INTERLEUKIN duces IgA production and acts additively with interleukin 5 for IgA production. 1. exp. Med., 170, 14151420. Splawski, J.B., McAnnally, L.M. & Lipsky, P.E. (1990), IL-2 dependence of the promotion of human B-cell differentiation by IL-6 (BSF-2). J. Immunol., 144, 562-569. Teranishi, T., Hirano, T., Lin, B.-H. & Onoue, K. (1984),
6
149
Demonstration of the involvement of interleukin-2 in the differentiation of Staphy(ococcrrsunrelis CowanI-stimulated B cells. J. Immunol., 133, 3062-3067. Van Vlasselaer, P., Punnonen, J. &de Vries, J.E. (1992), Transforming growth factor-p directs IgA switching in human B cells. J. Immunol., 148, 2062-2067. Van Snick, T. (1990), Interleukin-6. An overview. Ann. Rev. Immunol.,
IL6 and haematopoietic
8, 253-278.
stem cells
M. Ogawa Ralph H. Johnson Department of Veterans Affairs Medical Center and the Department Medical University of South Carolina, Charleston, SC 29401 (USA)
Why are we interested in the effects of IL6 in haematopoietic stem cells?
Haematopoiesis is a dynamic process characterized by a daily turnover of a large number of blood cells. This cell turnover is supported by a small population of cells in the bone marrow, termed haematopoietic stem cells. In the steady state marrow, the majority of stem cells are dormant in cell cycle and only small numbers of stem cells are the source of mature cells at any given time. For years, the mechanisms regulating the kinetics of haematopoietic stem cells remained unknown. Recent progress in growth factor biology resulted in identification of many haematopoietic growth factors and characterization of their roles in haematopoiesis. It is now generally held that the kinetics of haematopoietic stem cells is controlled by a number of positive and negative regulators. IL6 is one of the several positive regulators and the very first to be identified. An exciting prospect is that it may become possible to manipulate stem cells by growth factors for timely recovery of haematopoiesis in patients with therapyrelated bone marrow suppression and for more efficient insertion of genetic materials into the stem cell DNA in gene therapy of a variety of genetic and malignant processes. The positive regulators may be divided arbitrarily into two groups. The first group consists of IL3, IL4 and granulocyte/macrophage colony stimulating factor (GM-CSF) and the second group includes IL6, granulocyte-colony stimulating factor (G-CSF),
of Medicine,
IL1 1 and steel factor (c-kit ligand). The second group appears to be involved in triggering the entry into cell cycle of the dormant cells and the first appears to support continued proliferation of multipotential progenitors after they exit from the dormancy period.
Experimental
observations in culture
Our characterization of the mechanisms by which these factors regulate the stem cell kinetics was carried out in methylcellulose culture using murine blast
cell colony assay we developed earlier (Nakahata and Ogawa, 1982). Investigators in several laboratories observed that IL3 (Ihle et al., 1983), GM-CSF (Metcalf et al., 1980) and IL4 (Peschel et al., 1987) support formation
of multilineage
colonies in culture
indicating their effects on the proliferation of multipotential progenitors. We have demonstrated by replating of pooled blast cells in culture that IL3 (Suda et al., 1985) and IL4 (Kishi et al., 1989) support formation of multilineage colonies in the presence of erythropoietin. Since blast cell colonies have very high replating incidences (Nakahata and Ogawa, 1982), these observations were interpreted to indicate that IL3 and IL4 directly support proliferation of multipotential progenitors. In serial replating of murine blast cell colonies, we have also shown the GM-CSF also supports proliferation of multipotential progenitors directly (Koike et al., 1987). The notion that these factors do not trigger the entry into the cell cycle of the dormant progenitors was
46th FORUM
obtained using blast cell colonies from mice that had been treated with 150 mg/kg 5-fluorouracil (5-FU). Spleen and marrow cells from post-5-FU mice are known to be highly enriched for cell cycle dormant early haematopoietic progenitors including the progenitors of blast cell colonies and to be virtually devoid of actively cycling maturer progenitors (Hodgson and Bradley, 1979). When we carried out time-course observation of blast cell colony formation from post-5-FU spleen cells, the blast cell colonies emerged after random time intervals in the presence of IL3 (Suda et al., 1985). When the addition of IL3 was delayed by one week, the earlyappearing blast cell colonies were absent, whereas the later-appearing half of the blast cell colonies emerged at random intervals (Suda et al., 1985). These results indicated that while IL3 does not trigger the exit from G, of the dormant progenitors, it is an important factor for proliferation of multipotential progenitors. Identification of the second group of positive regulators (factors that appear to trigger the entry into cell cycle of dormant progenitors) was also made using methylcellulose culture. Serial observations (mapping) of