About this Journal Submit a Manuscript Table of Contents
TheScientificWorldJOURNAL
Volume 11 (2011), Article ID 671453, 9 pages
http://dx.doi.org/10.1100/2011/671453
Review Article

The Role of CD40/CD40 Ligand Interactions in Bone Marrow Granulopoiesis

1Department of Hematology, University of Crete School of Medicine, P.O. Box 1352, 71110 Heraklion, Crete, Greece
2Graduate Program “Molecular Basis of Human Disease”, University of Crete School of Medicine, 71003 Heraklion, Greece

Received 29 August 2011; Accepted 5 October 2011

Academic Editor: Marco Antonio Cassatella

Copyright © 2011 Irene Mavroudi and Helen A. Papadaki. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The CD40 ligand (CD40L) and CD40 are two molecules belonging to the TNF/TNF receptor superfamily, and their role in adaptive immune system has widely been explored. However, the wide range of expression of these molecules on hematopoietic as well as nonhematopoietic cells has revealed multiple functions of the CD40/CD40L interactions on different cell types and processes such as granulopoiesis. CD40 triggering on stromal cells has been documented to enhance the expression of granulopoiesis growth factors such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte/monocyte-colony-stimulating factor (GM-CSF), and upon disruption of the CD40/CD40L-signaling pathway, as in the case of X-linked hyperimmunoglobulin M (IgM) syndrome (XHIGM), it can lead to neutropenia. In chronic idiopathic neutropenia (CIN) of adults, however, under the influence of an inflammatory microenvironment, CD40L plays a role in granulocytic progenitor cell depletion, providing thus a pathogenetic cause of CIN.

1. INTRODUCTION

CD40 ligand (CD40L) is a type II transmembrane protein belonging to the tumor necrosis factor (TNF) family, and its gene is located on the q arm of chromosome X [1]. Following activation, it can be upregulated predominantly on CD4+ T-cells and platelets, but also on CD8+ T-cells, natural killer (NK) cells, B-cells, dentritic cells (DCs), monocytes/macrophages, basophils, eosinophils, and endothelial cells [1, 2]. Its receptor, CD40, is a type I transmembrane protein, belonging to the TNF receptor superfamily and is encoded by the gene located on the q arm of chromosome 20 [3]. CD40 is constitutively expressed on normal and leukemic B cells, as well as on monocytes, macrophages, endothelial cells, epithelial cells, smooth muscle cells (SMCs), DCs, fibroblasts, and adipocytes [1, 4].

The cytoplasmic domain of CD40 lacks intrinsic signaling activity, and upon ligation, it recruits adaptor proteins, namely, the tumour receptor-associated factors (TRAFs) to initiate different downstream signaling pathways resulting in a wide spectrum of cell-type specific actions [5]. The role of CD40-CD40L interactions on adaptive immunity has been extensively studied [6, 7]. Upon ligation, CD40 stimulates B-cell proliferation and differentiation into plasma cells, germinal center formation, immunoglobulin switching, and somatic hypermutations [8, 9], while it is also involved in the development of thymocytes and differentiation of naïve CD4+ T cells [1013]. Furthermore, CD40-40L interactions play an important role in innate immunity [6, 14], apoptosis [15, 16], inflammtion, and a number of autoimmune diseases [1720].

The role of CD40-CD40L dyad, however, has not been elucidated in normal granulopoiesis as well as in neutropenia states. In this paper we will highlight the role of CD40L in the development of granulocytic cells.

2. GRANULOPOIESIS

Granulopoiesis is a complex process in which a large number of granulocytes is formed from a small number of hemopoietic stem cells (HSCs) that can replicate and differentiate into multilineage-(common myeloid progenitors; CMPs), double-lineage-(granulocyte/macrophage progenitors; GMPs), and unilineage-committed progenitor cells which further multiply and differentiate into functional mature neutrophils [21, 22]. In early granulopoiesis, granulocyte/monocyte-colony-forming units (CFU-GM), which express the CD34+ surface antigen, give rise to granulocyte-colony-forming units (CFU-G), while in the later stages of neutrophil maturation, myeloblasts, being the first morphologically distinguishable cells of granulocytic lineage expressing both CD34 and CD33 antigens, can divide and differentiate into promyelocytes (CD34/CD33+), myelocytes (CD34/CD33+), which further differentiate into metamyelocytes, band cells (CD33/CD15+), and finally neutrophils [2326].

The whole process is strictly controlled by transcription factors, such as CCAAT/enhancer-binding protein alpha (c/EBPα), PU.1, c-Myb, lymphoid enhancer-binding factor-1 (LEF-1), c/EBPε [2730], and growth factors and cytokines like stem-cell factor (SCF), FMS-like tyrosine kinase 3 ligand (Flt3-L), interleukin(IL)-3, granulocyte/monocyte-colony-stimulating factor (GM-CSF), and granulocyte-colony stimulating factor (G-CSF) [3136]. In vivo, the growth factors that promote granulopoiesis are produced mainly in the bone marrow (BM) stromal microenvironment as indicated from in vitro  experiments with long-term BM cultures (LTBMCs), where a stromal layer of adherent cells consisting mostly of fibroblasts, macrophages, endothelial cells, and adipocytes can produce constitutively or after stimulation the above mentioned growth factors [3740].

Among the major regulators of granulopoiesis are the GM-CSF and G-CSF that can act through their receptors on a range of hematopoietic as well as nonhematopoietic cells [4143]. G-CSF is produced by monocytes and macrophages, fibroblasts, and endothelial cells following stimulation with lipopolysaccharide (LPS), IL-1, IL-3, GM-CSF, TNFα, and interferon (IFN)-γ [4448]. It controls the survival, proliferation, and differentiation of cells along the granulocytic pathway and is necessary for their terminal differentiation to mature neutrophils [4951]. GM-CSF is produced by macrophages, T lymphocytes, fibroblasts, endothelial cells, and stromal cells, which in most cases require stimulation with cytokines, antigens, or inflammatory agents [39, 5255].

GM-CSF promotes the proliferation and maturation of neutrophils, and macrophages from BM progenitors can interact with other factors, which may elevate or decrease cell growth in the presence of different amounts of the cytokine [35, 36, 56, 57].

3. THE GRANULOPOIESIS-PROMOTING EFFECT OF CD40L

As mentioned above, BM stromal cells express constitutively or under stimulation CD40 on their surface, and upon engagement with CD40L and/or other stimuli, they can upregulate the expression of GM-CSF and G-CSF, two of the key regulators of granulopoiesis. It has been demonstrated that CD40 triggering on endothelial cells as well as on SMCs enhances the production of GM-CSF [58, 59]. Endothelial cells and macrophages have also been reported to upregulate IL-1β and IFNγ expression upon CD40 ligation [6, 6062], which, in turn, act synergistically with CD40L on fibroblasts to induce GM-CSF expression [63]. Consistent with these hypothesis was the observed upregulation of GM-CSF on thymic epithelial cells following activation with IL1, IFNγ, and CD40L [64]. Furthermore, in a recent work from our group, it was demonstrated that CD40 engagement on BM stromal cells from healthy donors resulted in increased levels of both G- and GM-CSF in the supernatants of LTBMCs [65]. In addition, when BM mononuclear cells (BMMCs) obtained from healthy subjects were cocultured with the adherent-cell layer of normal LTBMCs in the presence of CD40L and assessed for clonogenic progenitor cells, the number of granulocytic-colony-forming units (CFU-G) was increased comparing with the untreated cultures [65]. Our data corroborate the granulopoiesis-inducing effect of CD40/CD40L through G- and GM-CSF induction BM stroma.

Flt3-L, which is another hematopoiesis/granulopoiesis-promoting factor that acts on primitive and myeloid-committed hematopoietic cells [66, 67], was shown to be upregulated upon CD40 stimulation on fibroblasts, endothelial cells, and stromal cells from LTBMCs. Furthermore, in CD40L-induced cocultures of endothelial cells (ECs) with CD34+ cells, the production of Flt3-L increased the number of clonogenic cells [68]. In the same work, CD40 ligation on all stromal cell types resulted in thrombopoietin (TPO) expression, a regulator of early hematopoiesis [69].

