IL-7 Activates the Phosphatidylinositol 3-Kinase/AKT Pathway in Normal Human Thymocytes but Not Normal Human B Cell Precursors

Contact with bone marrow stromal cells is crucial for the normal growth and development of B-cell precursors. We have previously shown that human bone marrow stromal cell tyrosine kinase activity can be activated by direct contact with B-lymphoid cells (J Immunol 155:2359, 1995). In the present study, we show that increased tyrosine phosphorylation of focal adhesion kinase, paxillin, and extracellular-related kinase 2 (or p42 MAP kinase) accounted for the major changes occurring in stromal cell tyrosine phosphorylation after 5 to 10 minutes of contact with the RAMOS B-lymphoma cell line. Although adhesion of B-cell precursors to stromal cells is primarily mediated by very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), VLA-4–deficient and adhesion-deficient RAMOS cells were equally capable of stimulating stromal cell tyrosine phosphorylation. Similar changes in the tyrosine phosphorylation pattern of stromal cells were induced by contact with normal human B-cell precursors and several other B-lineage cell lines. After 5 to 30 minutes of contact with stromal cells, no change in protein tyrosine phosphorylation was detected in RAMOS or normal human B-cell precursors removed from stromal cells. Pretreatment of stromal cells with cytochalasin D abrogated contact-mediated enhancement of stromal cell tyrosine phosphorylation, suggesting that an intact cytoskeleton was essential. These results suggest that B-cell contact activates stromal cell signaling cascades that regulate cytoskeletal organization and transcription, independent of the interaction mediated by VLA-4 and VCAM-1.

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Interleukin-7 induces the proliferation of normal human B-cell precursors

Blood ◽

10.1182/blood.v78.9.2229.bloodjournal7892229 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2229-2238

Author(s):

S Saeland ◽

V Duvert ◽

D Pandrau ◽

C Caux ◽

I Durand ◽

...

Keyword(s):

B Cell ◽

Target Cells ◽

Interleukin 7 ◽

Cd34 Cells ◽

Normal Human ◽

B Lineage ◽

La Jolla ◽

B Cell Precursors ◽

Dose Dependent ◽

Human B Cell

In the present study, we investigated the effects of human recombinant interleukin-7 (IL-7) on the proliferation of enriched hematopoietic cells isolated from human adult and fetal bone marrow (BM). In cultures of CD34+ cells, IL-7 was found to induce dose-dependent incorporation of 3H-thymidine (3H-TdR), but had no demonstrable effect on the development of myeloid colony-forming cells. Numbers of B-cell precursors (BCP), initially present within CD34+ populations and which included a CD34+CD20+ subset, were significantly increased when CD34+ BM cells were cultured in the presence of IL-7. This effect was most striking on CD20+ BCP, and resulted at least partly from higher numbers of cycling cells as indicated by Hoechst 33342 fluorescence (Calbiochem, Behring Diagnostics, La Jolla, CA). These results indicate that IL-7 promotes the growth of BCP within the CD34+ compartment. In line with the B-lineage affiliation of CD34+ target cells, committed BCP (CD10+ CD19+ surface IgM-) isolated from BM were also found to proliferate in response to IL-7. Interestingly, this effect of IL-7 was strongly potentiated by the addition of IL-3. Taken together, and in accordance with previous observations on murine cells, our data indicate that IL-7 acts as a growth factor during the ontogeny of human B lymphocytes.

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Human B cell precursors proliferate and express CD23 after CD40 ligation.

Journal of Experimental Medicine ◽

10.1084/jem.178.1.113 ◽

1993 ◽

Vol 178 (1) ◽

pp. 113-120 ◽

Cited By ~ 81

Author(s):

S Saeland ◽

V Duvert ◽

I Moreau ◽

J Banchereau

Keyword(s):

