Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6

Abstract

To explore the mechanisms involved in the pathogenesis of human multiple myeloma (MM), we investigated the potential role of interleukin-6 (IL-6), a B-cell differentiation factor in humans, and a growth factor for rat/mouse heterohybridomas and murine plasmacytomas. Using a heterohybridoma assay, we found that two well-documented human myeloma cell lines, RPMI 8226 and U266, did not secrete IL-6 and did not express RNA messengers for IL-6. Neutralizing antibodies to IL-6 did not inhibit their proliferation, and recombinant IL-6 did not stimulate it. Taken together, these data show that IL-6 is not the autocrine growth factor of these human myeloma cell lines. A high production of IL-6 was found in the bone marrows of patients with fulminating MM, compared with patients with inactive or slightly active MM, or to healthy donors. This IL-6 production was assigned to adherent cells of the bone-marrow environment but not to myeloma cells. A spontaneous proliferation of myeloma cells freshly isolated from patients was observed in short-term cultures. Recombinant IL-6 was able to amplify it two- to threefold. The spontaneous proliferation of the myeloma cells was inhibited by anti-IL-6 antibodies and reinduced by recombinant IL-6. After 2 to 3 weeks of culture, the myeloma-cell proliferation progressively declined and no IL-6-dependent myeloma cell lines could be obtained despite repeated additions of fresh IL-6 and costimulation with other cytokines such as tumor necrosis factor (TNF)beta, or IL-1 beta. These data demonstrated a paracrine but not autocrine regulation of the growth and differentiation of myeloma cells by IL-6.

Interferon‐γ+ and interleukin‐2+ T cells in peripheral blood from multiple myeloma patients in relation to disease status and maintenance therapy with interferon‐α2b (intron A)

“…Although IL-6 levels were similar in patients taking or not taking INFa2b during remission, we cannot conclude that they were determined entirely by T lymphocytes since their contribution may be insignificant in relation to the total pool of IL-6 in vivo. However, in view of the proposed role of IL-6 as a paracrine growth factor for MM cells (Klein et al, 1989), the data show no evidence that its availability was reduced by INFa2b. Although only nine patients were available for re-assessment, elevated levels of INFg þ T cells persisted in 7/9 patients.…”

“…The anti-proliferative effect of INFg against MM cells is as effective as dexamethasone in vitro, whereas INFa inhibits only immunoglobulin secretion (Palumbo et al, 1995). This effect is due to inhibition of the proliferative signal from IL-6, which is considered the major growth factor for MM in vitro (Kanawa et al, 1988;Klein et al, 1989).…”

The imbalance between Survivin and Bim mediates tumour growth and correlates with poor survival in patients with multiple myeloma

“…We have now focused our attention on Survivin overexpression in myeloma cells. We first studied the biological consequences of forced Survivin expression in the human myeloma cell line (HMCL), XG6, that presents both a low level of endogeneous Survivin and a growth-dependence on exogenous IL6 that closer mimics in vitro the cytokine-dependence observed in patients with MM (Kawano et al, 1988;Klein et al, 1989). Survivin overexpression was shown to overcome the in vitro IL6-dependence of XG6 cells and promoted tumour growth of myeloma cells in a subcutaneous xenograft model.…”

TLR4/TIRAP polymorphisms are associated with progression and survival of patients with symptomatic myeloma

“…To our knowledge this is the first report regarding the impact of genetic variations of the TLR4/TIRAP pathway on the outcomes of patients with myeloma independently of other disease characteristics. Our study was based on the established knowledge that a proinflammatory microenvironment supports myeloma plasma cell survival Klein et al, 1989;Zhang et al, 1989;Fowler et al, 2012) , (Nefedova et al, 2003), and we hypothesized that genetic factors which influence the inflammatory response may also influence outcomes after anti-myeloma therapy. Studies have shown that stimulating MM cells with TLR ligands enhances resistance to dexamethasone and promotes growth and proliferation of these cells (Bohnhorst et al, 2006;Jego et al, 2006).…”