4. CD40L AND NEUTROPENIA

The CD40-CD40L couple is implicated in different types of neutropenia with distinct pathogenetic cause. The X-linked hyperimmunoglobulin M (IgM) syndrome (XHIGM) is a rare immunodeficiency disease characterized by normal or elevated serum IgM, reduced levels of IgG, IgA, and IgE, and defective T-cell function. The most common clinical signs are infections, arthritis, and mucosal ulcers. In the majority of patients, the syndrome is due to mutations of the gene encoding for CD40L on chromosome X, and almost 70% of these patients have neutropenia, 45% of whom having chronic neutropenia, without the presence of antineutrophil antibodies [7072] (Table 1). The etiology of neutropenia in XHIGM is not well known, but it has been hypothesized that abnormal CD40L interactions with stromal cells resulting in ineffective synthesis of granulocyte-inducing growth-factors may have a role. In favor of this hypothesis is the finding that treatment of patients with recombinant G-CSF results in increased or normal levels of neutrophil counts [73, 74].

tab1
Table 1: Pathogenetic and pathophysiologic features of X-linked Hyper IgM Syndrome and Chronic Idiopathic Neutropenia.

Chronic idiopathic neutropenia (CIN) of adults is an acquired form of neutropenia representing the mild form of the spectrum of BM failure syndromes that are characterized by T-cell and cytokine-mediated suppression of hematopoiesis. The pathogenetic cause of neutropenia is in large due to impaired BM granulopoiesis, and it has been documented defective CFU-G growth potential of BMMCs as well as a lower frequency of CD34+/CD33+ cells which was correlated with Fas overexpression and accelerated Fas-mediated apoptosis within this strictly defined cell compartment [76]. In addition, an inflammatory BM microenvironment with elevated levels of TNFα, IL-1β, TGFβ1, IL-6 as well as IFN-γ and Fas-ligand-producing activated T-lymphocytes has been documented previously in CIN patients [75, 77, 78] (Table 1).

In a recent study of our group, it was demonstrated that CD40 was minimally expressed on normal BM granulocytic progenitor and precursor cells, namely, the CD34+, CD34/CD33+, and CD34/CD33/CD15+ cell subpopulations; however, CD40 was upregulated upon TNFα stimulus in in vitro cultures, and upon ligation with CD40L, it resulted in the increased amount of apoptotic cells in the CD40+ cell compartment compared to untreated cells or TNFα-treated cells [65]. Furthermore, CD40 triggering resulted in Fas expression on these cell populations, which upon stimulation with rhFasL in the presence of both TNFα and CD40L, it resulted in a further increase of apoptotic cells in an additive way. However, when Fas receptor was blocked, CD40L could still initiate apoptosis on granulocytic subpopulations, leading to the assumption that CD40-CD40L interactions can act either directly or indirectly via the Fas-FasL system to induce apoptotic effects on granulocytic progenitor and precursor cells [65]. By evaluating the clonogenic potential of normal and CIN BMMCs under the influence of rhCD40L, it was shown that the number of CFU-G of both groups was decreased although not in a statistically significant way in healthy controls. The prominent decrease of CFU-Gs in CIN patients could be due to increased endogenous TNFα levels in these patients [75] with a subsequent overexpression of CD40 on progenitor and precursor cell surface, rendering those cells more susceptible to the apoptotic effect of CD40 as shown above [65].

Finally, when clonogenic assays were performed with the nonadherent cells of LTBMCs following coculture with the adherent cells of stromal layer of LTBMCs in the presence of CD40L alone, the number of CFU-Gs was increased in the case of normal supernatant cells incubated on normal stromal layer as opposed to the decrease in the CFU-Gs in the case of CIN supernatant cells incubated on CIN stromal layer [65]. However, when the nonadherent cell of LTBMCs of CIN patients were incubated with normal stromal layer in the presence of CD40L alone, the decrease in CFU-Gs previously seen was less (unpublished data). These observations lead to the assumption that CD40L which can be expressed by activated T-lymphocytes present in the BM of CIN patients is a potent effector of granulocytic progenitor cell depletion, resulting in neutropenia, even counterbalancing the beneficial effect of elevated G-CSF found in those patients [75].

5. CONCLUSION

The fact that CD40L induces the expression of granulopoiesis-promoting factors such as G-CSF, GM-CSF, and Flt3-L from normal stromal cells leads to the hypothesis that the cytokine could act as a granulopoiesis stimulating molecule under steady state conditions. However, under the influence of an inflammatory microenvironment as in the case of CIN, where there are elevated levels of proinflammatory cytokines like TNFα and IFN-γ, which can induce further the expression of CD40 on granulocytic progenitor and precursor cells, CD40L can act as a granulopoiesis-inhibitory molecule due to increased apoptosis of these cell populations. Accordingly, the CD40-CD40L interactions display a dual effect on granulopoiesis (Figure 1).