B Cells ◽

B Cell ◽

Surface Membrane ◽

Cd40 Ligation ◽

Gamma Receptor ◽

Human B Cells ◽

Normal Human ◽

B Lineage ◽

B Cell Precursors ◽

Human B Cell

The CD40 surface membrane molecule plays an important role in the activation of mature human B cells, but its role in earlier stages of B lineage development is unknown. Here, we have investigated the effects of triggering the CD40 antigen on B cell precursors (BCP) by crosslinking with anti-CD40 antibody presented by Fc gamma-receptor type II-transfected murine Ltk- cells (CD40 system). CD10+ surface immunoglobulin negative (sIg-) BCP, freshly isolated from fetal bone marrow or precultured on stromal cells, proliferated in the CD40 system. This effect required the presence of IL-3, which acted as a specific cosignal among a panel of cytokines examined. The association of IL-10 and IL-7 potentiated the observed IL-3 and CD40-dependent BCP proliferation, demonstrating that IL-10 can act on early B lineage cells. CD40-dependent activation of fetal BCP did not favor maturation to sIg+ B cells, but resulted in the induction of high levels of surface membrane CD23. The emerging CD23+ BCP lacked sIg and CD10, and represented an important proportion of the cycling cells in the CD40-dependent cultures. Taken together, our data demonstrate that stimulation of the CD40 antigen induces expression of the CD23 gene, and regulates cell proliferation during normal human B cell ontogeny.

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Interleukin-13 inhibits the proliferation of normal and leukemic human B-cell precursors

Blood ◽

10.1182/blood.v84.7.2253.2253 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2253-2260 ◽

Cited By ~ 39

Author(s):

N Renard ◽

V Duvert ◽

J Banchereau ◽

S Saeland

Keyword(s):

Growth Inhibition ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Inhibitory Effect ◽

Interleukin 13 ◽

Normal Human ◽

B Lineage ◽

B Cell Precursors ◽

Cd23 Expression ◽

Human B Cell

Abstract Interleukin-13 (IL-13) is a T-cell-derived cytokine that displays homology with IL-4 and shares some of its biologic functions. We investigated the effects of IL-13 on normal human B-cell precursors (BCP) and their malignant counterparts in B-lineage acute lymphoblastic leukemia (BCP-ALL). IL-13 inhibited growth of CD19+ slg- normal BCP cultured in the presence or absence of bone marrow accessory stromal cells and IL-7. In addition, IL-13 inhibited proliferation of blasts isolated from leukemic patients and cells from established BCP-ALL lines. Differences were observed in a number of cases with respect to growth inhibition in response to IL-13 and IL-4. These results suggest heterogeneity in the expression of IL-13 and IL-4 receptors in B-cell ontogeny. Growth-inhibition by IL-13 could be reverted by anti-IL-4 receptor antibody, indicating that the IL-13 and IL-4 binding chains can be closely associated on BCP. We further showed that the inhibitory effect of IL-13 results from decreased cell-cycle activity. Finally, whereas IL-13 induced CD23 expression on BCP-ALL cells, it did not promote differentiation into slg+ B lymphocytes.

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Interleukin-13 inhibits the proliferation of normal and leukemic human B-cell precursors

Blood ◽

10.1182/blood.v84.7.2253.bloodjournal8472253 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2253-2260 ◽

Cited By ~ 1

Author(s):

N Renard ◽

V Duvert ◽

J Banchereau ◽

S Saeland

Keyword(s):

Growth Inhibition ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Inhibitory Effect ◽

Interleukin 13 ◽

Normal Human ◽

B Lineage ◽

B Cell Precursors ◽

Cd23 Expression ◽

Human B Cell

Interleukin-13 (IL-13) is a T-cell-derived cytokine that displays homology with IL-4 and shares some of its biologic functions. We investigated the effects of IL-13 on normal human B-cell precursors (BCP) and their malignant counterparts in B-lineage acute lymphoblastic leukemia (BCP-ALL). IL-13 inhibited growth of CD19+ slg- normal BCP cultured in the presence or absence of bone marrow accessory stromal cells and IL-7. In addition, IL-13 inhibited proliferation of blasts isolated from leukemic patients and cells from established BCP-ALL lines. Differences were observed in a number of cases with respect to growth inhibition in response to IL-13 and IL-4. These results suggest heterogeneity in the expression of IL-13 and IL-4 receptors in B-cell ontogeny. Growth-inhibition by IL-13 could be reverted by anti-IL-4 receptor antibody, indicating that the IL-13 and IL-4 binding chains can be closely associated on BCP. We further showed that the inhibitory effect of IL-13 results from decreased cell-cycle activity. Finally, whereas IL-13 induced CD23 expression on BCP-ALL cells, it did not promote differentiation into slg+ B lymphocytes.

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Interleukin 4 inhibits in vitro proliferation of leukemic and normal human B cell precursors.

Journal of Clinical Investigation ◽

10.1172/jci116042 ◽

1992 ◽

Vol 90 (5) ◽

pp. 1697-1706 ◽

Cited By ~ 19

Author(s):

D Pandrau ◽

S Saeland ◽

V Duvert ◽

I Durand ◽

A M Manel ◽

...

