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The Journal of Immunology, 2001, 167: 3550-3554.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Identification of a Hybrid Cytokine Consisting of IL-7 and the {beta}-Chain of the Hepatocyte Growth Factor/Scatter Factor1

Laijun Lai and Irving Goldschneider2

Department of Pathology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pre-pro-B cell growth-stimulating factor (PPBSF) is a heterodimer of IL-7 and a 30-kDa cofactor. Unlike monomeric IL-7, PPBSF selectively induces proliferation and differentiation of pre-pro-B cells and up-regulates IL-7R{alpha}-chain expression. Here we clone the PPBSF cofactor from bone marrow stromal cells and identify it as a variant {beta}-chain of hepatocyte growth factor (HGF), a pleiotropic cytokine homologous to plasminogen that regulates cell growth, motility, and morphogenesis. We further demonstrate that, in the presence of low m.w. heparin sulfate-derived oligosaccharides, rHGF{beta} combines with rIL-7 to form a biologically active heterodimer having the properties of PPBSF. The results indicate that PPBSF is a novel form of cytokine (hybrid cytokine) consisting of the bioactive components of two unrelated cytokines. Based on its heparin-binding and mitogenic properties, we postulate that the HGF{beta}-chain in PPBSF enables IL-7 to participate in cognate interactions at the stromal cell surface and to transduce signals effectively at low levels of IL-7R.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Considerable progress has been made in identifying stromal cell-derived growth factors that regulate pro-B cell and pre-B cell development. However, little is known about the factors that regulate pre-pro-B cell development. To approach this problem, we developed a long-term bone marrow (BM)3 lymphoid culture system that selectively supports the self-replication of pre-pro-B cells and their differentiation to pro-B cells (1, 2). Using this system, we have purified a pre-pro-B cell growth-stimulating factor (PPBSF) and demonstrated that it is a heterodimer of IL-7 and a 30-kDa cofactor (PPBSF-coF) (3, 4). Unlike monomeric IL-7, the IL-7/PPBSF-coF complex stimulates proliferation and differentiation of pre-pro-B cells and helps to initiate or up-regulate the expression of terminal deoxynucleotidyl transferase, cytoplasmic Igµ heavy chain, and IL-7R{alpha}-chain (Ref. 5 , and C. Wei, L. Lai, and I. Goldschneider, manuscript in preparation). The latter events appear to enable newly formed pro-B cells to proliferate and differentiate in response to monomeric IL-7 (3).

PPBSF-coF is produced constitutively by IL-7-/- BM stromal cells in our culture system (3, 6), and antisera raised to native PPBSF contain separable reactivities for IL-7 and PPBSF-coF (4). By itself, PPBSF-coF maintains the viability of pre-pro-B cells, whereas in the presence of IL-7 it forms functional complexes of PPBSF. However, despite interacting with IL-7, the PPBSF-coF differs functionally and serologically from stem cell factor (SCF), insulin-like growth factor-1, thymic stromal lymphopoietin, flk2/flt3 ligand, and pre-B cell growth-stimulating factor/stromal derived factor-1{beta}.

In the present study we determined by amino acid sequencing, RT-PCR analysis, and cDNA cloning that the PPBSF-coF is the free mitogenic {beta}-chain of hepatocyte growth factor (HGF)/scatter factor, a heparin-binding, stromal cell-derived, multifunctional cytokine closely homologous to plasminogen (reviewed in Ref. 7). This finding was wholly unexpected, as HGF is a pleiotropic factor that promotes parenchymal cell growth, motility, and morphogenesis in a broad spectrum of tissues; and as the HGF {beta}-chain had not previously been found to be produced independently of the HGF {alpha}-chain (receptor-binding domain for c-MET), with which it is secreted as an inactive single chain precursor (pro-HGF). We also demonstrated that, in the presence of low m.w. heparin sulfate (HS)-derived oligosaccharides, rHGF{beta} complexes with rIL-7 to form a heterodimer having the functional, physical, and serological properties of native PPBSF. Hence, PPBSF appears to represent a functionally unique and heretofore undescribed form of cytokine (hybrid cytokine) consisting of the complexed bioactive portions of two independently generated cytokines. The possible dual function of the IL-7/HGF{beta} hybrid cytokine in the induction of B lineage commitment and the regulation of early B cell development is discussed.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

(129xB6)F2 IL-7-/- and IL-7+/+ mice (generously provided by Dr. R. Murray, DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA) were used as donors of primary BM-adherent cell feeder layers and of enriched (>98%) populations of stromal cells generated by serial passage in vitro (3). Male 4- to 6-wk-old Lewis strain rats were used as donors of BM lymphoid precursor cells.