671453.fig.001
Figure 1: Schematic diagram of the CD40/CD40L interactions in the bone marrow. Under steady state conditions, CD40 is minimally expressed on the BM granulocytic progenitor cells, but it is constitutively expressed on BM stromal cells, and upon ligation with CD40 ligand (CD40L), it induces the production of FMS-like tyrosine kinase 3 ligand (Flt3-L), granulocyte-colony-stimulating factor (G-CSF), and granulocyte/monocyte-colony-stimulating factor (GM-CSF). Under inflammatory conditions, involving increased tumour necrosis factor-α (TNFα), Fas ligand (FasL), and CD40L production, as found in the BM microenvironment of chronic idiopathic neutropenia (CIN) patients, CD40 expression is upregulated in all stages of the granulocytic differentiation, and upon activation with CD40L, it induces the apoptotic cell death both directly and indirectly through Fas upmodulation, counterbalancing the beneficial effect of G-CSF and GM-CSF produced by BM stromal cells.

AUTHOR’S CONTRIBUTION

I. Mavroudi wrote the paper and H. A. Papadaki critically reviewed and revised the paper.

Acknowledgments

The studies conducted in Professor H. A. Papadaki’s laboratory were partly supported by a grant from the University Hospital of Heraklion and Grant no. 09SYN-13-880 of the Greek Ministry of National Education and Religious Affairs to H. A. Papadaki.