Keyword(s):

B Cell ◽

Interleukin 4 ◽

In Vitro Proliferation ◽

Normal Human ◽

B Cell Precursors ◽

Human B Cell

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Interleukin-7 induces the proliferation of normal human B-cell precursors

Blood ◽

10.1182/blood.v78.9.2229.2229 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2229-2238 ◽

Cited By ~ 42

Author(s):

S Saeland ◽

V Duvert ◽

D Pandrau ◽

C Caux ◽

I Durand ◽

...

Keyword(s):

B Cell ◽

Target Cells ◽

Interleukin 7 ◽

Cd34 Cells ◽

Normal Human ◽

B Lineage ◽

La Jolla ◽

B Cell Precursors ◽

Dose Dependent ◽

Human B Cell

Abstract In the present study, we investigated the effects of human recombinant interleukin-7 (IL-7) on the proliferation of enriched hematopoietic cells isolated from human adult and fetal bone marrow (BM). In cultures of CD34+ cells, IL-7 was found to induce dose-dependent incorporation of 3H-thymidine (3H-TdR), but had no demonstrable effect on the development of myeloid colony-forming cells. Numbers of B-cell precursors (BCP), initially present within CD34+ populations and which included a CD34+CD20+ subset, were significantly increased when CD34+ BM cells were cultured in the presence of IL-7. This effect was most striking on CD20+ BCP, and resulted at least partly from higher numbers of cycling cells as indicated by Hoechst 33342 fluorescence (Calbiochem, Behring Diagnostics, La Jolla, CA). These results indicate that IL-7 promotes the growth of BCP within the CD34+ compartment. In line with the B-lineage affiliation of CD34+ target cells, committed BCP (CD10+ CD19+ surface IgM-) isolated from BM were also found to proliferate in response to IL-7. Interestingly, this effect of IL-7 was strongly potentiated by the addition of IL-3. Taken together, and in accordance with previous observations on murine cells, our data indicate that IL-7 acts as a growth factor during the ontogeny of human B lymphocytes.

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Contact Between Human Bone Marrow Stromal Cells and B Lymphocytes Enhances Very Late Antigen-4/Vascular Cell Adhesion Molecule-1–Independent Tyrosine Phosphorylation of Focal Adhesion Kinase, Paxillin, and ERK2 in Stromal Cells

Blood ◽

10.1182/blood.v90.4.1626 ◽

1997 ◽

Vol 90 (4) ◽

pp. 1626-1635 ◽

Cited By ~ 22

Author(s):

Lisa J. Jarvis ◽

Jean E. Maguire ◽

Tucker W. LeBien

Keyword(s):

Bone Marrow ◽

B Cell ◽

Tyrosine Phosphorylation ◽

Stromal Cells ◽

Stromal Cell ◽

Late Antigen ◽

Normal Human ◽

B Cell Precursors ◽

Cell Adhesion Molecule 1 ◽

Human B Cell

Abstract Contact with bone marrow stromal cells is crucial for the normal growth and development of B-cell precursors. We have previously shown that human bone marrow stromal cell tyrosine kinase activity can be activated by direct contact with B-lymphoid cells (J Immunol 155:2359, 1995). In the present study, we show that increased tyrosine phosphorylation of focal adhesion kinase, paxillin, and extracellular-related kinase 2 (or p42 MAP kinase) accounted for the major changes occurring in stromal cell tyrosine phosphorylation after 5 to 10 minutes of contact with the RAMOS B-lymphoma cell line. Although adhesion of B-cell precursors to stromal cells is primarily mediated by very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), VLA-4–deficient and adhesion-deficient RAMOS cells were equally capable of stimulating stromal cell tyrosine phosphorylation. Similar changes in the tyrosine phosphorylation pattern of stromal cells were induced by contact with normal human B-cell precursors and several other B-lineage cell lines. After 5 to 30 minutes of contact with stromal cells, no change in protein tyrosine phosphorylation was detected in RAMOS or normal human B-cell precursors removed from stromal cells. Pretreatment of stromal cells with cytochalasin D abrogated contact-mediated enhancement of stromal cell tyrosine phosphorylation, suggesting that an intact cytoskeleton was essential. These results suggest that B-cell contact activates stromal cell signaling cascades that regulate cytoskeletal organization and transcription, independent of the interaction mediated by VLA-4 and VCAM-1.

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