Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4615-4621 ◽  
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Roberto Sala ◽  
Matteo Moroni ◽  
Mirca Lazzaretti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Lymphocytes ◽  
Bone Disease ◽  
Nuclear Factor Κb ◽  
Myeloma Cell ◽  
Nuclear Factor ◽  
Free System ◽  
Receptor Activator ◽  
Ifn Γ

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-κB ligand (RANKL), and interferon γ (IFN-γ) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti–interleukin 6 (anti–IL-6) or anti–IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-γ by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell–free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 μg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

The OPG/TRAIL Interaction in an In Vitro Osteoclastogenesis Model Derived from Human Multiple Myeloma-Bone Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2361-2361
Author(s):  
Stefano Molica
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Bone Disease ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Trail Receptors ◽  
Receptor Activator

Abstract The development of multiple myeloma (MM)-bone disease is mediated by increased recruitment and activity of osteoclasts (OCs). Osteoclastogenesis is regulated by a complex signaling system, that involves receptor activator of nuclear factor-kappa B (RANK), receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), all belonging to the Tumor Necrosis Factor (TNF) family. The aims of our study were to investigate: the MM T cell involvement in osteoclastogenesis, and the expression of the major osteoclastogenic mediators. Unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) isolated from 32 MM patients with or without osteolytic bone lesions, and parallel T cell-depleted cultures were used as in vitro osteoclastogenesis models. In addition, unstimulated and unfractionated PBMC cultures from 32 controls with nonneoplastic disease without any skeletal involvement were also established. Our results showed that the OCs derived from MM-bone disease PBMCs spontaneously developed and displayed a longer survival in a T cell-dependent way. Differently in T cell-depleted MM PBMC cultures, the addition of macrophage-colony stimulating factor (M-CSF) and RANKL was necessary to promote the formation of OCs, that however did not exibit a longer survival. MM-bone disease T cells overexpressed RANKL, OPG and TNF-related apoptosis inducing ligand (TRAIL), also detected in large amounts in the culture media. Despite high OPG levels, the persistence of osteoclastogenesis in our system can be related to the interaction between OPG and TRAIL, that were coimmunoprecipitated by a monoclonal antibody (mAb) against TRAIL. The evidence that TRAIL binds to OPG blocking OPG anti-osteoclastogenic effect is also supported by the addition of different concentrations of functional anti-TRAIL mAb, significantly decreasing the OC formation. The OCs developed from MM-bone disease PBMCs expressed a T cell-modulated balance of death and decoy TRAIL receptors. In particular, we found these OCs overexpressed TRAIL decoy receptor DcR2 in the presence of T cells, and death receptor DR4 in the T cell-depleted cultures. In conclusion, our results highlight that MM-bone disease T cells support the spontaneous OC formation with longer survival, involving the OPG/TRAIL interaction and the unbalanced OC expression of TRAIL death and decoy receptors.

Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1064-1069 ◽  
Author(s):  
Evangelos Terpos ◽  
Richard Szydlo ◽  
Jane F. Apperley ◽  
Evdoxia Hatjiharissi ◽  
Marianna Politou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Bone Disease ◽  
Dominant Role ◽  
Prognostic Index ◽  
Risk Groups ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Bone Remodeling Markers ◽  
Receptor Activator

Abstract Interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and β2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.

Induction of Multiple Myeloma-Specific Cytotoxic T Lymphocytes Using HLA-A2.1-Specific CD19 and CD20 Peptides.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2477-2477
Author(s):  
Jooeun Bae ◽  
Jeff A. Martinson ◽  
Hans G. Klingemann ◽  
Steven Treon ◽  
Kenneth C. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Lymphocytes ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Specific Ctls ◽  
Ifn Γ ◽  
Hla A2.1

