Autocrine Interleukin-6 Production Research Articles

Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop.

Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial-mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.

Increased autocrine interleukin-6 production is significantly associated with worse clinical outcome in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) remains incurable with current standard therapy. We have previously reported that an increased expression of interleukin‐6 (IL‐6) receptor CD126 leads to resistance of CLL cells to chemotherapy and worse prognosis for patients with CLL. In this study, we determine whether autocrine IL‐6 production by CLL B cells is associated with poor clinical outcome and explore IL‐6‐mediated survival mechanism in primary CLL cells. Our results demonstrate that higher levels of autocrine IL‐6 are significantly associated with shorter absolute lymphocyte doubling time, patients received treatment, without complete remission, advanced Binet stages, 17p/11q deletion, and shorter time to first time treatment and progression‐free survival. IL‐6 activated both STAT3 and nuclear factor kappa B (NF‐κB) in primary CLL cells. Blocking IL‐6 receptor and JAK2 inhibited IL‐6‐mediated activation of STAT3 and NF‐κB. Our study demonstrates that an increased autocrine IL‐6 production by CLL B‐cells are associated with worse clinical outcome for patients with CLL. IL‐6 promotes CLL cell survival by activating both STAT3 and NF‐κB through diverse signaling cascades. Neutralizing IL‐6 or blocking IL‐6 receptor might contribute overcoming the resistance of CLL cells to chemotherapy. We propose that the measurement of autocrine IL‐6 could be a useful approach to predict clinical outcome.

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth.

Interleukin-6 has an important role in the pathophysiology of multiple myeloma where it supports the growth and survival of the malignant plasma cells in the bone marrow. It belongs to a family of cytokines which use the glycoprotein 130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor. Targeting interleukin-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies. Here, efforts were made to elucidate the contribution of interleukin-6 and glycoprotein 130 signaling in malignant plasma cell growth in vivo In the xenograft severe combined immune deficiency model employing our interleukin-6-dependent plasma cell line INA-6, the lack of human interleukin-6 induced autocrine interleukin-6 production and a proliferative response to other cytokines of the glycoprotein 130 family. Herein, mice were treated with monoclonal antibodies against human interleukin-6 (elsilimomab/B-E8), the interleukin-6 receptor (B-R6), and with an antibody blocking glycoprotein 130 (B-R3). While treatment of mice with interleukin-6 and interleukin-6 receptor antibodies resulted in a modest delay in tumor growth, the development of plasmacytomas was completely prevented with the anti-glycoprotein 130 antibody. Importantly, complete inhibition was also achieved using F(ab')2-fragments of monoclonal antibody B-R3. Tumors harbor activated signal transducer and activator of transcription 3, and in vitro, the antibody inhibited leukemia inhibitory factor stimulated signal transducer and activator of transcription 3 phosphorylation and cell growth, while being less effective against interleukin-6. In conclusion, the growth of INA-6 plasmacytomas in vivo under interleukin-6 withdrawal remains strictly dependent on glycoprotein 130, and other glycoprotein 130 cytokines may substitute for interleukin-6. Antibodies against glycoprotein 130 are able to overcome this redundancy and should be explored for a possible therapeutic window.

Potential Crosstalk of Interleukin-6-Heme Oxygenase-1 Dependent Mechanism Involved in Resistance to Lenalidomide in Multiple Myeloma Cells

Interleukin-6 (IL-6), as one of the most important multiple myeloma (MM) survival factors, has been verified to determine poor prognosis of MM. IL-6 mainly originates from paracrine of bone marrow stromal cells and autocrine of MM cells. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. The HO-1 expression levels in bone marrow CD138+ cells of MM patients, which were significantly higher than those of healthy donors, were positively correlated with serum IL-6 levels and intracellular IL-6 mRNA expression levels. Cultivating U266 and CD138+ cells with exogenous IL-6 in vitro induced high HO-1 expressions and allowed them to resist lenalidomide, probably because IL-6 activated the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Without IL-6 co-culture, on the other hand, up-regulating HO-1 expressions in U266 cells and bone marrow CD138+ cells from MM patients significantly up-regulated the mRNA expression level of IL-6 and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced of p38 MAPK phosphorylation. Down-regulating HO-1 expression sensitized U266 and CD138+ cells toward lenalidomide. Therefore, we postulated that HO-1 predominantly controlled IL-6 paracrine and autocrine, and that IL-6 in bone marrow microenvironment of MM patients stimulated MM cells to highly express HO-1 and to resist lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, thus further augmenting the drug resistance and exacerbating the disease. This study provides valuable experimental evidence for using HO-1 as a possible marker for MM prognosis and drug resistance and as a potential treatment target. DisclosuresNo relevant conflicts of interest to declare.

