Cytotoxic Lymphocyte Maturation Factor (interleukin 12) is a Synergistic Growth Factor for Hematopoietic Stem Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 1993 Aug 1

PMID 7688022

Citations 26

Authors

S E Jacobsen

O P Veiby

E B Smeland

Affiliations

Soon will be listed here.

Abstract

The recently cloned cytotoxic lymphocyte maturation factor (interleukin 12 [IL-12]) has been described as a growth factor for mature lymphocytes. The present study investigated whether purified recombinant murine IL-12 (rMuIL-12) also could affect the proliferation of primitive bone marrow progenitor cells. Using a population of Lin-Sca-1+ murine bone marrow stem cells, we now demonstrate that IL-12 is a potent synergistic factor for primitive hematopoietic stem cells. The synergy of IL-12 was observed in single-cell cloning assays, demonstrating that its effects are directly mediated. Specifically, IL-12 enhanced stem cell factor-induced myelopoiesis of Lin-Sca-1+ cells sevenfold, and synergized with colony-stimulating factors (CSFs) to induce proliferation of Lin-Sca-1+ stem cells. IL-12 increased the number of responding progenitor cells as well as the size of the colonies formed. IL-12 also increased colony formation of high proliferative potential colony-forming cells with multiple CSF combinations. The effects of IL-12 were concentration dependent with a 50% effective dose of 2-20 and 20-200 ng/ml, resulting in maximum stimulation. Furthermore, a neutralizing anti-IL-12 antibody blocked the synergistic effects of rMuIL-12. In addition, IL-12 was found to have synergistic effects on more committed bone marrow progenitors as well. Our results therefore suggest that in addition to being a potent lymphopoietic stimulator, IL-12 is a regulator of the growth of hematopoietic stem cells and their myeloid progeny.

Citing Articles

Retinal ganglion cells induce stem cell-derived neuroprotection via IL-12 to SCGF-β crosstalk.

Xia Q, Chang K, Sun Y, Nahmou M, Noro T, Cheng Y Stem Cell Res Ther. 2025; 16(1):90.

PMID: 40001251 PMC: 11863831. DOI: 10.1186/s13287-025-04198-5.

Offspring affected with Zika virus infection retain molecular footprints in the bone marrow and blood cells.

Udenze D, Trus I, Lipsit S, Napper S, Karniychuk U Emerg Microbes Infect. 2022; 12(1):2147021.

PMID: 36369716 PMC: 9869997. DOI: 10.1080/22221751.2022.2147021.

Interleukin-12 supports in vitro self-renewal of long-term hematopoietic stem cells.

Zhang S, Morita M, Wang Z, Ooehara J, Zhang S, Xie M Blood Sci. 2022; 1(1):92-101.

PMID: 35402790 PMC: 8974953. DOI: 10.1097/BS9.0000000000000002.

Deriving a Boolean dynamics to reveal macrophage activation with in vitro temporal cytokine expression profiles.

Ramirez R, Herrera A, Ramirez J, Qian C, Melton D, Shireman P BMC Bioinformatics. 2019; 20(1):725.

PMID: 31852428 PMC: 6921543. DOI: 10.1186/s12859-019-3304-5.

Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects.

Gokhale M, Vainstein V, Tom J, Thomas S, Lawrence C, Gluzman-Poltorak Z Exp Hematol Oncol. 2014; 3(1):11.

PMID: 24725395 PMC: 3991894. DOI: 10.1186/2162-3619-3-11.