References

  1. U. Schönbeck and P. Libby, “The CD40/CD154 receptor/ligand dyad,” Cellular and Molecular Life Sciences, vol. 58, no. 1, pp. 4–43, 2001.
  2. C. Van Kooten and J. Banchereau, “CD40-CD40 ligand: a multifunctional receptor-ligand pair,” Advances in Immunology, vol. 61, pp. 1–77, 1996. View at Scopus
  3. N. Ramesh, V. Ramesh, J. F. Gusella, and R. Geha, “Chromosomal localization of the gene for human B-cell antigen CD40,” Somatic Cell and Molecular Genetics, vol. 19, no. 3, pp. 295–298, 1993. View at Scopus
  4. M. Poggi, J. Jager, O. Paulmyer-Lacroix et al., “The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes,” Diabetologia, vol. 52, no. 6, pp. 1152–1163, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. G. A. Bishop, C. R. Moore, P. Xie, L. L. Stunz, and Z. J. Kraus, “TRAF proteins in CD40 signaling,” Advances in Experimental Medicine and Biology, vol. 597, pp. 131–151, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. I. S. Grewal and R. A. Flavell, “CD40 and CD154 in cell-mediated immunity,” Annual Review of Immunology, vol. 16, pp. 111–135, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. T. M. Foy, A. Aruffo, J. Bajorath, J. E. Buhlmann, and R. J. Noelle, “Immune regulation by CD40 and its ligand GP39,” Annual Review of Immunology, vol. 14, pp. 591–617, 1996. View at Publisher · View at Google Scholar · View at Scopus
  8. L. F. Lu, C. L. Ahonen, E. F. Lind et al., “The in vivo function of a noncanonical TRAF2-binding domain in the C-terminus of CD40 in driving B-cell growth and differentiation,” Blood, vol. 110, no. 1, pp. 193–200, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. C. L. Ahonen, E. M. Manning, L. D. Erickson et al., “The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells,” Nature Immunology, vol. 3, no. 5, pp. 451–456, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. R. J. Dunn, C. J. Luedecker, H. S. Haugen, C. H. Clegg, and A. G. Farr, “Thymic overexpression of CD40 ligand disrupts normal thymic epithelial organization,” Journal of Histochemistry and Cytochemistry, vol. 45, no. 1, pp. 129–141, 1997. View at Scopus
  11. S. J. Jenkins, G. Perona-Wright, and A. S. MacDonald, “Full development of Th2 immunity requires both innate and adaptive sources of CD154,” Journal of Immunology, vol. 180, no. 12, pp. 8083–8092, 2008. View at Scopus
  12. A. D. Straw, A. S. MacDonald, E. Y. Denkers, and E. J. Pearce, “CD154 plays a central role in regulating dendritic cell activation during infections that induce TH1 or TH2 responses,” Journal of Immunology, vol. 170, no. 2, pp. 727–734, 2003. View at Scopus
  13. G. Iezzi, I. Sonderegger, F. Ampenberger, N. Schmitz, B. J. Marsland, and M. Kopf, “CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 3, pp. 876–881, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. M. R. Alderson, R. J. Armitage, T. W. Tough, L. Strockbine, W. C. Fanslow, and M. K. Spriggs, “CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40,” Journal of Experimental Medicine, vol. 178, no. 2, pp. 669–674, 1993. View at Scopus
  15. E. J. Schattner, K. B. Elkon, D. H. Yoo et al., “CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway,” Journal of Experimental Medicine, vol. 182, no. 5, pp. 1557–1565, 1995. View at Publisher · View at Google Scholar · View at Scopus
  16. S. C. Afford, S. Randhawa, A. G. Eliopoulos, S. G. Hubscher, L. S. Young, and D. H. Adams, “CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface Fas ligand expression and amplifies Fas-mediated hepatocyte death during allograft rejection,” Journal of Experimental Medicine, vol. 189, no. 2, pp. 441–446, 1999. View at Publisher · View at Google Scholar · View at Scopus
  17. D. Lievens, A. Zernecke, T. Seijkens et al., “Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis,” Blood, vol. 116, no. 20, pp. 4317–4327, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Meers, A. Kasran, L. Boon et al., “Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40-CD40L interactions with T helper cells,” Leukemia, vol. 21, no. 12, pp. 2411–2419, 2007. View at Publisher · View at Google Scholar · View at Scopus