Abstract We have identified novel CD19 and CD20 antigen-derived HLA-A2.1-specific immunogenic peptides, CD19150–158 (KLMSPKLYV) and CD20188–196 (SLFLGILSV), for generating cytotoxic T lymphocytes (CTLs) against malignant B-cell diseases. Initial testing showed that the CTLs displayed antigen-specific and HLA-A2.1-restriced cytotoxic activity against both Burkitt’s lymphoma and chronic lymphoid leukemia cell lines. The observed cytotoxic activity of the CTLs was shown to be specific to the CD19150–158 or the CD20188–196 peptides. Additionally, the CTLs displayed a distinct phenotype (majority CD69+/CD45RO+) along with a significant (p<0.05) increase in cell proliferation and IFN-γ release following re-stimulation with HLA-A2.1+/CD19+/CD20+ tumor cell lines. Based on emerging information that clonogenic myeloma cells express CD19 and/or CD20, we evaluated the activity of the CD19 and CD20 peptide specific-CTLs against several multiple myeloma cell lines. Five of 10 myeloma cell lines evaluated were HLA-A2.1-positive and expressed both CD19 and CD20 antigens. CD19 peptide specific-CTLs generated from normal donors were able to specifically lyse CD19+/HLA-A2.1+ MM cell lines (30% lysis; 10:1 E:T ratio) but did not lyse CD19−/HLA-A2.1+ or CD19+/HLA-A2.1− cell lines. Similarly, the CD20-specific CTLs generated from normal donors lysed CD20+/HLA-A2.1+ MM cell lines (25% lysis; 10:1 E:T ratio), in a manner restricted to HLA-A2.1 and specific to antigens. We next showed IFN-γ production by the CTLs after exposure to CD19+/HLA-A2.1+ or CD20+/HLA-A2.1+ MM cells. Moreover, we have demonstrated the ability to expand CD20-CTLs under serum-free culture conditions while maintaining their cytotoxic activity (28–49%). In ongoing studies, we are evaluating the ability of CD19- and CD20-specific CTLs to eliminate clonogenic myeloma cells in vitro and in vivo in a SCID mouse model of myeloma. These preclinical studies strongly suggest that immunogenic CD19 and CD20 peptide-based vaccines represent a promising immunotherapeutic approach in myeloma.

The role of serum osteoprotegerin and receptor–activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery

2015 ◽  
Vol 34 (6) ◽  
pp. 655-661 ◽  
Author(s):  
José A. Balsa ◽  
Christian Lafuente ◽  
Jesús M. Gómez-Martín ◽  
Julio Galindo ◽  
Roberto Peromingo ◽  
...  
Keyword(s):  
Obesity Surgery ◽  
Bone Disease ◽  
Metabolic Bone Disease ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Metabolic Bone ◽  
Receptor Activator

scholarly journals Small Molecule Inhibitors Targeting Nuclear Factor κB Activation Markedly Reduce Expression of Interleukin-2, but Not Interferon-γ, Induced by Phorbol Esters and Calcium Ionophores

2021 ◽  
Vol 22 (23) ◽  
pp. 13098
Author(s):  
Yumiko Tanaka ◽  
Ayaka Nakao ◽  
Yasunobu Miyake ◽  
Yukina Higashi ◽  
Riho Tanigaki ◽  
...  
Keyword(s):  
T Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Effector T Cells ◽  
Nuclear Factor ◽  
Ifn Γ ◽  
Primary Effector ◽  
Mouse Lymphoma

The T-box transcription factor Eomesodermin (Eomes) promotes the expression of interferon-γ (IFN-γ). We recently reported that the small molecule inhibitors, TPCA-1 and IKK-16, which target nuclear factor κB (NF-κB) activation, moderately reduced Eomes-dependent IFN-γ expression in mouse lymphoma BW5147 cells stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM). In the present study, we investigated the direct effects of NF-κB on IFN-γ expression in mouse lymphoma EL4 cells and primary effector T cells. Eomes strongly promoted IFN-γ expression and the binding of RelA and NFATc2 to the IFN-γ promoter when EL4 cells were stimulated with PMA and IM. Neither TPCA-1 nor IKK-16 reduced IFN-γ expression; however, they markedly decreased interleukin (IL)-2 expression in Eomes-transfected EL4 cells. Moreover, TPCA-1 markedly inhibited the binding of RelA, but not that of Eomes or NFATc2 to the IFN-γ promoter. In effector CD4+ and CD8+ T cells activated with anti-CD3 and anti-CD28 antibodies, IFN-γ expression induced by PMA and A23187 was not markedly decreased by TPCA-1 or IKK-16 under conditions where IL-2 expression was markedly reduced. Therefore, the present results revealed that NF-κB is dispensable for IFN-γ expression induced by PMA and calcium ionophores in EL4 cells expressing Eomes and primary effector T cells.

Sign in / Sign up

Export Citation Format

Share Document