the development of individual blast cell colonies revealed that blast cell colonies emerged after random time intervals in the presence of IL3, and that the addition of IL6 to the cultures containing IL3 significantly hastened the appearance of blast cell colonies (Ikebuchi et al., 1987). Since doubling times of the blast cell colonies did not differ significantly between the two experimental groups, these results suggested that IL6 shortens the period in which the progenitors for the blast cell colonies reside. A different line of support for the effects of IL6 on the kinetics of primitive progenitors was provided by Bodine et al. (1989), who reported more efficient retroviral labelling of reconstituting murine stem cells by use of IL6. Subsequently, we found that G-C$F (Ikebuchi et al., 1988), IL11 (Musashi ef al., 1991a) and steel factor (Tsuji et al., 1991) also work synergistically with IL3 and shorten the G, period of primitive murine haematopoietic progenitors. IL4 also interacts synergistically with IL6 (Kishi et al., 1989; Rennick er al., 1987) and IL1 1 (Musashi et al., 1991b) but not steel factor (Tsuji et al., 1991). Using human bone marrow blast cell colony assay, the synergism was also observed between IL3 and the individual synergistic factors. First, IL6 was shown to hasten the development and augment the number of blast cell colonies from CD3Cpositive human bone marrow cells (Leary et al., 1988). In this culture system, IL1 did not reveal synergism with IL3, indicating that the effects of IL1 on the primitive haematopoietic progenitors reported earlier are probably due to the indirect effects in part mediated by IL6 and G-CSF. Recently, using CD34-positive, HLA-DR-negative and lineage-negative human bone
IN IMMUNOLOGY
marrow cells, we have obtained more definitive evidence that IL6, G-CSF, IL1 1 and leukaemia inhibitory factor/differentiation-inducing activity (LIF/DIA) act as triggers for the entry into cell cycle of dormant haematopoietic progenitors (Leary el al., 1992). When the highly enriched human marrow cells were plated in methylcellulose culture, neither IL3 nor any of the synergistic factors individually supported colony formation. Only when IL3 and one of the synergistic factors were combined was formation of colonies including multilineage colonies seen. To further document the concept that the synergistic factors trigger cell division of dormant haematopoietic progenitors, we carried out mapping studies of colony development from individual CD3Cpositive HLA-DR-negative bone marrow cells. The control culture was established with IL3 and IL6. In the experimental group, the addition of IL6 was delayed by one week. The plates were examined daily on an inverted microscope and initiation and rate of gowth of the blast cell colonies was recorded. Thirteen and ten blast colonies were observed in the control and experimental groups, respectively. Since doubling times of the individual blast cell colonies did not differ significantly between the two groups, the results indicated strongly that IL6 triggers the cell division of dormant haematopoietic stem cells. In vivo effects of IL6
Following the description of the in vitro effects of IL6 on haematopoiesis, murine studies indicated in vivo effects of IL6 on multipotential progenitors. IL6 or a combination of IL3 and IL6 given to mice with radiation-induced haematopoietic suppression (Patchen et al., 1991) and mice with bone marrow transplantation (Okano et al., 1989) was shown to facilitate multilineage recovery, indicating the effects of IL6 in vivo on dormant multipotential progenitors.
References
Bodine, D.M., Karlsson, S. & Nienhuis, A. W. (1989), Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirusmediated gene transfer into hematopoietic stem cells. Proc. natl. Acad. Sci. (Wash.), 86, 8897-8901. Hodgson, G.S. & Bradley, T.R. (1979), Properties of haematopoietic stem cells surviving 5-fluorouracil treatment : evidence for a pre-CFU-S cell? Nature (Lond.), 281, 381-382. Ihle, J.N., Keller, J., Oroszlan, S., Henderson, L.E., Copeland, T.D., Fitch, F., Prystowsky, M.B., Goldwasser,E., Schrader, J.W., Palaszynski, E., Dy, M. & Lebel, B. (1983), Biologic properties of homogeneous interleukin-3. - I. Demonstration of WEHIgrowth factor activity, mast cell growth factor activity,
INTERLEUKIN P cell stimulating factor activity, colony-stimulating factor activity and histamine-producing cellstimulating factor activity. J. Immunol., 131, 282-287. Ikebuchi, K., Wong, G.G., Clark, S.C., Ihle, J.N., Hirai, Y. & Ogawa, M. (1987), Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoieticprogenitors.Proc. nafl. Acud. Sci. (Wash.), 84, 90359039. Ikebuchi, K., Clark, S.C., Ihle, J.N., Souza, L.M. & Ogawa, M. (1988), Granulocyte colony-stimulatingfactor enhancesinterleukin-3-dependent proliferation of multipotential hemopoieticprogenitors. Proc. null. Acud. Sci. (Wash.), 85, 3445-3449. Kishi, K., Ihle, J.N., Urdal, D.L. & Ogawa, M. (1989), Murine B-cell stimulatory factor-l (BSF-l)/interleukin-4 (IL-4) is a multi-CSF which actsdirectly on primitive hemopoieticprogenitors.J. Cell Physiol., 139,
463-488.