Cytokines and Abs

Recombinant murine IL-3, IL-7, GM-CSF, HGF, and erythropoietin (EPO) were purchased from R&D Systems (Minneapolis, MN), as were anti-HGF and anti-IL-7 Abs. Affinity-purified goat polycolonal Ab reactive with human and mouse HGF{beta}, 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-7+/+ 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 electrophoresis, the proteins were transferred onto ProBlott membrane (Applied Biosystems, Foster City, CA) using a trans-Blot SD Semidry Transfer Cell (model 200/2.0; Bio-Rad, Hercules, CA), then stained with Coomassie brilliant blue R-250 (Bio-Rad). The 30-kDa band was excised and sent to the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University for direct NH2-terminal sequencing.

Molecular cloning and sequencing of HGF{beta}

Total RNA was isolated with TRIzol Reagent (Life Technologies, Gaithersburg, MD) from populations of enriched IL-7-/- BM stromal cells. Random-primed first-strand cDNA was generated using Moloney murine leukemia virus reverse transcriptase (RETRO Script; Ambion, Austin, TX). PCRs were performed using Taq polymerase (Life Technologies) and primers designed to amplify the entire coding sequence of mouse HGF: 5'-CAGTCTGCTCGAACTGCA-3' (in 5' flanking region), and 5'-TGGCCTCTTCTATGGCTA-3' (in 3' 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. The amplified fragments were separated on 1% agarose gel and visualized by ethidium bromide. The small amplified fragment was cloned into plasmid vectors according to the instructions of the TA Cloning kit (Invitrogen, San Diego, CA). The plasmid DNA was purified and sequenced.

Production of rHGF{beta} proteins

The small PCR-amplified fragment was subcloned into the mammalian expression vector pcDNA3.1(+) (Invitrogen) with a BamHI-XhoI site. The plasmid was transfected into Chinese hamster ovary (CHO) cells (LIPOFECTAMINE Plus Reagent; Life Technologies). The serum-free supernatant from the transfected CHO cells was evaluated for HGF{beta} protein by ELISA. The HGF{beta} gene was also subcloned into the prokaryotic fusion protein expression vector pCAL-n (Stratagene, La Jolla, CA) with a BamHI-EcoRI site and transformed into Escherichia coli BL21(DE3). The HGF{beta} and calmodulin-binding-peptide fusion protein was purified by calmodulin affinity resin, and the peptide was released by thrombin. The purified proteins were electrophoresed in 12% SDS-PAGE and transferred to Immobilon-P membranes (Millipore, Bedford, MA). The membranes were incubated with anti-HGF Ab or anti-HGF{beta} Ab and HRP-labeled anti-goat IgG. Bound Ab was detected using the ECL system (Amersham Pharmacia Biotech, Piscataway, NJ).

Binding assays

Bovine kidney HS (Sigma, St. Louis, MO) was digested with heparitinase I at 37° for 1 h, and the products were ultrafiltrated by Centriprep-3 (m.w. cut-off 3000; Amicon, Beverly, MA) (7). rIL-7 and rHGF{beta} were mixed in the presence or absence of the low m.w. HS-derived oligosaccharides for 1 h. The mixtures were subjected to SDS-PAGE under nonreducing conditions and to Western blotting using anti-HGF{beta} Ab and anti-IL-7 mAb, as described above.

