Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells

Abstract

Interleukin-6 (IL-6) has been suggested to play a major role in multiple myeloma. To investigate the source and target cells of IL-6 activity in multiple myeloma, expression of the cytokine and its receptor genes by myeloma plasma cells was studied. Tumor cells were sorted from bone marrow aspirates of myeloma patients using 4-parameter gating. Myeloma cells were identified as CD38high CD45negative- intermediate and by their light-scatter characteristics. Sorted cells contained only myeloma plasma cells. No contaminating cells were present as determined morphologically, by monoclonal cytoplasmic Ig analysis, and by polymerase chain reaction (PCR) amplification of marker genes. Myeloma cells from 45% of patients expressed IL-6. IL-6 receptor transcripts were found in 68% of the specimens. IL-6 gene expression correlated with expression of the IL-6 receptor gene (P < .005). Correlations observed between the expression of CD45, a protein tyrosine phosphatase expressed by B lymphocytes but not by plasma cells, and the expression of the IL-6 and IL-6-receptor genes (P < .0002 and P < .005, respectively) suggest that an autocrine IL-6 loop is functioning in myeloma in preplasma cells.

Cytokine expression and regulation of human plasma cells: disappearance of interleukin‐10 and persistence of transforming growth factor‐β1

“…The results also agree with observations by others: IL-6 production in normal bone marrow cultures is derived from stromal cells [4]. In myeloma cells, IL-6 expression is associated with an immature phenotype [18]. The finding that increased serum IL-6 is of worse prognostic significance than increased IL-10 in multiple myeloma [19] could also be explained by the maturation sequence of the cytokine expression as observed above; IL-10-expressing cells can be more differentiated.…”

Protein kinase C‐delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis

“…Interleukin 6 (IL-6) is one of the major growth and survival factors of myeloma cells (Hata et al, 1993). Its biological activity results from the interaction between the IL-6 and its receptor complex (Thabard et al, 2001).…”

Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells

“…The IL-6 receptor and its signal transducer, namely gp130, are expressed on most myeloma cells. It has been emphasized that IL-6 is essential for replication of myeloma cell lines [12,13] and native MCC [19,20,24] and, although it is prevalently considered a paracrine growth factor [14], it seems likely that highly immature myeloma cells produce IL-6 as an autocrine factor of proliferation and differentiation [42]. We found that both proliferation and the SI of some in vitro established native MCC were mostly unchanged in the presence of increasing levels of IL-6, suggesting that it was not necessary for their autocrine or paracrine expansion.…”