Interleukin-17A: A T-Cell-Derived Growth Factor for Murine and Human Mesenchymal - 《stemcells》干细胞学杂志干细胞之家



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作者：Weitao Huanga, Vincent La Russab, Azam Alzoubib, Paul Schwarzenbergera作者单位：a Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama, USA;b Department of Pharmacology, Tulane University, New Orleans, Louisiana, USA 3 x4 O( R; `3 Q# {+ z9 q0 h
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      【摘要】* B0 d' ^3 Z! }6 U0 V$ d+ U
   Interleukin-17A (IL-17A) is a proinflammatory cytokine expressed in activated T-cells. It is required for microbial host defense and is a potent stimulator of granulopoiesis. In a dose-dependent fashion, IL-17A expanded human mesenchymal stem cells (MSCs) and induced the proliferation of mature stroma cells in bone marrow-derived stroma cultures. Recombinant human interleukin-17A (rhIL-17A) nearly doubled colony-forming unit-fibroblast (CFU-f) frequency and almost tripled the surface area covered by stroma. In a murine transplant model, in vivo murine (m)IL-17A expression enhanced CFU-f by 2.5-fold. Enrichment of the graft with CD4  T-cell resulted in a 7.5-fold increase in CFU-f in normal C57BL/6, but only threefold in IL-17Ra¨C/¨C mice on day 14 post-transplant. In this transplant model, in vivo blockade of IL-17A in C57BL/6 mice resembled the phenotype of IL-17Ra¨C/¨C mice. Approximately half of the T-cell-mediated effect on MSC recovery following radiation-conditioned transplantation was attributed to the IL-17A/IL-17Ra pathway. Pluripotent MSCs have the potential of regenerating various tissues, and mature stroma cells are critical elements of the hematopoietic microenvironment (HME). The HME is pivotal for formation and maintenance of functional blood cells. As a newly identified stroma cell growth factor, IL-17A might have potential applications for novel treatment approaches involving MSCs, such as tissue graft engineering. , G8 {$ w! N( n  L
      【关键词】 Mesenchymal stem cells Hematopoeitic microenvironment T-cells Interleukin- Stroma
   INTRODUCTION6 Y+ s- U$ @" `5 ]$ f+ S- ^
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Interleukin-17A (IL-17A) is a T-cell-derived, proinflammatory cytokine whose expression is induced in activated T-cells, specifically in CD4  T-cells .

"Bone marrow stroma cells" originate from pluripotent cells in the marrow, and these primitive precursor cells are also called mesenchymal stem or progenitor cells (MSCs) .

T-cells exert important regulatory functions on the hematopoietic system, although the mechanisms remain elusive. For instance, in transplantation settings, T-cell depletion of donor grafts leads to delayed or failed engraftment. This in turn leads to delayed or failed formation of functional hematopoietic lineages with increased risk of infectious complications or death . Here, we have investigated the hypothesis that IL-17A might be one of the elusive T-cell-derived regulatory factors that exert a proliferative effect on MSC precursors.

MATERIALS AND METHODS+ c( U7 Z0 X7 J! x( \: z' p

Animals# @. i, A0 c/ f8 e/ J7 n2 w& `
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The generation of the IL-17Ra¨C/¨C mouse has been described previously . Unless otherwise noted, 3 x 109 plaque-forming units of adenovirus were intravenously injected. -Irradiation was performed by giving myeloablative doses in two fractions 4 hours apart using a cobalt source (Gammacell 1000; Atomic Energy of Canada, Ottawa, ON, Canada; 1000 rads for C57BL/6 and 850 rads for IL17Ra¨C/¨C mice).' b, I& m5 ]1 |0 P5 }; ~
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Human Bone Marrow Stroma Culture and Human CFU-f Assays) c1 T" X  l4 e6 d1 S
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Human bone marrow cells were obtained from volunteer donors through iliac crest aspiration using an IRB approved protocol. Cells were immediately Ficoll-purified, and low-density (  X' V' B4 Z8 W( f/ t; g
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Murine Cell Culture and Cell Isolation% N& L3 H0 j! ~8 u; ~6 K. W0 g