  19. A. L. Peters, L. L. Stunz, and G. A. Bishop, “CD40 and autoimmunity: the dark side of a great activator,” Seminars in Immunology, vol. 21, no. 5, pp. 293–300, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Pyrovolaki, I. Mavroudi, P. Sidiropoulos, A. G. Eliopoulos, D. T. Boumpas, and H. A. Papadaki, “Increased expression of CD40 on bone marrow CD34+ hematopoietic progenitor cells in patients with systemic lupus erythematosus: contribution to fas-mediated apoptosis,” Arthritis and Rheumatism, vol. 60, no. 2, pp. 543–552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. K. Akashi, D. Traver, T. Miyamoto, and I. L. Weissman, “A clonogenic common myeloid progenitor that gives rise to all myeloid lineages,” Nature, vol. 404, no. 6774, pp. 193–197, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Zhu and S. G. Emerson, “Hematopoietic cytokines, transcription factors and lineage commitment,” Oncogene, vol. 21, no. 21, pp. 3295–3313, 2002. View at Publisher · View at Google Scholar · View at Scopus
  23. K. Shinjo, A. Takeshita, K. Ohnishi, and R. Ohno, “Granulocyte colony-stimulating factor receptor at various differentiation stages of normal and leukemic hematopoietic cells,” Leukemia and Lymphoma, vol. 25, no. 1-2, pp. 37–46, 1997. View at Scopus
  24. L. W. M. M. Terstappen, M. Safford, and M. R. Loken, “Flow cytometric analysis of human bone marrow. III. Neutrophil maturation,” Leukemia, vol. 4, no. 9, pp. 657–663, 1990. View at Scopus
  25. R. G. Andrews, B. Torok-Storb, and I. D. Bernstein, “Myeloid-associated differentiation antigens on stem cells and their progeny identified by monoclonal antibodies,” Blood, vol. 62, no. 1, pp. 124–132, 1983. View at Scopus
  26. J. D. Griffin, D. Linch, and K. Sabbath, “A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells,” Leukemia Research, vol. 8, no. 4, pp. 521–534, 1984. View at Scopus
  27. A. C. Ward, D. M. Loeb, A. A. Soede-Bobok, I. P. Touw, and A. D. Friedman, “Regulation of granulopoiesis by transcription factors and cytokine signals,” Leukemia, vol. 14, no. 6, pp. 973–990, 2000. View at Scopus
  28. J. A. Lekstrom-Himes, “The role of C/EBPε in the terminal stages of granulocyte differentiation,” Stem Cells, vol. 19, no. 2, pp. 125–133, 2001. View at Scopus
  29. A. D. Friedman, “Transcriptional regulation of granulocyte and monocyte development,” Oncogene, vol. 21, no. 21, pp. 3377–3390, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. J. Skokowa, G. Cario, M. Uenalan et al., “LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia,” Nature Medicine, vol. 12, no. 10, pp. 1191–1197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. V. C. Broudy, “Stem cell factor and hematopoiesis,” Blood, vol. 90, no. 4, pp. 1345–1364, 1997. View at Scopus
  32. D. N. Haylock, M. J. Horsfall, T. L. Dowse et al., “Increased recruitment of hematopoietic progenitor cells underlies the ex vivo expansion potential of FLT3 ligand,” Blood, vol. 90, no. 6, pp. 2260–2272, 1997. View at Scopus
  33. S. D. Lyman, L. James, L. Johnson et al., “Cloning of the human homologue of the murine flt3 ligand: a growth factor early hematopoietic progenitor cells,” Blood, vol. 83, no. 10, pp. 2795–2801, 1994. View at Scopus
  34. W. L. Blalock, C. Weinstein-Oppenheimer, F. Chang et al., “Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs,” Leukemia, vol. 13, no. 8, pp. 1109–1166, 1999. View at Scopus
  35. S. G. Emerson, Y. C. Yang, S. C. Clark, and M. W. Long, “Human recombinant granulocyte-macrophage colony stimulating factor and interleukin 3 have overlapping but distinct hematopoietic activities,” Journal of Clinical Investigation, vol. 82, no. 4, pp. 1282–1287, 1988. View at Scopus
  36. F. J. Bot, L. Van Eijk, P. Schipper, B. Backx, and B. Lowenberg, “Synergistic effects between GM-CSF and G-CSF or M-CSF on highly enriched human marrow progenitor cells,” Leukemia, vol. 4, no. 5, pp. 325–328, 1990. View at Scopus
  37. S. Gartner and H. S. Kaplan, “Long-term culture of human bone marrow cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 77, no. 8, pp. 4756–4759, 1980. View at Scopus
  38. L. H. Coutinho, A. Will, J. Radford, R. Schiro, N. G. Testa, and T. M. Dexter, “Effects of recombinant human granulocyte colony-stimulating factor (CSF), human granulocyte macrophage-CSF, and gibbon interleukin-3 on hematopoiesis in human long-term bone marrow culture,” Blood, vol. 75, no. 11, pp. 2118–2129, 1990. View at Scopus
  39. K. Kaushansky, V. C. Broudy, J. M. Harlan, and J. W. Adamson, “Tumor necrosis factor-γ and tumor necrosis factor-β (lymphotoxin) stimulate the production of granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in vivo,” Journal of Immunology, vol. 141, no. 10, pp. 3410–3415, 1988. View at Scopus
  40. M. L. Linenberger, F. W. Jacobson, L. G. Bennett, V. C. Broudy, F. H. Martin, and J. L. Abkowitz, “Stem cell factor production by human marrow stromal fibroblasts,” Experimental Hematology, vol. 23, pp. 1104–1114, 1995.
