Expression of IL-6 and IL-6 receptors by circulating clonotypic B cells in multiple myeloma: potential for autocrine and paracrine networks.
OBJECTIVE
To investigate the participation of clonotypic MM B cells in the IL-6 network in patients with multiple myeloma.


METHODS
CD19(+) B cells from 45 patients with multiple myeloma and from 18 healthy donors were sorted and their expression of IL-6, IL-6 receptor (CD126) characterized by flow cytometry, in situ RT-PCR, and ELISA measurement of IL-6 and soluble IL-6R. Expression of CD31 was detected by flow cytometry.


RESULTS
Interleukin-6 (IL-6) is a pleiotropic cytokine often overexpressed in multiple myeloma (MM). IL-6 induces growth and inhibits apoptosis of MM plasma cells, and upregulates the activity of osteoclasts. MM plasma cells, the most mature component of the MM clone, secrete IL-6 and induce IL-6 production from other cell types. However, the MM clone also includes circulating clonotypic B lymphocytes. Using ELISA and in situ RT-PCR we demonstrate here that, unlike the healthy control B cells, MM B cells express IL-6 mRNA and secrete IL-6 protein. In vitro, MM B cells were the major producers of IL-6 in peripheral blood mononuclear cells. On average, 50% of MM B cells express the IL-6 receptor (IL-6R, CD126), suggestive of autocrine stimulation. They also express CD31, potentially facilitating their paracrine interactions with osteoclast precursors.


CONCLUSIONS
Secretion of IL-6 by circulating clonotypic B cells in MM may contribute to the autocrine and paracrine cytokine networks that maintain the malignant clone and are responsible for disruption of normal bone metabolism in this incurable disease.
Szczepek
A J
AJ
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Belch
A R
AR
Pilarski
L M
LM
D019898:Autocrine Communication; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D009101:Multiple Myeloma / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015850:Interleukin-6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6