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The Hepatocyte Growth Factor/Scatter Factor Cutting Edge: Identification of a Hybrid Cytokine Consisting of IL-7 and the β-Chain of the Hepatocyte Growth Factor/Scatter Factor This information is current as Laijun Lai and Irving Goldschneider of September 23, 2021. J Immunol 2001; 167:3550-3554; ; doi: 10.4049/jimmunol.167.7.3550 http://www.jimmunol.org/content/167/7/3550 Downloaded from References This article cites 30 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/167/7/3550.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ● Cutting Edge: Identification of a Hybrid Cytokine Consisting of IL-7 and the ␤-Chain of the Hepatocyte Growth Factor/Scatter Factor1 Laijun Lai and Irving Goldschneider2 initiate or up-regulate the expression of terminal deoxynucleotidyl Pre-pro-B cell growth-stimulating factor (PPBSF) is a het- transferase, cytoplasmic Ig␮ heavy chain, and IL-7R␣-chain (Ref. erodimer of IL-7 and a 30-kDa cofactor. Unlike monomeric 5, and C. Wei, L. Lai, and I. Goldschneider, manuscript in prepara- IL-7, PPBSF selectively induces proliferation and differentia- tion). The latter events appear to enable newly formed pro-B cells Downloaded from tion of pre-pro-B cells and up-regulates IL-7R␣-chain expres- to proliferate and differentiate in response to monomeric IL-7 (3). sion. Here we clone the PPBSF cofactor from bone marrow PPBSF-coF is produced constitutively by IL-7Ϫ/Ϫ BM stromal stromal cells and identify it as a variant ␤-chain of hepatocyte cells in our culture system (3, 6), and antisera raised to native growth factor (HGF), a pleiotropic cytokine homologous to PPBSF contain separable reactivities for IL-7 and PPBSF-coF (4). plasminogen that regulates cell growth, motility, and morpho- By itself, PPBSF-coF maintains the viability of pre-pro-B cells, genesis. We further demonstrate that, in the presence of low whereas in the presence of IL-7 it forms functional complexes of http://www.jimmunol.org/ m.w. heparin sulfate-derived oligosaccharides, rHGF␤ com- PPBSF. However, despite interacting with IL-7, the PPBSF-coF bines with rIL-7 to form a biologically active heterodimer hav- differs functionally and serologically from stem cell factor (SCF), ing the properties of PPBSF. The results indicate that PPBSF insulin-like growth factor-1, thymic stromal lymphopoietin, is a novel form of cytokine (hybrid cytokine) consisting of the flk2/flt3 ligand, and pre-B cell growth-stimulating factor/stromal bioactive components of two unrelated cytokines. Based on its derived factor-1␤. heparin-binding and mitogenic properties, we postulate that In the present study we determined by amino acid sequencing, the HGF␤-chain in PPBSF enables IL-7 to participate in cog- RT-PCR analysis, and cDNA cloning that the PPBSF-coF is the ␤ nate interactions at the stromal cell surface and to transduce free mitogenic -chain of hepatocyte growth factor (HGF)/scatter factor, a heparin-binding, stromal cell-derived, multifunctional cy- by guest on September 23, 2021 signals effectively at low levels of IL-7R. The Journal of Im- tokine closely homologous to plasminogen (reviewed in Ref. 7). munology, 2001, 167: 3550–3554. This finding was wholly unexpected, as HGF is a pleiotropic factor that promotes parenchymal cell growth, motility, and morphogen- onsiderable progress has been made in identifying stro- esis in a broad spectrum of tissues; and as the HGF ␤-chain had not mal cell-derived growth factors that regulate pro-B cell previously been found to be produced independently of the HGF C and pre-B cell development. However, little is known ␣-chain (receptor-binding domain for c-MET), with which it is about the factors that regulate pre-pro-B cell development. To ap- secreted as an inactive single chain precursor (pro-HGF). We also proach this problem, we developed a long-term bone marrow demonstrated that, in the presence of low m.w. heparin sulfate (BM)3 lymphoid culture system that selectively supports the self- (HS)-derived oligosaccharides, rHGF␤ complexes with rIL-7 to replication of pre-pro-B cells and their differentiation to pro-B form a heterodimer having the functional, physical, and serological cells (1, 2). Using this system, we have purified a pre-pro-B cell properties of native PPBSF. Hence, PPBSF appears to represent a growth-stimulating factor (PPBSF) and demonstrated that it is a functionally unique and heretofore undescribed form