Cell subpopulations were isolated from organs (spleen) using the Miltenyi microbead isolation system for CD4  T-cells (L3T4), following the instructions of the manufacturer (Miltenyi Biotec, Auburn, CA, http://www.miltenyibiotec.com). Cells were double-purified for all in vivo experiments. Purity of the separation was confirmed by using flow cytometry with a non-competing monoclonal antibody (GK1.5, ATCC, Manassas, VA, http://www.atcc.org; FACSCalibur, Becton, Dickinson and Company, Franklin Lakes, NJ, http://www.bd.com). All T-cell fractions were also plated in cytokine-supplemented semisolid agar (Sigma-Aldrich, St. Louis, http://www.sigmaaldrich.com) using previously described techniques to identify potentially contaminating primary hematopoietic precursor cells .
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CFU-f assays were performed on primary murine hematopoietic tissue by flushing murine bone marrow from both femuri and filtering cells through nylon mesh for removal of connective tissue fragments. Spleens were ground between glass slides, and tissue fragments were also removed through filtration through nylon mesh. Red blood cell lysis was accomplished using a hypotonic solution of NH4Cl. Defined numbers of cells were placed into six-well plates (Costar) and cultured with medium made up of DMEM (Gibco) and 10% FCS (Hyclone). All nonadherent cells were decanted 8 hours later, and dishes were supplemented with fresh medium. Change of culture medium was performed every 2¨C3 days. At 2 weeks, adherent cells were stained with trypan blue and fixed with methanol. Scoring of colonies adherent to the bottom of the plastic was performed under low amplification with transmission light microscopy.  V1 i0 T$ W/ G8 \& F

Statistical Analysis  b7 y, ?8 @. Y& [' O4 z4 Y" t
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Data were analyzed by analysis of variance using the statistical program StatView (Abacus Concepts, Calabasas, CA). A p value of + P. R+ F, I! V9 ^7 Q7 E% K
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RESULTS) h: [+ o& X6 A6 M
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rhIL-17A Increases the Frequency of Human Stroma Cell Colonies (CFU-f) and Expands the Total Surface Area Covered by Human Bone Marrow Stroma Cell Colonies  ]1 a* a( b2 p2 ~

Primary human bone marrow cells were obtained by aspiration from the iliac crest of human volunteers, and stroma cultures were established as described. Fresh bone marrow cells were plated with biologically active rhIL-17A or heat-inactivated rhIL-17A added to the culture medium at different concentrations (0¨C50 ng/ml). Results with heat-inactivated rhIL-17A at all doses were identical with the dose of 0 ng/ml rhIL-17A. A total of six individual donors were used, and three sets of quadruplicate dishes were plated from each donor for each individual experiment. At 2 weeks, the total plate surface was stained, and the surface area covered by stroma colonies, as well as their frequency, was computed. Reported results for the effect of IL-17A were similar and reproducible for each individual donor. Data presented reflect the combined mean of different donors ¡À SEM. A dose-dependent increase of CFU-f frequency and surface area covered were seen in the rhIL-17A-treated plates. At 50 ng/ml rhIL-17A, the average number of CFU-f colonies was increased by nearly 60% over control (35 ¡À 1.7 vs. 20 ¡À 1.1) (p % a' Z9 R# A& t7 y* z) m6 j

Figure 1. Effect of rhIL-17A on human bone marrow-derived CFU-f in vitro. Primary human bone marrow-derived stroma cell cultures from six individual donors were plated in quadruplicate for each donor at exposed to different concentrations (0¨C50 ng/ml) with biologically active rhIL-17A or heat-inactivated rhIL-17A. Results with heat-inactivated rhIL-17A at all doses were identical with the dose of 0 ng/ml rhIL-17A. At 2 weeks, the total plate surface was stained, scored, and computed. The depicted data represent the mean results of all donors ¡À SEM. Statistical significance is indicated by asterisks. (A): Average number of CFU-f colonies. (B): Total area of stroma covering the plate surface. (C): Average colony size. (D): Frequency of CFU-f for colonies measuring more than 30 mm2 and a size of 16¨C30 mm2 at different rhIL-17A culture concentrations. Abbreviations: CFU-F, colony-forming unit-fibroblast; rhIL, recombinant human interleukin.- T7 w8 s0 r8 Z0 t5 A! T* V  `

rhIL-17A Increases the Average Size of Primary Human Bone Marrow-Derived Stroma Colonies and Induces Formation of Giant-Sized CFU-f% z6 P* F8 I6 Y# |