Pre-pro-B cell growth-stimulating activity

Freshly harvested rat BM cells were added to 2 ml of RPMI 1640 containing 20% lot-selected, defined FBS in 35-mm-diameter culture plate wells (2 x 106 cells/well) and incubated at 37°C in 5% CO2 in the presence of 5 ng/ml rIL-7 and/or rHGF{beta}. Anti-HGF or anti-HGF{beta} Ab was added to some cultures at the same time. Ten days later, the nonadherent cells were harvested for phenotypic analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of the PPBSF-coF as the {beta}-chain of HGF

Partial NH2-terminal amino acid sequence analysis of purified PPBSF-coF from IL-7+/+ mice (Fig. 1Go) showed that, when allowances are made for known single nucleotide substitutions at positions 8, 10, and 11, the first 17 amino acid residues were identical with those predicted by published cDNA nucleotide sequences for mouse, rat, and human HGF {beta}-chain (8). The identity of the PPBSF-coF as the HGF {beta}-chain was confirmed by Western blot analyses, in which PPBSF-coF reacted with Ab against full-length HGF and the HGF {beta}-chain (Fig. 2Go), but not the HGF {alpha}-chain (data not shown). In addition, both anti-HGF and anti-HGF{beta} Abs neutralized the PPBSF activity in IL-7+/+ CM (data not shown, but see Fig. 5Go).



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  		FIGURE 1. Partial NH2-terminal amino acid sequence identity of purified mouse PPBSF-coF from enriched IL-7+/+ BM stromal cells. Comparison with the predicted amino acid sequences for the HGF {beta}-chain in mouse, rat, and human as derived from the published nucleotide sequences. Positions of reported nucleotide substitutions are indicated in boxes.

 


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  		FIGURE 2. Confirmation of the identity of the PPBSF-coF as HGF{beta} by Western blotting analyses. Affinity purified PPBSF was electrophoresed under reducing conditions and developed with anti-HGF or anti-HGF{beta} Abs. The 30-kDa PPBSF-coF, but not the 25-kDa IL-7 component, reacted with Abs against HGF{beta}.

 


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  		FIGURE 5. PPBSF activity is reconstituted by rIL-7/rHGF{beta} complexes formed in culture by adding 5 ng of rIL-7 and 5 ng of rHGF{beta} to medium containing 20% FBS (A), or preformed in the presence of HS-derived oligosaccharides before being added to the cultures (B). Freshly harvested rat BM cells (5 x 105 cells/ml) were cultured in each well in the presence or absence of anti-HGF{beta} Ab. Nonadherent lymphoid cells were phenotyped on day 10. Means of triplicate wells. Ab controls (normal goat serum) were negative (data not shown).

 
Identification and cloning of a variant of HGF mRNA

Two products were obtained when mRNA transcripts from IL-7-/- mouse BM stromal cells were analyzed by RT-PCR (Fig. 3Go). One of these products corresponded to the full-length HGF cDNA (2230 bp), and the other to the coding sequence of HGF{beta} (840 bp). The cDNA of the shorter product was cloned, and the nucleotide sequence was found to concur precisely with the published mouse HGF{beta} cDNA sequence. In addition, the signal sequence was identical with that in full-length HGF cDNA.



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  		FIGURE 3. RT-PCR analysis of the HGF mRNA transcripts from mouse BM stromal cells. First-stand cDNA from cultured IL-7-/- mouse BM stromal cells were subjected to PCR with primers designed to amplify the entire coding sequence of mouse HGF. Both the 2230-bp PCR product corresponding to full-length HGF and a novel 840-bp product were present.

 
The HGF{beta}-chain cDNA was then transfected into CHO cells or transformed into E. coli BL21 (DE3). HGF{beta} protein was detected by ELISA in the supernatant of HGF{beta} (but not empty vector)-transfected cells, and by SDS-PAGE and Western blotting after release from the prokaryotic fusion protein (data not shown).

Formation and biological activity of a heterodimer of rIL-7 and rHGF{beta}

As both IL-7 and HGF are heparin-binding molecules (9, 10), we tested the ability of rIL-7 and rHGF{beta} to form a heterodimer when equal concentrations (250 ng/ml) were mixed in serum-free medium in the presence or absence of low m.w HS-derived oligosaccharides. The results in Fig. 4Go show that rHGF{beta} and rIL-7 migrated at 30 and 14.5 kDa, respectively, in the absence of the HS-derived oligosaccharides, and at 45 kDa in their presence. At higher concentrations of IL-7 and HGF{beta} (>=1000 ng/ml), larger complexes were also detected, but the heterodimeric form continued to predominate (data not shown). Comparable results were obtained when FBS (5–20%) was substituted for HS-derived oligosaccharides.