  41. J. DiPersio, P. Billing, S. Kaufman, P. Eghtesady, R. E. Williams, and J. C. Gasson, “Characterization of the human granulocyte-macrophage colony-stimulating factor receptor,” Journal of Biological Chemistry, vol. 263, no. 4, pp. 1834–1841, 1988. View at Scopus
  42. A. W. Wognum, Y. Westerman, T. P. Visser, and G. Wagemaker, “Distribution of receptors for granulocyte-macrophage colony-stimulating factor on immature CD34+ bone marrow cells, differentiating monomyeloid progenitors, and mature blood cell subsets,” Blood, vol. 84, no. 3, pp. 764–774, 1994. View at Scopus
  43. K. Tsuji and Y. Ebihara, “Expression of G-CSF receptor on myeloid progenitors,” Leukemia and Lymphoma, vol. 42, no. 6, pp. 1351–1357, 2001. View at Scopus
  44. K. M. Zsebo, V. N. Yuschenkoff, S. Schiffer et al., “Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF,” Blood, vol. 71, no. 1, pp. 99–103, 1988. View at Scopus
  45. H. P. Koeffler, J. Gasson, J. Ranyard, L. Souza, M. Shepard, and R. Munker, “Recombinant human TNF(α) stimulates production of granulocyte colony-stimulating factor,” Blood, vol. 70, no. 1, pp. 55–59, 1987.
  46. W. E. Fibbe, J. Van Damme, A. Billiau et al., “Interleukin 1 induces human marrow stromal cells in long-term culture to produce granulocyte colony-stimulating factor and macrophage colony-stimulating factor,” Blood, vol. 71, no. 2, pp. 430–435, 1988. View at Scopus
  47. W. Oster, A. Lindemann, R. Mertelsmann, and F. Herrmann, “Granulocyte-macrophage colony-stimulating factor (CSF) and multilineage CSF recruit human monocytes to express granulocyte CSF,” Blood, vol. 73, no. 1, pp. 64–67, 1989. View at Scopus
  48. B. Sallerfors and T. Olofsson, “Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) secretion by adherent monocytes measured by quantitative immunoassays,” European Journal of Haematology, vol. 49, no. 4, pp. 199–207, 1992. View at Scopus
  49. G. J. Lieschke, D. Grail, G. Hodgson et al., “Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization,” Blood, vol. 84, no. 6, pp. 1737–1746, 1994. View at Scopus
  50. F. Liu, H. Y. Wu, R. Wesselschmidt, T. Kornaga, and D. C. Link, “Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice,” Immunity, vol. 5, no. 5, pp. 491–501, 1996. View at Publisher · View at Google Scholar · View at Scopus
  51. M. Germeshausen, J. Skokowa, M. Ballmaier, C. Zeidler, and K. Welte, “G-CSF receptor mutations in patients with congenital neutropenia,” Current Opinion in Hematology, vol. 15, no. 4, pp. 332–337, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. I. N. Rich, “A role for the macrophage in normal hemopoiesis. I. Functional capacity of bone-marrow-derived macrophages to release hemopoietic growth factors,” Experimental Hematology, vol. 14, no. 8, pp. 738–745, 1986. View at Scopus
  53. J. Y. Chan, D. J. Slamon, and S. D. Nimer, “Regulation of expression of human granulocyte/macrophage colony-stimulating factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 22, pp. 8669–8673, 1986. View at Scopus
  54. V. C. Broudy, K. Kaushansky, J. M. Harlan, and J. W. Adamson, “Interleukin 1 stimulates human endothelial cells to produce granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor,” Journal of Immunology, vol. 139, no. 2, pp. 464–468, 1987. View at Scopus
  55. D. Rennick, G. Yang, L. Gemmell, and F. Lee, “Control of hemopoiesis by a bone marrow stromal cell clone: lipopolysaccharide- and interleukin-1-inducible production of colony-stimulating factors,” Blood, vol. 69, no. 2, pp. 682–691, 1987. View at Scopus
  56. K. Hestdal, S. E. W. Jacobson, F. W. Ruscetti, D. L. Longo, T. C. Boone, and J. R. Keller, “Increased granulopoiesis after sequential administration of transforming growth factor-β1 and granulocyte-macrophage colony-stimulating factor,” Experimental Hematology, vol. 21, no. 6, pp. 799–805, 1993. View at Scopus
  57. G. T. Williams, C. A. Smith, E. Spooncer, T. M. Dexter, and D. R. Taylor, “Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis,” Nature, vol. 343, no. 6253, pp. 76–79, 1990. View at Publisher · View at Google Scholar · View at Scopus
  58. J. Déchanet, C. Grosset, J. L. Taupin et al., “CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells,” Journal of Immunology, vol. 159, no. 11, pp. 5640–5647, 1997. View at Scopus
  59. M. Stojakovic, R. Krzesz, A. H. Wagner, and M. Hecker, “CD154-stimulated GM-CSF release by vascular smooth muscle cells elicits monocyte activation—role in atherogenesis,” Journal of Molecular Medicine, vol. 85, no. 11, pp. 1229–1238, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. V. Henn, J. R. Slupsky, M. Gräfe et al., “CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells,” Nature, vol. 391, no. 6667, pp. 591–594, 1998. View at Publisher · View at Google Scholar · View at Scopus