At 2 weeks, the sizes of individual colonies were measured. A dose-dependent increase in individual colony size was recorded for cultures with biologically active rhIL-17A. At a concentration of 50 ng/ml rhIL-17A, the average colony size increased by almost 60% (11 mm2 vs. 19 mm2) (p 9 ?* s/ Y) ?9 N, V

mIL-17A Expression Increases Stroma Cell Precursor Frequency (CFU-f) in Mice In Vivo Following Autologous Bone Marrow Transplantation
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Lethally irradiated IL-17Ra¨C/¨C mice or their normal C57BL/6 littermate controls were rescued with syngeneic bone marrow (5 x 106 bone marrow-derived cells) (n = 6 per group and data point). The mice were also treated with AdmIL-17A or a control virus encoding the luciferase gene (AdCMVLuc). Bone marrow-derived and spleen-derived CFU-f were scored at day 14. In C57BL/6 mice treated with Ad-mIL17A, CFU-f frequency was more than doubled at 14 days in bone marrow-derived cells and almost tripled in spleen-derived cells compared with animals treated with the control virus AdCMVLuc (p
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Figure 2. Effect of in vivo mIL-17A expression on CFU-f formation following autologous bone marrow transplantation in mice. Lethally irradiated IL-17R¨C/¨C mice or their normal C57BL6 littermate controls were rescued with syngeneic mononuclear bone marrow (5 x 106 cells) and at the same time injected with Ad-mIL17A or AdCMVLuc (A, B). Another group of animals was also injected with virus but was not irradiated or transplanted (C). CFU-f BM and CFU-f Spleen were scored at day 14. (A): Results for irradiated and transplanted C57BL6 mice. (B): Results for IL-17R¨C/¨C mice. (C): Results for unirradiated, untransplanted C57BL6 mice. Data represent the mean ¡À SEM of five individual animals. Statistical significance is indicated by asterisks. Abbreviations: AdCMVLuc, control virus encoding the luciferase gene; Ad-mIL17A, adenovirus encoding mIL-17A; CFU-f, colony-forming unit-fibroblast; CFU-f BM, bone marrow-derived CFU-f; CFU-f Spleen, spleen-derived CFU-f; mIL, murine interleukin.

Blockade of IL-17Ra Reduces CFU-f Formation Following Autologous Bone Marrow Transplantation In Vivo* w) H% ?# T' A8 d2 i  a

C57BL/6 mice were lethally irradiated and reconstituted with 5 x 106 mononuclear bone marrow-derived cells and 1 x 107 CD4  double-selected T-cells (n = six per group and data point). The animals were divided into two groups, which were treated with a previously described construct capable of in vivo blockade of mIL-17A . The construct is an adenovirus encoding the soluble mIL-17A receptor, and for prolongation of its half-life, it was linked to the murine immunoglobulin Fc fragment (Ad-mIL17RaFc). Control animals were treated with a control virus encoding the luciferase gene (AdCMVLuc). CFU-f formation was reduced by more than 50% in the Ad-mIL17RaFc treated animals (p / ~$ R* u$ y* @: j0 }
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Figure 3. Effect of IL-17A blockade on CFU-f formation following CD4  T-cell-enriched autologous bone marrow transplantation. C57BL6 mice were lethally irradiated and reconstituted with 5 x 106 mononuclear bone marrow-derived cells and 1 x 107 CD4  double-selected T-cells. For in vivo mIL-17A blockade, mice were injected with Ad-mIL17RaFc; control animals were injected with the luciferase gene encoding adenovirus (AdCMVLuc). CFU-f formation was scored from bone marrow and plotted as the mean ¡À SEM of five individual animals. Statistical significance is indicated by asterisks. Abbreviations: Ad-Luc, Adenovirus-Luciferase (adenovirus-encoding luciferase); Ad-mIL17RaFc, soluble mIL-17A receptor Fc; CFU-f, colony-forming unit macrophage.9 a  l1 S2 ]9 M+ v. R
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CD4  T-Cells Enhance CFU-f Formation Following Autologous Bone Marrow Transplantation in Wild-Type Mice and Less in IL-17Ra¨C/¨C Mice# p& G" z, U, G" _

IL-17Ra¨C/¨C mice and normal C57BL/6 littermate controls were lethally irradiated and reconstituted with 5 x 106 syngeneic mononuclear bone marrow-derived cells (n = 6 per group and data point). Donor marrow was either depleted of CD4  and CD8  T-cells in vivo prior to harvest using the specific antibodies GK1.3 and xx or, if indicated, supplemented prior re-infusion with spleen-derived double-column-purified CD4  T-cells that were added to the graft at a dose of 1 x 107. Depletion was validated by flow using different CD4 /CD8  antibodies (BD Pharmingen, San Diego, http://www.bdbiosciences.com/pharmingen). The purity of T-cells fractions was analyzed by flow cytometry, as well as by their ability to form hematopoietic colonies to exclude contamination with hematopoietic progenitor cells (colony-forming unit-granulocyte/macrophage, granulocyte/erythroid/macrophage/megakaryocyte HPP, or CFU-f). None of the CD4  T-cell fractions used for transplantation were contaminated with cells of repopulating ability. Following transplantation of either strain with CD4  - and CD8  -depleted bone marrow cell fractions, similar CFU-f formation was observed in both groups, which was statistically not significantly different between C57BL/6 and IL-17Ra¨C/¨C animals (2.2 ¡À 0.5 vs. 2.3 ¡À 2.4, respectively). The addition of CD4  T-cells resulted in a 7.5-fold increase of CFU-f in normal mice (16.5 ¡À 2.5) (p

Figure 4. Effect of CD4  T-cells on CFU-f formation following autologous bone marrow transplantation in normal and in IL-17Ra¨C/¨Cmice. Lethally irradiated IL-17Ra¨C/¨C mice or their normal C57BL6 littermate controls were rescued with 5 x 106 CD4  depl. Where indicated, grafts were supplemented with 1 x 107 CD4  add. CFU-f formation was scored from bone marrow and is plotted as the mean ¡À SEM of five individual animals. Statistical significance is indicated by asterisks. Abbreviations: CD4  add., double column-purified CD4  T-cells; CD4  depl., CD4  T-cell-depleted syngeneic mononuclear bone marrow cells; CFU-f, colony-forming unit-fibroblast; IL-17Ra¨C/¨C, CFU-f obtained from IL-17Ra¨C /¨C.% \/ \/ @4 s+ y% r

DISCUSSION$ L% [' a, h0 u+ {4 n2 j' u

In our current working model, activated T-cells express IL-17A within the HME. IL-17A binds to mature stroma cells, which express the receptor IL-17Ra at high levels. IL-17Ra signaling leads to expression and release of various downstream mediators, resulting in stimulation of granulopoiesis . We conducted experiments examining the role of T-cells from a different angle. We hypothesized that T-cells might serve as cofactors for MSC survival and expansion and that they were required for the reconstitution of bone marrow stroma cells after myeloablative therapy following stem cell rescue. We hypothesized that T-cells might exert a direct stimulatory effect on stroma cells via the IL-17A/IL-17Ra pathway. In contrast to most of the quoted human studies, however, we used an autologous rodent model of BMT, using -irradiation as the only conditioning treatment. Allogeneic T-cell-mediated suppression of stroma cells or stroma precursors therefore would not be a phenomenon to be expected in this experimental setup.' u# U6 X0 L8 O$ ]
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Although protocols for in vitro murine bone marrow-derived stroma cell cultures are being used, they are experimentally more difficult to perform, and results often are less consistent compared with cultures performed with primary human bone marrow stroma cells . Studies to investigate the role of mIL-17A/IL-17Ra on stroma cells in vivo were conducted in both normal controls and IL-17Ra¨C/¨C mice.
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The data demonstrated that IL-17A significantly increased colony frequency, as well as the size of individual colonies, of human CFU-f in vitro in a dose-dependent manner. Because IL-17A is not expressed or is expressed only at very low levels in T-cells under normal physiologic conditions, IL-17A is considered an emergency response cytokine, whose expression is reserved for situations such as infections, where it enhances myeloid host defense . It is possible that other, yet to be identified mediators may be involved that are required for creating a synergistic cytokine milieu in vivo that enables effective stimulation of MSCs.6 t: {7 Y' H# ?/ |' t: n- H$ s