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  		FIGURE 4. Recombinant IL-7 forms a heterodimer with rHGF{beta} in the presence of low m.w. HS-derived oligosacchrides. Recombinant IL-7 (250 ng) was added to serum-free culture medium containing rHGF{beta} (250 ng) in the presence or absence of low m.w. HS-derived oligosaccharides. One hour later, duplicate aliquots of each mixture were electrophoresed on a single gel under nonreducing conditions. The proteins were then transferred to an Immobilon-P membrane, one half of which was developed with anti-HGF{beta} Ab (A) and the other half with anti-IL-7 mAb (B). In each instance, a 45-kDa heterodimer was observed in the presence (lane 2), but not the absence (lane 1), of the HS-derived oligosaccharides.

 
Two approaches were used to confirm that the IL-7/HGF{beta} heterodimer had biological activity. In the first, rat BM cells were incubated in culture medium (plus 20% FBS) containing rIL-7 and/or rHGF{beta}. As anticipated (3), both rIL-7 and rHGF{beta} were able to maintain the viability of pre-pro-B cells, but neither was able to stimulate their proliferation or differentiation to pro-B cells. However, when added concurrently, these reagents significantly enhanced the generation of pre-pro-B cells and pro-B cells (Fig. 5GoA), presumably by forming PPBSF complexes comparable to those present in stromal cell CM (3, 4). In the second approach, the purified rIL-7/rHGF{beta} heterodimer preformed in the presence of HS-derived oligosaccharides was added directly to the culture medium (Fig. 5GoB). In both instances the bioactivity was neutralized by anti-HGF{beta} Ab.

To test the specificity of the interaction of IL-7 with HGF{beta}, several other heparin-binding factors involved in lymphohemopoiesis (GM-CSF, IL-3, EPO) (11) were mixed with rIL-7 or rHGF{beta} in the presence of HS-derived oligosaccharides. No detectable complexes were formed (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Inasmuch as pro-HGF is converted by targeted protease digestion to a disulfide-linked heterodimer comprised of a 60-kDa {alpha}-chain and a 30-kDa {beta}-chain (7), it could be argued that the free HGF{beta}-chain (PPBSF-coF) observed in culture supernatants (3) is an enzymatic cleavage fragment that normally would be degraded in vivo. However, both RT-PCR analysis of mRNA transcripts and cDNA cloning of the shorter product proved otherwise. Rather, the PPBSF-coF is a variant HGF that lacks the {alpha}-chain domain. While unique, this finding is consistent with the identification of several other variant HGFs and transcripts produced by alternative splicing of the HGF gene (12, 13, 14, 15). Among these, an 85-kDa native and a 28-KDa variant HGF {alpha}-chain is produced by human BM stromal cells (16).

Although a great deal is known about the actions of HGF in nonhemopoietic tissues, its role in the regulation of hemopoiesis, and particularly lymphopoiesis, is fragmentary (7). HGF has been proposed to regulate hemopoiesis in mouse fetal liver and adult BM, where it apparently can substitute for the SCF and c-kit system (17). HGF is produced by BM stromal cells and synergizes with IL-3 or GM-CSF to support the growth of hemopoietic progenitor cells and myeloid tumor cell lines, all of which express the HGF receptor, c-MET (18). In addition, HGF has been found to promote adhesion of hemopoietic progenitor cells to fibronectin (18). In the presence of EPO, HGF induces the formation of colonies along the erythroid lineage, whereas in the presence of EPO and SCF, HGF supports the growth of multipotent colonies (19). Furthermore, IL-11, which is thought to up-regulate c-MET, synergizes with HGF to support in vitro colony formation by hemopoietic stem cells (20). Thus, HGF appears to be an important mediator of paracrine interactions between stromal and hemopoietic cells that preferentially acts in the window of differentiation between multipotent stem cells and committed progenitors. However, by itself, HGF does not appear to stimulate proliferation of hemopoietic precursors. This suggests, as one possibility, that the primary role of HGF in hemopoiesis is to enhance signal transduction by lineage-specific cytokines.

Among lymphoid cells, mRNA for c-MET has been identified in thymocytes, and HGF increases the generation of mature T cells in fetal thymus organ cultures (21). c-MET is also expressed on early B lineage cells in BM (19), and may help to regulate integrin-mediated adhesion and migration of B cells in germinal centers (22). Furthermore, upon activation, B cells bind large amounts of HGF via HS moieties, thereby promoting the phosphorylation of c-MET and of several substrates (7).

Therefore, the question arises as to why the IL-7/HGF{beta} hybrid cytokine, in contrast to HGF, HGF{beta}, and monomeric IL-7, selectively supports the proliferation and differentiation of pre-pro-B cells. Two possibilities are immediately apparent: 1) the need for cognate interactions of pre-pro-B cells with BM stromal cells (23); and 2) the expression of only low levels of the IL-7R{alpha}-chain (5). Our working hypothesis is that the heparin-binding IL-7/HGF{beta} hybrid cytokine, like HGF (11), functions primarily as a cell surface or extracellular matrix-bound molecule; and that it, unlike IL-7, effectively transduces signals for proliferation and differentiation in the presence of low levels of IL-7R{alpha}. We further postulate that PPBSF enables the resulting pro-B cells to respond to monomeric IL-7 by up-regulating the expression of IL-7R{alpha} (Ref. 5 , and C. Wei, L. Lai, and I. Goldschneider, manuscript in preparation). Our hypothesis is consistent with the demonstration that: 1) extracellular matrix glycoproteins can selectively increase the IL-7-dependent proliferation of early B lineage cells (24); 2) differentiation of pre-pro-B cells to pro-B cells requires signaling through high affinity IL-7R complexes (5); and 3) pre-BCR signaling can modulate the IL-7 response (25). It may also help to explain why excess IL-7 fails to increase pre-pro-B cell generation in vivo (26, 27), and why IL-7 does not stimulate proliferation of pro-B cells from IL-7 knockout mice in vitro unless these cells are first treated with PPBSF (Ref. 5 , and C. Wei, L. Lai, and I. Goldschneider, manuscript in preparation).

To our knowledge, this is the first demonstration of a naturally occurring hybrid cytokine (i.e., a functional complex of the bioactive portions of two or more disparate cytokines or growth factors). Although IL-12 and related "composite" cytokines (e.g., IL-23, cytokine-like factor-cardiotrophin-like cytokine complex) also are heterodimers, they are structurally analogous to cytokine-receptor complexes rather than hybrid cytokines (28, 29, 30). However, many cytokines other than HGF and IL-7 are known to interact with HS (11), and some of these in theory could form functional homodimeric or heterodimeric complexes. For example, HS-derived oligosaccharides induce fibroblast growth factor to form homodimers that facilitate fibroblast growth factor receptor dimerization (31). Hence, the discovery of the IL-7/HGF{beta} complex is significant not only because it provides a functionally unique factor that helps to regulate the earliest stages of B lymphocyte development, but also because it may presage the existence of other hybrid cytokines. Therefore, it will be important to determine how signaling by PPBSF differs from that of monomeric IL-7 (and HGF), and whether the HGF{beta} moiety binds to the IL-7R complex itself or to another receptor on the pre-pro-B cell surface. It will also be of interest to investigate the intriguing possibility that PPBSF may help to induce the commitment of hemopoietic stem cells to development along the B (and possibly T) lymphoid pathways.


   Footnotes
 
1 This study was supported in part by National Institutes of Health Grant AI 32752. Back

2 Address correspondence and reprint requests to Dr. Irving Goldschneider, Department of Pathology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030. E-mail address: igoldsch{at}neuron.uchc.edu Back

3 Abbreviations used in this paper: BM, bone marrow; CM, conditioned medium; coF, cofactor; HGF, hepatocyte growth factor; HS, heparin sulfate; PPBSF, pre-pro-B cell growth-stimulating factor; SCF, stem cell factor; EPO, erythropoietin; CHO, Chinese hamster ovary. Back

Received for publication May 21, 2001. Accepted for publication August 14, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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