Koike, K., Ogawa, M., Ihle, J.N., Miyake, T., Shimizu, T., Miyajima, A., Yokota, T. & Arai, K. (1987), Recombinantmurinegranulocyte-macrophage (GM) colony-stimulatingfactor supportsformation of GM and multipotentialblastcell coloniesin culture: Comparison with the effects of interleukin-3. J. Cell Physiol.,
131, 458-464.
Leary, A.G., Ikebuchi, K., Hirai, Y., Wong, G.G., Yang, Y.-C., Clark, S.C. & Ogawa, M. (1988), Synergism betweeninterleukin-6 and interleukin-3 in supporting proliferation of human hemopoieticstem cells: Comparison with interleukin-la. Blood, 7 1, 1759-1763.
Leary, A.G., Zeng, H.Q., Clark, S.C. & Ogawa, M. (1992), Growth factor requirementsfor survival in G, and entry into the cell cycle of primitive human hemopoietic progenitors. Proc. nutl. Acud. Sci. (Wash.) (in press). Metcalf, D., Johnson,G.R. &Burgess,A.W. (1980),Direct stimulationby purified GM-CSF of the proliferation of multipotentialand erythroid precursors.Blood, 55, 138-147.
6 Musashi,M., Yang, Y.-C., Paul, S.R., Clark, S.C., Sudo, T. & Ogawa, M. (1991a),Direct and synergisticeffects of interleukin-11on murinehemopoiesis in culture. Proc. null. Acud. Sci. (Wash.), 88, 765-769. Musashi,M., Clark, S.C., Sudo, T., Urdal, D.L. & Ogawa, M. (1991b), Synergistic interactions between interleukin-11and interleukin-4in supportof proliferation of primitive hemopoieticprogenitorsof mice. Blood,
78,
1448-1451.
Nakahata, T. & Ogawa, M. (1982), Identification in culture of a classof hemopoieticcolony-forming units with extensivecapability to self-renewand generate multipotential colonies. Proc. nutl. Acud. Sci. (Wash.), 79, 3843-3847. Okano, A., Suzuki, C., Takatsuki, F., Akiyama, Y., Koike, K., Nakahata, T., Hirano, T., Kishimoto,T., Ozawa, K. & Asano, S. (1989), Effects of interleukin-6 on hematopoiesisin bone marrowtransplantedmice. Transplantation, 47, 738-740. Patchen,M.L., MacVittie, T.J., Williams,J.L., Schwartz, G.N. & Souza, L.M. (1991), Administration of interleukin-6 stimulatesmultilineagehematopoiesis and acceleratesrecovery from radiation-induced hematopoieticdepression.Blood, 77, 472-480. Peschel,C., Paul, W.E., Ohara, J. & Green, I. (1987),Effects of B-cell stimulatory factor-l/interleukin-4 on hematopoieticprogenitor cells. Blood, 70, 254-263. Rennick, D., Yang, G., Muller-Sieburg, C., Smith, C., Arai, N., Takabe, Y. & Gemmell, L. (1987), Interleukin 4 (B-cell stimulatory factor 1) can enhanceor antagonize the factor-dependent growth of hemopoieticprogenitor cells. Proc. nut/. Acud. Sci. (Wash.), 84, 6889-6893. Suda, T., Suda, J., Ogawa, M. & Ihle, J.N. (1985), Permissiverole of interleukin3 (IL-3) in proliferation and differentiation of multipotential hemopoieticprogenitors in culture. J. Cell Physiol., 124, 182-190. Tsuji, K., Zsebo,K.M. & Ogawa,M. (1991),Enhancement of murine blast cell colony formation in culture by recombinantrat stemcell factor (rrSCF), ligand for c-kit. Blood,
78, 1223-1229.