There appears to be a discrepancy between a 2.5-fold increase in MSCs with in vivo expression of mIL-17A and a 7.5-fold increase with T-cell enrichment. However, blockade of the IL-17A/IL-17Ra pathway leads to approximately 50% reduction of the T-cell-mediated effect on stroma cells. Clearly, IL-17A is more effective in the context of T-cells than solely as recombinant protein. This could be interpreted that although IL-17A by itself can expand MSCs in vivo, T-cells are more effective, likely because activated T-cells secrete or display some other factors that could be synergistic with IL-17A in stimulating MSC expansion and proliferation. In support of this hypothesis are the results from the experiments in which the IL-17A/IL-17Ra pathway was neutralized (Fig. 3). Blockade of IL-17A in C57BL/6 mice transplanted with CD4  supplemented grafts still resulted in increased CFU-f, although it was significantly reduced over nonblocked controls. These findings closely resembled IL-17Ra¨C/¨C animals that were transplanted with CD4  T-cell enriched grafts compared with normal littermates. This indicates that T-cells exert their effects in vivo on mature stroma cells and their precursors via the IL-17A/IL-17Ra mechanism, but also through other, not yet identified mechanisms.6 Y5 b& U! X4 p, s' O7 O% w3 v

Whereas T-cell depletion after radiation injury increased mortality in various animal models and led to increased engraftment failure in human transplantation, adoptive transfer of T-cells following radiation injury enhanced hematopoietic recovery and survival; however, the exact mechanisms remain unknown . Radiation, as part of its nonspecific tissue-damaging effect, induces IL-17A expression at very high levels in T-cells in vivo. -Irradiation induced IL-17A expression in T-cells only in vivo, not in vitro. The level of induction was close to half of what could be elicited under ex vivo stimulation with Concavalin A (manuscript submitted for publication).6 H. t3 _+ [3 i' [6 O2 V/ k
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It is conceivable that T-cells facilitate hematopoietic recovery following radiation injury through different and independent mechanisms within an intricate network and dynamic interactions among stroma cells of the HME, lineage-specific precursors, and mature cells. Under this physiologic need of tissue repair, stroma proliferation and stroma precursor expansion is stimulated via the IL-17A/IL-17Ra pathway. It is possible that this is one of several mechanisms leading to accelerated recovery of the HME as part of restoration of normal hematopoiesis. However, further experiments will be required to establish definitive correlations that would allow validating this hypothesis.

As a primary growth factor for stroma cells and MSCs, IL-17A could be explored for therapeutic use. MSCs are being investigated for graft engineering of various tissues. IL-17A might have a role in bone marrow failure situations caused by a dysfunctional HME. For instance, T-cell deficiency conditions, such as AIDS at a late stage, are commonly associated with trilineage bone marrow failure, and it has been suggested that this might be the result of an impaired and failing HME . Detailed investigations to determine the exact role of IL-17A in this condition will be needed.
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DISCLOSURES& {& @9 y/ T  ^! G7 v
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The authors indicate no potential conflicts of interest.$ {; b) Y4 B9 W5 l6 V
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ACKNOWLEDGMENTS
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We thank Dr. Darwin Prockop (Tulane University, New Orleans, LA) for helpful suggestions during the planning and conduct of the experiments, as well as review of the manuscript.9 H! O" ]6 \9 L  p
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