  61. B. Lienenlüke, T. Germann, R. A. Kroczek, and M. Hecker, “CD154 stimulation of interleukin-12 synthesis in human endothelial cells,” European Journal of Immunology, vol. 30, no. 10, pp. 2864–2870, 2000. View at Publisher · View at Google Scholar · View at Scopus
  62. D. H. Wagner, R. D. Stout, and J. Suttles, “Role of the CD40-CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte interleukin-1 synthesis,” European Journal of Immunology, vol. 24, no. 12, pp. 3148–3154, 1994. View at Publisher · View at Google Scholar · View at Scopus
  63. M. C. Rissoan, C. Van Kooten, P. Chomarat et al., “The functional CD40 antigen of fibroblasts may contribute to the proliferation of rheumatoid synovium,” Clinical and Experimental Immunology, vol. 106, no. 3, pp. 481–490, 1996. View at Scopus
  64. A. H. M. Galy and H. Spits, “CD40 is functionally expressed on human thymic epithelial cells,” Journal of Immunology, vol. 149, no. 3, pp. 775–782, 1992. View at Scopus
  65. I. Mavroudi, V. Papadaki, K. Pyrovolaki, P. Katonis, A. G. Eliopoulos, and H. A. Papadaki, “The CD40/CD40 ligand interactions exert pleiotropic effects on bone marrow granulopoiesis,” Journal of Leukocyte Biology, vol. 89, no. 5, pp. 771–783, 2011. View at Publisher · View at Google Scholar
  66. L. S. Rusten, S. D. Lyman, O. P. Veiby, and S. E. W. Jacobsen, “The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro,” Blood, vol. 87, no. 4, pp. 1317–1325, 1996. View at Scopus
  67. H. E. Broxmeyer, L. Lu, S. Cooper, L. Ruggieri, Z. H. Li, and S. D. Lyman, “Flt3 ligand stimulates/costimulates the growth of myeloid stem/progenitor cells,” Experimental Hematology, vol. 23, no. 10, pp. 1121–1129, 1995. View at Scopus
  68. A. Solanilla, J. Déchanet, A. El Andaloussi et al., “CD40-ligand stimulates myelopoiesis by regulating flt3-ligand and thrombopoietin production in bone marrow stromal cells,” Blood, vol. 95, no. 12, pp. 3758–3764, 2000. View at Scopus
  69. C. A. De Graaf and D. Metcalf, “Thrombopoietin and hematopoietic stem cells,” Cell Cycle, vol. 10, no. 10, pp. 1582–1589, 2011. View at Publisher · View at Google Scholar
  70. J. P. DiSanto, J. Y. Bonnefoy, J. F. Gauchat, A. Fischer, and G. De Saint Basile, “CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM,” Nature, vol. 361, no. 6412, pp. 541–543, 1993. View at Publisher · View at Google Scholar · View at Scopus
  71. J. Levy, T. Espanol-Boren, C. Thomas et al., “Clinical spectrum of X-linked hyper-IgM syndrome,” Journal of Pediatrics, vol. 131, no. 1 I, pp. 47–54, 1997. View at Publisher · View at Google Scholar · View at Scopus
  72. R. C. Allen, R. J. Armitage, M. E. Conley et al., “CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome,” Science, vol. 259, no. 5097, pp. 990–993, 1993. View at Scopus
  73. W. C. Wang, J. Cordoba, A. J. Infante, and M. E. Conley, “Successful treatment of neutropenia in the hyper-immunoglobulin M syndrome with granulocyte colony-stimulating factor,” American Journal of Pediatric Hematology/Oncology, vol. 16, no. 2, pp. 160–163, 1994. View at Scopus
  74. M. Mori, S. Nonoyama, M. Neubauer, T. Mitsuda, T. Kosuge, and S. Yokota, “Mutation analysis and therapeutic response to granulocyte colony-stimulating factor in a case of hyperimmunoglobulin M syndrome with chronic neutropenia,” Journal of Pediatric Hematology/Oncology, vol. 22, no. 3, pp. 288–289, 2000. View at Publisher · View at Google Scholar · View at Scopus
  75. H. A. Papadaki, J. Palmblad, and G. D. Eliopoulos, “Non-immune chronic idiopathic neutropenia of adult: an overview,” European Journal of Haematology, vol. 67, no. 1, pp. 35–44, 2001. View at Publisher · View at Google Scholar · View at Scopus
  76. H. A. Papadaki, A. G. Eliopoulos, T. Kosteas et al., “Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells,” Blood, vol. 101, no. 7, pp. 2591–2600, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. H. A. Papadaki, K. Stamatopoulos, A. Damianaki et al., “Activated T-lymphocytes with myelosuppressive properties in patients with chronic idiopathic neutropenia,” British Journal of Haematology, vol. 128, no. 6, pp. 863–876, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Spanoudakis, H. Koutala, M. Ximeri, K. Pyrovolaki, K. Stamatopoulos, and H. A. Papadaki, “T-cell receptor Vβ repertoire analysis in patients with chronic idiopathic neutropenia demonstrates the presence of aberrant T-cell expansions,” Clinical Immunology, vol. 137, no. 3, pp. 384–395, 2010. View at Publisher · View at Google Scholar · View at Scopus