Autocrine Production of Interleukin-6: A Mechanism of Interleukin-6 Independence in Dexamethasone-Resistant 7TD1 Murine Myeloma Cells

Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 cell line (7TD1-Dxm) and have shown that one mechanism of resistance to dexamethasone is due to inhibition of cytochrome c release. We have also observed that 7TD1-Dxm cells proliferate independently of externally-added IL6. This study therefore aimed to elucidate the mechanisms responsible for IL6-independent proliferation in 7TD1-Dxm cells. Our results indicated that 7TD1-Dxm cells produced IL6 in an autocrine fashion. We have observed that dexamethasone-resistant 7TD1 cells become dexamethasone-resistant and IL6-independent for proliferation concomitantly. This strongly suggests that production of IL6 by 7TD1-Dxm cells may play an important role in the development of dexamethasone resistance. Consequently, further investigation of the molecular mechanisms responsible for IL6 production may be helpful in delineating the mechanisms leading to dexamethasone resistance.

Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells

It has been widely reported that Interleukin-6 (IL-6) is overexpressed in the serum and ascites of ovarian cancer (OVCA) patients, and elevated IL-6 level correlates with poor prognosis and survival. However, the exact role that IL-6 plays in this malignancy or whether IL-6 can regulate tumorigenic properties has not been established. Here we demonstrate that overexpression of IL-6 in non-IL-6-expressing A2780 cells (by transfecting with plasmid encoding for sense IL-6) increases anchorage-independent growth, proliferation, adhesion and invasion, while depletion of endogenous IL-6 expression in IL-6-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) decreases. Further investigation indicates that IL-6 promotes OVCA cell proliferation by altering cell cycle distribution rather than inhibiting apoptosis and that IL-6-enhanced OVCA cell invasive may be associated with increased matrix metalloproteinase (MMP)-9 but not MMP-2 proteolytic activity. In addition, overexpressing or deleting of IL-6 in OVCA cells enhances or reduces its receptor (IL-6Rα and gp130) expression and basal phosphorylation levels of both ERK and Akt, and additional treatment with specific inhibitor of the ERK or Akt signaling pathway significantly inhibits the proliferation of IL-6-overexpressing A2780 cells. Our data suggest that the autocrine production of IL-6 by OVCA cells regulates tumorigenic properties of these cells by inducing IL-6 signaling pathways. Thus, regulation of IL-6 expression or its related signaling pathway may be a promising strategy for controlling the progression of OVCA.

2.21 Autocrine Interleukin-6 Production Correlated with Survival of Chronic Lymphocytic Leukaemia Cells

2.21 Autocrine Interleukin-6 Production Correlated with Survival of Chronic Lymphocytic Leukaemia Cells

2.46 Signal Transducer and Activator of Transcription 3 and Nuclear Factor κB Activation Regulate Autocrine Interleukin-6 Production and Indicate the Prognosis of CLL

2.46 Signal Transducer and Activator of Transcription 3 and Nuclear Factor κB Activation Regulate Autocrine Interleukin-6 Production and Indicate the Prognosis of CLL

Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells

BackgroundSpontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-κB. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells.ResultsInhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. The pharmacological inhibition of NF-κB, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells.ConclusionsThis study is the first to directly address the role Stat3 plays on the autocrine production of IL-6, which occurs through a positive-feedback loop. Our biochemical and genetic studies clearly demonstrated that Jak2/Stat3, in combination with other IL-6 downstream pathways, contributed frequently and substantially to IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples. Our findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance.