6
149
Demonstration of the involvement of interleukin-2 in the differentiation of Staphy(ococcrrsunrelis CowanI-stimulated B cells. J. Immunol., 133, 3062-3067. Van Vlasselaer, P., Punnonen, J. &de Vries, J.E. (1992), Transforming growth factor-p directs IgA switching in human B cells. J. Immunol., 148, 2062-2067. Van Snick, T. (1990), Interleukin-6. An overview. Ann. Rev. Immunol.,
IL6 and haematopoietic
8, 253-278.
stem cells
M. Ogawa Ralph H. Johnson Department of Veterans Affairs Medical Center and the Department Medical University of South Carolina, Charleston, SC 29401 (USA)
Why are we interested in the effects of IL6 in haematopoietic stem cells?
Haematopoiesis is a dynamic process characterized by a daily turnover of a large number of blood cells. This cell turnover is supported by a small population of cells in the bone marrow, termed haematopoietic stem cells. In the steady state marrow, the majority of stem cells are dormant in cell cycle and only small numbers of stem cells are the source of mature cells at any given time. For years, the mechanisms regulating the kinetics of haematopoietic stem cells remained unknown. Recent progress in growth factor biology resulted in identification of many haematopoietic growth factors and characterization of their roles in haematopoiesis. It is now generally held that the kinetics of haematopoietic stem cells is controlled by a number of positive and negative regulators. IL6 is one of the several positive regulators and the very first to be identified. An exciting prospect is that it may become possible to manipulate stem cells by growth factors for timely recovery of haematopoiesis in patients with therapyrelated bone marrow suppression and for more efficient insertion of genetic materials into the stem cell DNA in gene therapy of a variety of genetic and malignant processes. The positive regulators may be divided arbitrarily into two groups. The first group consists of IL3, IL4 and granulocyte/macrophage colony stimulating factor (GM-CSF) and the second group includes IL6, granulocyte-colony stimulating factor (G-CSF),
of Medicine,
IL1 1 and steel factor (c-kit ligand). The second group appears to be involved in triggering the entry into cell cycle of the dormant cells and the first appears to support continued proliferation of multipotential progenitors after they exit from the dormancy period.
Experimental
observations in culture
Our characterization of the mechanisms by which these factors regulate the stem cell kinetics was carried out in methylcellulose culture using murine blast
cell colony assay we developed earlier (Nakahata and Ogawa, 1982). Investigators in several laboratories observed that IL3 (Ihle et al., 1983), GM-CSF (Metcalf et al., 1980) and IL4 (Peschel et al., 1987) support formation
of multilineage
colonies in culture
indicating their effects on the proliferation of multipotential progenitors. We have demonstrated by replating of pooled blast cells in culture that IL3 (Suda et al., 1985) and IL4 (Kishi et al., 1989) support formation of multilineage colonies in the presence of erythropoietin. Since blast cell colonies have very high replating incidences (Nakahata and Ogawa, 1982), these observations were interpreted to indicate that IL3 and IL4 directly support proliferation of multipotential progenitors. In serial replating of murine blast cell colonies, we have also shown the GM-CSF also supports proliferation of multipotential progenitors directly (Koike et al., 1987). The notion that these factors do not trigger the entry into the cell cycle of the dormant progenitors was
46th FORUM
obtained using blast cell colonies from mice that had been treated with 150 mg/kg 5-fluorouracil (5-FU). Spleen and marrow cells from post-5-FU mice are known to be highly enriched for cell cycle dormant early haematopoietic progenitors including the progenitors of blast cell colonies and to be virtually devoid of actively cycling maturer progenitors (Hodgson and Bradley, 1979). When we carried out time-course observation of blast cell colony formation from post-5-FU spleen cells, the blast cell colonies emerged after random time intervals in the presence of IL3 (Suda et al., 1985). When the addition of IL3 was delayed by one week, the earlyappearing blast cell colonies were absent, whereas the later-appearing half of the blast cell colonies emerged at random intervals (Suda et al., 1985). These results indicated that while IL3 does not trigger the exit from G, of the dormant progenitors, it is an important factor for proliferation of multipotential progenitors. Identification of the second group of positive regulators (factors that appear to trigger the entry into cell cycle of dormant progenitors) was also made using methylcellulose culture. Serial observations (mapping) of the development of individual blast cell colonies revealed that blast cell colonies emerged after random time intervals in the presence of IL3, and that the addition of IL6 to the cultures containing IL3 significantly hastened the appearance of blast cell colonies (Ikebuchi et al., 1987). Since doubling times of the blast cell colonies did not differ significantly between the two experimental groups, these results suggested that IL6 shortens the period in which the progenitors for the blast cell colonies reside. A different line of support for the effects of IL6 on the kinetics of primitive progenitors was provided by Bodine et al. (1989), who reported more efficient retroviral labelling of reconstituting murine stem cells by use of IL6. Subsequently, we found that G-C$F (Ikebuchi et al., 1988), IL11 (Musashi ef al., 1991a) and steel factor (Tsuji et al., 1991) also work synergistically with IL3 and shorten the G, period of primitive murine haematopoietic progenitors. IL4 also interacts synergistically with IL6 (Kishi et al., 1989; Rennick er al., 1987) and IL1 1 (Musashi et al., 1991b) but not steel factor (Tsuji et al., 1991). Using human bone marrow blast cell colony assay, the synergism was also observed between IL3 and the individual synergistic factors. First, IL6 was shown to hasten the development and augment the number of blast cell colonies from CD3Cpositive human bone marrow cells (Leary et al., 1988). In this culture system, IL1 did not reveal synergism with IL3, indicating that the effects of IL1 on the primitive haematopoietic progenitors reported earlier are probably due to the indirect effects in part mediated by IL6 and G-CSF. Recently, using CD34-positive, HLA-DR-negative and lineage-negative human bone
IN IMMUNOLOGY
marrow cells, we have obtained more definitive evidence that IL6, G-CSF, IL1 1 and leukaemia inhibitory factor/differentiation-inducing activity (LIF/DIA) act as triggers for the entry into cell cycle of dormant haematopoietic progenitors (Leary el al., 1992). When the highly enriched human marrow cells were plated in methylcellulose culture, neither IL3 nor any of the synergistic factors individually supported colony formation. Only when IL3 and one of the synergistic factors were combined was formation of colonies including multilineage colonies seen. To further document the concept that the synergistic factors trigger cell division of dormant haematopoietic progenitors, we carried out mapping studies of colony development from individual CD3Cpositive HLA-DR-negative bone marrow cells. The control culture was established with IL3 and IL6. In the experimental group, the addition of IL6 was delayed by one week. The plates were examined daily on an inverted microscope and initiation and rate of gowth of the blast cell colonies was recorded. Thirteen and ten blast colonies were observed in the control and experimental groups, respectively. Since doubling times of the individual blast cell colonies did not differ significantly between the two groups, the results indicated strongly that IL6 triggers the cell division of dormant haematopoietic stem cells. In vivo effects of IL6
Following the description of the in vitro effects of IL6 on haematopoiesis, murine studies indicated in vivo effects of IL6 on multipotential progenitors. IL6 or a combination of IL3 and IL6 given to mice with radiation-induced haematopoietic suppression (Patchen et al., 1991) and mice with bone marrow transplantation (Okano et al., 1989) was shown to facilitate multilineage recovery, indicating the effects of IL6 in vivo on dormant multipotential progenitors.
References
Bodine, D.M., Karlsson, S. & Nienhuis, A. W. (1989), Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirusmediated gene transfer into hematopoietic stem cells. Proc. natl. Acad. Sci. (Wash.), 86, 8897-8901. Hodgson, G.S. & Bradley, T.R. (1979), Properties of haematopoietic stem cells surviving 5-fluorouracil treatment : evidence for a pre-CFU-S cell? Nature (Lond.), 281, 381-382. Ihle, J.N., Keller, J., Oroszlan, S., Henderson, L.E., Copeland, T.D., Fitch, F., Prystowsky, M.B., Goldwasser,E., Schrader, J.W., Palaszynski, E., Dy, M. & Lebel, B. (1983), Biologic properties of homogeneous interleukin-3. - I. Demonstration of WEHIgrowth factor activity, mast cell growth factor activity,
INTERLEUKIN P cell stimulating factor activity, colony-stimulating factor activity and histamine-producing cellstimulating factor activity. J. Immunol., 131, 282-287. Ikebuchi, K., Wong, G.G., Clark, S.C., Ihle, J.N., Hirai, Y. & Ogawa, M. (1987), Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoieticprogenitors.Proc. nafl. Acud. Sci. (Wash.), 84, 90359039. Ikebuchi, K., Clark, S.C., Ihle, J.N., Souza, L.M. & Ogawa, M. (1988), Granulocyte colony-stimulatingfactor enhancesinterleukin-3-dependent proliferation of multipotential hemopoieticprogenitors. Proc. null. Acud. Sci. (Wash.), 85, 3445-3449. Kishi, K., Ihle, J.N., Urdal, D.L. & Ogawa, M. (1989), Murine B-cell stimulatory factor-l (BSF-l)/interleukin-4 (IL-4) is a multi-CSF which actsdirectly on primitive hemopoieticprogenitors.J. Cell Physiol., 139,
463-488.
Koike, K., Ogawa, M., Ihle, J.N., Miyake, T., Shimizu, T., Miyajima, A., Yokota, T. & Arai, K. (1987), Recombinantmurinegranulocyte-macrophage (GM) colony-stimulatingfactor supportsformation of GM and multipotentialblastcell coloniesin culture: Comparison with the effects of interleukin-3. J. Cell Physiol.,
131, 458-464.
Leary, A.G., Ikebuchi, K., Hirai, Y., Wong, G.G., Yang, Y.-C., Clark, S.C. & Ogawa, M. (1988), Synergism betweeninterleukin-6 and interleukin-3 in supporting proliferation of human hemopoieticstem cells: Comparison with interleukin-la. Blood, 7 1, 1759-1763.
Leary, A.G., Zeng, H.Q., Clark, S.C. & Ogawa, M. (1992), Growth factor requirementsfor survival in G, and entry into the cell cycle of primitive human hemopoietic progenitors. Proc. nutl. Acud. Sci. (Wash.) (in press). Metcalf, D., Johnson,G.R. &Burgess,A.W. (1980),Direct stimulationby purified GM-CSF of the proliferation of multipotentialand erythroid precursors.Blood, 55, 138-147.
6 Musashi,M., Yang, Y.-C., Paul, S.R., Clark, S.C., Sudo, T. & Ogawa, M. (1991a),Direct and synergisticeffects of interleukin-11on murinehemopoiesis in culture. Proc. null. Acud. Sci. (Wash.), 88, 765-769. Musashi,M., Clark, S.C., Sudo, T., Urdal, D.L. & Ogawa, M. (1991b), Synergistic interactions between interleukin-11and interleukin-4in supportof proliferation of primitive hemopoieticprogenitorsof mice. Blood,
78,
1448-1451.
Nakahata, T. & Ogawa, M. (1982), Identification in culture of a classof hemopoieticcolony-forming units with extensivecapability to self-renewand generate multipotential colonies. Proc. nutl. Acud. Sci. (Wash.), 79, 3843-3847. Okano, A., Suzuki, C., Takatsuki, F., Akiyama, Y., Koike, K., Nakahata, T., Hirano, T., Kishimoto,T., Ozawa, K. & Asano, S. (1989), Effects of interleukin-6 on hematopoiesisin bone marrowtransplantedmice. Transplantation, 47, 738-740. Patchen,M.L., MacVittie, T.J., Williams,J.L., Schwartz, G.N. & Souza, L.M. (1991), Administration of interleukin-6 stimulatesmultilineagehematopoiesis and acceleratesrecovery from radiation-induced hematopoieticdepression.Blood, 77, 472-480. Peschel,C., Paul, W.E., Ohara, J. & Green, I. (1987),Effects of B-cell stimulatory factor-l/interleukin-4 on hematopoieticprogenitor cells. Blood, 70, 254-263. Rennick, D., Yang, G., Muller-Sieburg, C., Smith, C., Arai, N., Takabe, Y. & Gemmell, L. (1987), Interleukin 4 (B-cell stimulatory factor 1) can enhanceor antagonize the factor-dependent growth of hemopoieticprogenitor cells. Proc. nut/. Acud. Sci. (Wash.), 84, 6889-6893. Suda, T., Suda, J., Ogawa, M. & Ihle, J.N. (1985), Permissiverole of interleukin3 (IL-3) in proliferation and differentiation of multipotential hemopoieticprogenitors in culture. J. Cell Physiol., 124, 182-190. Tsuji, K., Zsebo,K.M. & Ogawa,M. (1991),Enhancement of murine blast cell colony formation in culture by recombinantrat stemcell factor (rrSCF), ligand for c-kit. Blood,
78, 1223-1229.
