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Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells
D Chauhan1, H Uchiyama, M Urashima
1Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Abstract:
We and others have shown that some freshly isolated multiple myeloma (MM) cells and derived cell lines express interleukin 6 (IL-6) receptors and proliferate in vitro in response to IL-6; a subset of MM cells also expresses IL-6 mRNA, is intracytoplasmic IL-6 positive and secretes IL-6. We have shown that MM cells express the cell surface adhesion molecules CD29/CDw49d(VLA-4), CD18/CD11a(LFA-1) and CD44, and may localize to marrow via specific adherence to both extracellular matrix proteins and to bone marrow stromal cells (BMSCs). MM cell adhesion triggers IL-6 secretion by normal and MM BMSCs and related IL-6-mediated tumor cell growth. Our attempts to block MM cell adhesion to BMSC-induced IL-6 secretion by using antibodies to CD29/CDw49d, CD18/11a, and/or CD44 demonstrated minimal effects, suggesting that another ligand-receptor interaction triggers IL-6 secretion when MM cells and BMSCs are juxtaposed. Both MM cells and BMSCs express CD40. Triggering of MM cells and BMSCs via CD40 upregulates IL-6 secretion in both MM cells and MM-derived cell lines, as well as BMSCs and BMSC lines, suggesting the possibility of both autocrine and paracrine MM cell growth triggered via CD40. Finally, experiments using the LP 101 BMSC line transiently transfected with IL-6 promoter fragments linked to chloramphenicol acetyltransferase reporter gene demonstrate that adhesion of MM cells induces IL-6 gene transcription in BMSCs, which is conferred via the NF-kappa B binding motif.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Multiple myeloma (MM) cell adhesion to bone marrow stromal cells (BMSCs) triggers interleukin-6 (IL-6) secretion, promoting tumor growth. CD40 signaling, not previously identified adhesion molecules, appears to drive this IL-6 production and MM cell proliferation.
Area of Science:
- Hematology
- Cancer Biology
- Immunology
Background:
- Multiple myeloma (MM) cells express interleukin-6 (IL-6) receptors and can proliferate in response to IL-6.
- MM cells adhere to bone marrow stromal cells (BMSCs) via cell surface molecules, which stimulates IL-6 secretion and tumor growth.
Purpose of the Study:
- To investigate the mechanisms by which MM cell adhesion to BMSCs induces IL-6 secretion.
- To identify the specific ligand-receptor interactions involved in MM cell-BMSC communication and subsequent IL-6 production.
Main Methods:
- Flow cytometry to analyze cell surface molecule expression (CD29/CDw49d, CD18/CD11a, CD44, CD40).
- In vitro co-culture assays of MM cells and BMSCs.
- Antibody-mediated blockade of cell adhesion molecules.
- Reporter gene assays (chloramphenicol acetyltransferase) to assess IL-6 gene transcription.
- Western blotting to analyze NF-kappa B activation.
Main Results:
- MM cell adhesion to BMSCs significantly increases IL-6 secretion from BMSCs.
- Antibodies targeting CD29/CDw49d, CD18/CD11a, and CD44 showed minimal effect on BMSC-induced IL-6 secretion.
- Both MM cells and BMSCs express CD40, and CD40 triggering upregulates IL-6 secretion in both cell types.
- MM cell adhesion induces IL-6 gene transcription in BMSCs, mediated through the NF-kappa B binding motif.
Conclusions:
- CD40 signaling is a critical pathway for IL-6 secretion induced by MM cell-BMSC interaction.
- This CD40-mediated IL-6 production may contribute to both autocrine and paracrine MM cell growth.
- Targeting the CD40 pathway could represent a novel therapeutic strategy for multiple myeloma.
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