Autocrine IL6/STAT3 Signaling Enhances Survival of Chronic Lymphocytic Leukaemia Cells

AbstractAbstract 3598Signal transducer and activator of transcription 3 (STAT3) proteins have been found to play an important role in cancer cell survival and proliferation. The activation of STAT3 signalling pathways require interleukin-6 (IL6) and tyrosine kinase (JAK2) phosphorylation. Previous studies have shown that in patients with CLL elevated levels of serum IL6 correlate with adverse disease features and shorter survival. Methods:We investigated the relationship of CLL cell autocrine IL6 production, STAT3 activation and apoptosis resistance. Thirty-six CLL patients with high lymphocyte counts were investigated. Westen blot, flow cytometry, gene transfection and fluorescent microscopy techniques were used. Results:Autocrine IL6 production in CLL cells cultured for 24 hours was higher in Binet stage B/C patients (61pg/ml, range 1.4–297pg/ml) as compared with stage A patients (6.1pg/ml, range 0–23pg/ml) (p=0.02). Patients with high autocrine IL6 production had a higher ratio of phosphorylated STAT3/ total STAT3, indicating a high level of STAT3 activation and apoptosis resistance. Activation of the IL6/JAK2/STAT3 pathway by exogenous IL6 led to increased expression of anti-apoptotic proteins Mcl-1 and Bcl-xl. STAT3 activation by exogenous IL6 led to increased resistance of CLL cells to spontaneous in vitro apoptosis (mean increase in viable cells over control: 15%, range 2–36%; p=0.00008). This was associated with preservation of mitochondrial function: decreased cytochrome C release (p=0.004), mitochondrial membrane potential collapse (p=0.0004) and ROS generation (p=0.0007). This study demonstrates that higher autocrine IL6 production by CLL correlates with STAT3 activation and apoptosis resistance in CLL. The IL6/JAK2/STAT3 signal pathway may reveal new therapeutic targets. Disclosures:Gribben:Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

Abstract 3378: E-cadherin suppresses breast cancer cell growth and interleukin-6 production

Abstract Carcinomas arise from epithelial tissues and represent the most common type of human cancer. E-cadherin is an epithelial-specific intercellular adhesion molecule, which localizes to epithelial cell adherens junctions and is a critical mediator of carcinoma cell invasion and metastasis. Although impaired E-cadherin expression can be clinically utilized to predict breast cancer cell invasiveness, metastasis, and patient survival, E-cadherin has received less attention for its role as a putative regulator of epithelial cell growth. We have previously shown that interleukin-6 (IL-6), a pleiotropic inflammatory cytokine associated with poor clinical outcome in breast cancer patients, is a potent growth factor and repressor of E-cadherin in human breast cancer cells. Consistent with clinical reports and our previous findings, we hypothesized that E-cadherin repression may be responsible for IL-6-induced breast cancer cell growth. The current study demonstrated that IL-6 enhanced the growth rates of estrogen receptor-alpha (ERα)-positive breast cancer cells in a three-dimensional (3D) tumor growth assay (TGA) in a dose-dependent manner. We showed that IL-6 also repressed E-cadherin protein levels in ERα-positive breast cancer cells in a 3D TGA in a dose-dependent manner. We have previously shown that IL-6 treatment does not affect E-cadherin-negative MDA-MB-231 cell growth, and the current study showed similar results in MCF-7 cells which express Twist and therefore lack E-cadherin. MDA-MB-231 cells lack E-cadherin and express IL-6, thus allowing us to express stable ectopic E-cadherin to evaluate its impact on cell growth and IL-6 production. Ectopic E-cadherin expression significantly suppressed MDA-MB-231 cell growth (P-value < 0.005) and IL-6 production (P-value < 0.00005) as measured by 3D TGA and ELISA, respectively. Our current findings reveal an association between enhanced breast cancer cell growth and E-cadherin repression following exposure to IL-6. Furthermore, we demonstrated that E-cadherin suppresses breast cancer cell growth and IL-6 production, which suggests a positive feedback loop in which IL-6 promotes E-cadherin repression, thereby inducing autocrine IL-6 production in breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3378.

Interleukin-6, multidrug resistance protein-1 expression and response to paclitaxel in women with metastatic breast cancer: results of cancer and leukemia group B trial 159806

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m(2) over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.

