养的药物协同作用基因表达调控/免疫学造血干细胞/细胞学造血干细胞/药物作用白细胞介素11/药理学白细胞介素11受体α亚单位白细胞介素3/药理学巨核细胞/细胞学巨核细胞/药物作用膜蛋白质类/分析小鼠近交C57BL 原癌基因蛋白质c-kit/分析受体白细胞介素/遗传学受体白细胞介素11 重组蛋白质类/药理学干细胞因子/药理学动物女(雌)性人类小鼠

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Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro

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BLOOD 2000年第5期96卷 1748-1755页

作者： Bryder, D Jacobsen, SEW Univ Lund Hosp Inst Lab Med Stem Cell Lab S-22185 Lund Sweden

Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-ll have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of Introduction HSC fate by different cytokines, However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all Lin(-)Sca-1(+)kit(+) bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-ll revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-ll, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3. (C) 2000 by The American Society of Hematology.

关键词：抗原 CD34/血液抗原 Ly/血液细胞分裂/药物作用细胞谱系细胞培养的流式细胞术造血干细胞移植造血干细胞/化学造血干细胞/细胞学造血干细胞/药物作用白细胞介素11/药理学白细胞介素3/药理学膜蛋白质类/血液膜蛋白质类/药理学小鼠同源小鼠近交C57BL 小鼠近交系原癌基因蛋白质c-kit/血液重组蛋白质类/药理学干细胞因子/药理学血小板生成素/药理学时间因素动物人类小鼠

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