References

Stanley E, Metcalf D, Maritz J, Yeo G . Standardized bioassay for bone marrow colony stimulating factor in human urine: levels in normal man. J Lab Clin Med. 1972; 79(4):657-68. View

Watt S, Visser J . Recent advances in the growth and isolation of primitive human haemopoietic progenitor cells. Cell Prolif. 1992; 25(4):263-97. DOI: 10.1111/j.1365-2184.1992.tb01440.x. View

Bartelmez S, Stanley E . Synergism between hemopoietic growth factors (HGFs) detected by their effects on cells bearing receptors for a lineage specific HGF: assay of hemopoietin-1. J Cell Physiol. 1985; 122(3):370-8. DOI: 10.1002/jcp.1041220306. View

Stanley E, Bartocci A, Patinkin D, Rosendaal M, Bradley T . Regulation of very primitive, multipotent, hemopoietic cells by hemopoietin-1. Cell. 1986; 45(5):667-74. DOI: 10.1016/0092-8674(86)90781-6. View

Ikebuchi K, Wong G, Clark S, Ihle J, Hirai Y, Ogawa M . Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1987; 84(24):9035-9. PMC: 299686. DOI: 10.1073/pnas.84.24.9035. View

Kobayashi M, Fitz L, Ryan M, Hewick R, Clark S, Chan S . Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989; 170(3):827-45. PMC: 2189443. DOI: 10.1084/jem.170.3.827. View

McNiece I, Bertoncello I, Kriegler A, Quesenberry P . Colony-forming cells with high proliferative potential (HPP-CFC). Int J Cell Cloning. 1990; 8(3):146-60. DOI: 10.1002/stem.5530080302. View

Spangrude G, Scollay R . A simplified method for enrichment of mouse hematopoietic stem cells. Exp Hematol. 1990; 18(8):920-6. View

Stern A, Podlaski F, Hulmes J, Pan Y, Quinn P, Wolitzky A . Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990; 87(17):6808-12. PMC: 54627. DOI: 10.1073/pnas.87.17.6808. View

10.

Williams D, Eisenman J, Baird A, Rauch C, van Ness K, March C . Identification of a ligand for the c-kit proto-oncogene. Cell. 1990; 63(1):167-74. DOI: 10.1016/0092-8674(90)90297-r. View

11.

Zsebo K, Wypych J, McNiece I, Lu H, Smith K, Karkare S . Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver--conditioned medium. Cell. 1990; 63(1):195-201. DOI: 10.1016/0092-8674(90)90300-4. View

12.

Spangrude G, Johnson G . Resting and activated subsets of mouse multipotent hematopoietic stem cells. Proc Natl Acad Sci U S A. 1990; 87(19):7433-7. PMC: 54761. DOI: 10.1073/pnas.87.19.7433. View

13.

Gubler U, Chua A, Schoenhaut D, Dwyer C, McComas W, Motyka R . Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991; 88(10):4143-7. PMC: 51614. DOI: 10.1073/pnas.88.10.4143. View

14.

Gately M, Desai B, Wolitzky A, Quinn P, Dwyer C, Podlaski F . Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991; 147(3):874-82. View

15.

Spangrude G, Smith L, Uchida N, Ikuta K, Heimfeld S, Friedman J . Mouse hematopoietic stem cells. Blood. 1991; 78(6):1395-402. View

16.

Lowry P, Zsebo K, Deacon D, Eichman C, Quesenberry P . Effects of rrSCF on multiple cytokine responsive HPP-CFC generated from SCA+Lin- murine hematopoietic progenitors. Exp Hematol. 1991; 19(9):994-6. View

17.

Metcalf D . Control of granulocytes and macrophages: molecular, cellular, and clinical aspects. Science. 1991; 254(5031):529-33. DOI: 10.1126/science.1948028. View

18.

Williams N, Bertoncello I, Kavnoudias H, Zsebo K, McNiece I . Recombinant rat stem cell factor stimulates the amplification and differentiation of fractionated mouse stem cell populations. Blood. 1992; 79(1):58-64. View

19.

Li C, Johnson G . Rhodamine123 reveals heterogeneity within murine Lin-, Sca-1+ hemopoietic stem cells. J Exp Med. 1992; 175(6):1443-7. PMC: 2119242. DOI: 10.1084/jem.175.6.1443. View

20.

Bradley T, Hodgson G . Detection of primitive macrophage progenitor cells in mouse bone marrow. Blood. 1979; 54(6):1446-50. View