Toll-like receptors mediate proliferation and survival of multiple myeloma cells

Multiple myeloma (MM) is an incurable B-cell malignancy characterized by accumulation of malignant plasma cells in bone marrow (BM) and recurrent or persistent infections. Toll-like receptors (TLRs) are essential in the host defense against infections and today 10 human TLRs (TLR1-TLR10) and one TLR-homolog (RP105) have been characterized. B cells express several TLRs (mainly TLR1, 6, 7, 9, 10 and RP105) and TLR-initiated responses in B cells include proliferation, anti-apoptosis effect and plasma cell (PC) differentiation. The present study was designed to analyze the role of TLRs in MM. We show that frequent expressions of TLRs were detected in cell lines from MM patients (minimum six TLRs in each). In comparison, only few TLRs (mainly TLR1 and or RP105) were found expressed in PCs from BM of healthy donors. In addition, TLR-specific ligands induce increased proliferation and survival of the MM cell lines, partially due to an autocrine interleukin-6 production. Importantly, we demonstrate that also PC from MM patients proliferates in response to TLR-specific ligands. In conclusion, TLR-ligands may contribute to increased growth and survival of MM cells in MM patients.

BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production

AbstractThe transcription repressor BCL-6 is known to play critical roles in B-cell lymphomagenesis, germinal center formation, and balanced Th1/Th2 differentiation. In macrophages, although BCL-6 has also been shown to regulate the expression of several chemokine genes, its function in other aspects of macrophage biology has not been studied. In addition, the precise role of BCL-6 in cell proliferation is poorly understood in general. Here we report that BCL-6-/- macrophages hyperproliferate due to an accelerated G1/S transition accompanied by increased cyclin D2 and c-myc and decreased expression of p27. Crucial to this enhanced proliferation is spontaneous interleukin 6 (IL-6) production and signal transducer and activator of transcription 3 (STAT3) activation in BCL-6-/- macrophages. In colony-forming assays, BCL- 6-/- bone marrow progenitor cells form spontaneous macrophage colonies that can be inhibited by anti-IL-6 antibodies. Gene expression studies demonstrate that BCL-6 binds to several sequence motifs scattered in the IL-6 locus and can repress IL-6 transcription both in 293T cells and in macrophages. In conclusion, our results indicate that BCL-6 negatively regulates proliferation of the monocytic/macrophage lineage by suppressing an autocrine IL-6/STAT3-mediated gene expression program. Our work also suggests that BCL-6 prevents abnormal Th2 differentiation by suppressing basal level IL-6 production in antigen-presenting cells (APCs). (Blood. 2005;105:1777-1784)

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

AbstractIn 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-6Rα 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.

Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds.

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces apoptotic cell death that was suppressed by the calcium ionophore A23187 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspase activation but not with suppression of wild-type-p53-induced expression of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or TG required extracellular Ca2+ and was specifically abolished by the calcineurin inhibitor cyclosporin A. IL-6 induced immediate early activation of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristine in M1 cells that did not express p53 by a cyclosporin A-sensitive mechanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but was suppressed by the cytokines IL-6, IL-3, or interferon gamma. The results indicate that these Ca2+-mobilizing compounds can suppress some pathways of apoptosis suppressed by cytokines but do so by a different mechanism.

Cytokine Network in Human Multiple Myeloma

In multiple myeloma (MM), an overproduction of IL-6, indicated by increased plasma C-reactive protein levels, is found in 37% of MM patients at diagnosis and is associated with disease aggressiveness, myeloma-cell proliferation, and poor prognosis. IL-6 is produced by the tumoral environment mainly and not by myeloma cells themselves. IL-6 is a major growth factor for malignant plasmablastic cells in vitro, and it is possible to reproducibly obtain IL-6-dependent myeloma-cell lines. Moreover, anti-IL-6 therapies in patients with terminal disease block myeloma-cell proliferation in vivo. The myeloma-cell growth factor activity of IL-6 is probably the consequence of IL-6 being a growth factor for normal plasmablastic cells. Hematopoietic cytokines (GM-CSF, IL-3, IL-5, G-CSF) synergize with IL-6 to support myeloma-cell proliferation. IFN-alpha and TNF induce an autocrine production of IL-6 in myeloma-cell lines and make possible the autonomous growth of these cell lines. On the contrary, IFN-gamma completely inhibits the IL-6-mediated myeloma-cell proliferation. The identification of some major cytokines involved in the control of the myeloma clone has immediate therapeutic implications, because some of these cytokines are, or might be, used in the treatment of patients with MM.