Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis

Abstract

In this study, flow cytometry was used to evaluate interleukin-6 (IL-6) production by bone marrow mononuclear cells from 47 patients with multiple myeloma (MM) in different clinical stages and 15 patients with monoclonal gammopathy of undetermined significance. In patients with MM, autocrine IL-6 production paralleled the clinical disease stage. The largest proportion of syndecan-1 ؉ /IL-6 ؉ cells was detected in patients with resistant relapse or primary refractory disease, suggesting that tumor progression involves expansion of myeloma cells producing IL-6. The authors assessed autocrine IL-6 production and in vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970, which showed different sensitivities to the addition of exogenous IL-6. Autocrine IL-6 production was observed in IL-6-independent MCC-2, MCC-3, and MCC-5 cloned from patients with aggressive disease and in the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-6 were syndecan-1 ؉ and IL-6 ؊ . Blocking experiments with anti-IL-6 monoclonal antibody from clone AH65, which binds IL-6-IL-6R␣ complexes, prevented cell proliferation of IL-6 ؉ MCCs. Flow cytometry evaluations after propidium iodide staining revealed different susceptibilities of MCCs to cell death. IL-6-producing MCCs showed minimal spontaneous and dexamethasone-induced apoptosis, whereas a regular amplitude of apoptosis occurred in the IL-6 ؊ MCCs. These data provide evidence that autocrine IL-6 reflects a highly malignant phenotype of myeloma cells. In fact, autocrine IL-6 production and deregulated apoptosis may induce expansion of selective IL-6 ؉ myeloma cells resistant to spontaneous and drug-induced cell death. IntroductionInterleukin 6 (IL-6), a pleiotropic cytokine produced by a variety of cells, is the most important growth factor for human multiple myeloma (MM). 1-3 Several findings support in vivo and in vitro roles for IL-6 in the disease: specifically, (1) serum IL-6 and IL-6R levels were found to correlate with disease activity 4-6 ; (2) therapy with anti-IL-6 monoclonal antibody (mAb) transiently reversed disease manifestations 7 ; (3) in vitro proliferation of myeloma cells was suppressed by neutralizing mAbs to either IL-6 or its cellular receptors [8][9] ; and (4) inactivation of IL-6 messenger RNA by antisense oligonucleotides inhibited proliferation of plasma cells. 10 Furthermore, other cytokines, such as IL-1, IL-3, and granulocytemacrophage colony-stimulating factor, regulate myeloma cell proliferation in synergy with IL-6 11 or by inducing IL-6 production in myeloma cells or the tumor environment. [12][13] The cellular origin of IL-6 is controversial. Several authors [13][14][15][16] showed that it is produced by the myeloma cells themselves (autocrine hypothesis). Other studies, [17][18][19] however, point to its paracrine production by cells in the bone marrow (BM) and suggest that proliferation of myeloma cells depends on close contact with stromal cells. [20][21...

C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases

“…In addition, interleukin (IL) -1 and -6 network is upregulated (Vidal-Vanaclocha et al, 2000;Miki et al, 2004). Interleukin 1 is involved in the development of metastasis in animal studies and IL-6, apart from being a growth factor, promotes resistance to apoptosis (Vidal-Vanaclocha et al, 1994Chauhan et al, 1997;Frassanito et al, 2001;Jee et al, 2001). This creates a microenvironment that favours tumour angiogenesis, proliferation, growth and metastases.…”

The MicroRNA let-7a Modulates Interleukin-6-dependent STAT-3 Survival Signaling in Malignant Human Cholangiocytes

“…□ S The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure. 1 To whom correspondence should be addressed: Division of Gastroenterology and Hepatology, The Ohio State University Medical Center, N201 Doan Hall, 410 West 10 th Ave., Columbus, OH 43210. Tel.…”

“…IL-6 has been implicated in tumor growth in many of these tumors, and elevated IL-6 expression has been associated with poor outcomes and resistance to chemotherapy (1). Experimentally, growth of prostate cancer and cholangiocarcinoma xenografts in athymic mice has been shown to be increased by enforced expression of IL-6 by activation of cell survival signaling (2,3).…”

Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects

“…[21][22][23] A limitation of the anti-IL-6 treatments was the very large production of endogenous IL-6 in some patients with MM that could not be neutralized by the anti-IL-6 mAb. 24,25 As blocking IL-6 can increase the apoptosis of myeloma cells induced by dexamethasone (DEX) 26 and the drug sensitivity of tumour cells, 27,28 we have investigated the possibility of treating patients having MM with the B-E8 anti-IL-6 mAb, high dose of DEX (40 mg/day for 4 days), and high dose of melphalan (140 mg/m 2 ) supported by autologous stem cell transplantation (ASCT). The anti-IL-6 mAb was given before and during DEX-HDM to potentiate the apoptotic effect of DEX and HDM.…”