Abnormal expression of the IL-6 gene has been suggested to be involved in the pathogenesis of a variety of diseases, especially rheumatoid arthritis, Castleman's disease, mesangial proliferative glomerulonephritis, multiple myeloma and Kaposi's sarcoma.
Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (<i>p</i> < 0.001).
Additionally, IL‑6 and MIP‑1α expression were significantly upregulated when MSCs from MM patients were cultured in the myeloma associated condition medium.
Also, IL-6 produced by either a paracrine or autocrine mechanism can support the growth of the myeloma cells that may be manifested clinically by an elevated labeling index.
Although a reason for the overexpression in myeloma cells is not understood, very interestingly, the promoter region of the HM1.24 gene has a tandem repeat of three cis elements for a transcription factor, STAT3, which mediates interleukin-6 (IL-6) response gene expression.
Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment.
Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity.
An interleukin-6-dependent myeloma cell line ANBL6 was used and treated with dexamethasone, doxorubicin, and melphalan in the presence of bone marrow stromal cells.
Analysis of the transcriptional activity of 5'-regulatory sequences from the human Mcl-1 gene in MM cells demonstrated high levels of IL-6-independent indicator gene activation as predicted.
ANBL-6, a myeloma cell line, proliferates in response to interleukin 6 (IL-6) stimulation, coculture with bone marrow stromal cells, and when harboring a constitutively active mutant N-ras gene.
Anti-IL-6 antibody and IL-6 antisense oligonucleotide suppressed the IL-6 stimulated myeloma cell proliferation, indicating that IL-6 induced the myeloma cell proliferation via an autocrine loop.
As IL-6 and TGF-beta are important for the generation of T-helper 17 (T(H)17) cells, we evaluated and observed a significantly elevated baseline and induced frequency of T(h)17 cells in peripheral blood mononuclear cells (PBMCs) and BM mononuclear cells (BMMCs) from MM patients compared with healthy donors.
Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb.
BMMCs and BMSCs from patients with MM secreted significantly more IL-6 than those from healthy donors (n = 3, P < .001); moreover, after stimulation using CD40L, IL-6 secretion was fourfold greater (n = 3, P < .001) from MM BMMCs and BMSCs than from normal BMMCs and BMSCs.
Cancer cells may often support their own growth, survival, and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myeloma and prostate or renal cancer.
Collectively, these results demonstrate that NF-κB activation cannot only promote the emergence of IL6 independence during myeloma progression but can also confer resistance to dexamethasone and INCB018424.
Combining MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MM cell lines which can overcome the prosurvival effects of growth factors such as interleukin-6 and insulin-like growth factor-1.
Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ.