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.

Human Myeloma Cells Promote the Recruitment of Osteoblast Precursors: Mediation by Interleukin-6 and Soluble Interleukin-6 Receptor

“…The osteolytic bone disease that develops in patients with multiple myeloma is characterized by an increase in bone resorption and a decrease in bone formation. Studies have shown that myeloma cells can produce a number of factors that promote bone resorption, (13–19) although the specific identity of the factor(s) responsible in vivo remain unclear. However, no data are available investigating the factors responsible for modulating bone formation.…”

Phenotypic and molecular analysis of six human cell lines derived from patients with plasma cell dyscrasia

“…Production of IL‐1 may be of pathological significance in the biology of multiple myeloma mainly because of its ability to act as an osteoclast‐activating factor and influence IL‐6 production via PGE 2 . Healthy individuals express the gene for IL‐1β (but not IL‐1α) constitutively in their peripheral blood and bone (Cluitmans et al , 1995), but in patients with MM, the source of IL‐1 has been controversial (Lichtenstein et al , 1989; Cozzolino et al , 1989; Borset et al , 1993). Recently Costes et al (1998) demonstrated IL‐1β protein production in tumoural samples of the majority of patients with MM.…”

The NF-κB Activating Pathways in Multiple Myeloma

“…Aberrant activation of the NF-κB family of transcription factors in myeloma cells causes heightened expressions of a variety of tumor-promoting cytokines, which further act in an autocrine loop on malignant cells. Clinical studies involving serum and bone marrow samples derived from MM patients revealed a substantially augmented level of TNF, IL-1, IL-6 and BAFF [ 108 , 109 , 110 , 111 ]. Analysis of MMCLs confirmed that myeloma cells were indeed capable of inducing the expression of genes encoding tumor-promoting cytokines.…”