of cytokine heterodimer of IL-7 and a 30-kDa cofactor (PPBSF-coF) (3, 4). (hybrid cytokine) consisting of the complexed bioactive portions Unlike monomeric IL-7, the IL-7/PPBSF-coF complex stimulates of two independently generated cytokines. The possible dual func- proliferation and differentiation of pre-pro-B cells and helps to tion of the IL-7/HGF␤ hybrid cytokine in the induction of B lin- eage commitment and the regulation of early B cell development is discussed. Department of Pathology, School of Medicine, University of Connecticut Health Cen- ter, Farmington, CT 06030 Materials and Methods Received for publication May 21, 2001. Accepted for publication August 14, 2001. Animals The costs of publication of this article were defrayed in part by the payment of page ϫ Ϫ/Ϫ ϩ/ϩ charges. This article must therefore be hereby marked advertisement in accordance (129 B6)F2 IL-7 and IL-7 mice (generously provided by Dr. R. with 18 U.S.C. Section 1734 solely to indicate this fact. Murray, DNAX Research Institute of Cellular and Molecular Biology, Palo 1 This study was supported in part by National Institutes of Health Grant AI 32752. Alto, CA) were used as donors of primary BM-adherent cell feeder layers Ͼ 2 and of enriched ( 98%) populations of stromal cells generated by serial Address correspondence and reprint requests to Dr. Irving Goldschneider, Depart- passage in vitro (3). Male 4- to 6-wk-old Lewis strain rats were used as ment of Pathology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030. E-mail address: [email protected] donors of BM lymphoid precursor cells. 3 Abbreviations used in this paper: BM, bone marrow; CM, conditioned medium; coF, Cytokines and Abs cofactor; HGF, hepatocyte growth factor; HS, heparin sulfate; PPBSF, pre-pro-B cell growth-stimulating factor; SCF, stem cell factor; EPO, erythropoietin; CHO, Chinese Recombinant murine IL-3, IL-7, GM-CSF, HGF, and erythropoietin (EPO) hamster ovary. were purchased from R&D Systems (Minneapolis, MN), as were anti-HGF Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 ● The Journal of Immunology 3551 and anti-IL-7 Abs. Affinity-purified goat polycolonal Ab reactive with hu- man and mouse HGF␤, and HRP-linked anti-goat IgG were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Amino acid sequence analysis of PPBSF PPBSF was purified from IL-7ϩ/ϩ BM stromal cell conditioned medium (CM) on an anti-IL-7 immunoaffinity column as previously described (3, 4). The bound Ag was eluted, dialyzed for 16 h in PBS (pH 7.2) at 4°C, and loaded on a 12% SDS-PAGE gel under reducing conditions. After elec- trophoresis, the proteins were transferred onto ProBlott membrane (Ap- plied Biosystems, Foster City, CA) using a trans-Blot SD Semidry Transfer FIGURE 1. Partial NH2-terminal amino acid sequence identity of puri- Cell (model 200/2.0; Bio-Rad, Hercules, CA), then stained with Coomassie fied mouse PPBSF-coF from enriched IL-7ϩ/ϩ BM stromal cells. Com- brilliant blue R-250 (Bio-Rad). The 30-kDa band was excised and sent to parison with the predicted amino acid sequences for the HGF ␤-chain in the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale mouse, rat, and human as derived from the published nucleotide sequences. University for direct NH -terminal sequencing. 2 Positions of reported nucleotide substitutions are indicated in boxes. Molecular cloning and sequencing of HGF␤ Total RNA was isolated with TRIzol Reagent (Life Technologies, Gaith- PPBSF-coF as the HGF ␤-chain was confirmed by Western blot ersburg, MD) from populations of enriched IL-7Ϫ/Ϫ BM stromal cells. Random-primed first-strand cDNA was generated using Moloney murine analyses, in which PPBSF-coF reacted with Ab against full-length HGF and the HGF ␤-chain (Fig. 2), but not the HGF ␣-chain (data leukemia virus reverse transcriptase (RETRO Script; Ambion, Austin, TX). Downloaded from PCRs were performed using Taq polymerase (Life Technologies) and not shown). In addition, both anti-HGF and anti-HGF␤ Abs neu- primers designed to amplify the entire coding sequence of mouse HGF: tralized the PPBSF activity in IL-7ϩ/ϩ CM (data not shown, but Ј Ј Ј Ј 5 -CAGTCTGCTCGAACTGCA-3 (in 5 flanking region), and 5 -TGGC see Fig. 5). CTCTTCTATGGCTA-3Ј (in 3Ј flanking region). PCR was performed as follows: 95°C for 5 min, 30 cycles of 94°C for 1 min, 60°C for 1 min, and 72°C for 1 min followed by a final extension at 72°C for 5 min.
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