Production of interleukin-1 by bone marrow myeloma cells

Abstract

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

“…Macrophages constitute a major physiological source of TNF, and respond to TNF by inducing inflammatory signals and the production of cytokines [34]. Some studies have suggested that LTa also stimulates macrophages to express inflammatory cytokines [68,69], but TNF and LTa signalling have not been directly compared in these cells. We therefore examined signal transduction and cytokine production in bone marrow-derived macrophages (BMDMs) stimulated by Fc-TNF or Fc-LTa.…”

Myeloproliferation in long‐term plasmacytoma‐regressor mice

“…It was reported that the development of multiple myeloma in humans and of plasmacytoma in mice is accompanied by deranged immunoregulatory circuits in the tumor-bearing host (Ulrich and Zolla-Pazner, 1982). This derangement may be caused by a de-regulated secretion of immunoregulatory molecules by host immunocytes (Cozzolino et al, 1989), by a secretion of such molecules from the tumor cells themselves (Jourdan et al, 1991) and/or by abnormalities in the number or function of regulatory cells (MacKenzie et al, 1991;Chen and Heller, 1982).…”

Biologic and clinical significance of cytokine production in B‐cell malignancies

“…In addition, myeloma cell lines are perhaps more representative of the myeloma stem cell population, which is a minor part of the malignant clone. IL-1 production by MM bone marrow plasma cells has been demonstrated recently (40). Since IL-1 is perhaps the most effective stimulant of IL-6 gene transcription and protein secretion in numerous cell types, such as fibroblasts, monocytes, and endothelial cells (8,25), it is conceivable that the two cytokines are functionally linked within the myeloma cell population.…”

“…Continuous lines established from M M patients produce large amounts of LT (48); although a direct demonstration of surface receptors for this cytokine on myeloma cells still is lacking, the observation that TNF induces CLL cell proliferation may suggest that also myeloma cells can support their own growth through LT secretion. Interestingly, the same cells also express TNF gene, even though the protein cannot be demonstrated in culture supernatants (40,48).…”

“…A remarkable condition is bone destruction in MM. The abundant production of IL-1 by myeloma cells (40) can be held responsible for the osteoclast activation, evident in histologic sections of MM bone marrow. Although culture supernatants of fresh myeloma cells in most cases do not contain TNF/LT biologic activity, it cannot be ruled out that minute amounts of these cytokines are actually released in vivo.…”