|Year : 2017 | Volume
| Issue : 3 | Page : 566-571
Effect of levamisole on expression of CD138 and interleukin-6 in human multiple myeloma cell lines
B Nageshwari1, Ramchander Merugu2
1 Department of Biotechnology, Government College Autonomous, Rajamahendravaram, Andhra Pradesh, India
2 Department of Biochemistry, Mahatma Gandhi University, Nalgonda, Telangana, India
|Date of Web Publication||24-May-2018|
Dr. B Nageshwari
Department of Biotechnology, Government College Autonomous, Rajamahendravaram, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Multiple myeloma (MM) is a B-cell malignancy accounting for 0.8% of all cancer deaths globally. This malignancy is characterized by lytic bone disease renal insufficiency, anemia, hypercalcemia, and immunodeficiency. The myeloma cells have enhanced expression of CD138. CD138 is a transmembrane heparin sulfate glycoprotein expressed on different types of adherent and nonadherent cells.CD138 is used as a standard marker for identification of tumor cells. AIMS AND OBJECTIVES: Despite introduction of many therapeutic agents, the management of multiple myeloma (MM) remains a challenge and search for new therapeutic agents is in progress. In this study, we attempted to evaluate the effect of an alkaline phosphatase inhibitor, levamisole on expression of CD138, and level of interleukin-6 (IL-6) in human MM cell lines RPMI 8226 and U266 B1. MATERIAL AND METHODS: U266B1 and RPMI 8226 cell lines were obtained from the National Centre for Cell Sciences, Pune. Alkaline phosphatase assay, Interleukin-6 assay and CD138 expression on myeloma cells by flow cytometry were investigated when the cells were exposed to Levamisole. RESULTS: Levamisole-mediated growth inhibition of myeloma cells in vitro is associated with a loss of CD138 and increased IL-6 secretion. The increased secretion of IL-6 by myeloma cells could be an attempt to protect themselves from apoptosis. CONCLUSION: Levamisole inhibited CD138 expression and affected the levels of IL-6 in a dose-dependent manner. The results of the present study add new dimension to levamisole's mode of action as inhibitor of CD138 and IL-6 and as an antiapoptotic agent.
Keywords: Apoptosis, CD138, interleukin-6, levamisole, multiple myeloma
|How to cite this article:|
Nageshwari B, Merugu R. Effect of levamisole on expression of CD138 and interleukin-6 in human multiple myeloma cell lines. Indian J Cancer 2017;54:566-71
| » Introduction|| |
Multiple myeloma (MM) is a B-cell malignancy accounting for about 0.8% of all cancer deaths globally. This malignancy is characterized by lytic bone disease renal insufficiency, anemia, hypercalcemia, and immunodeficiency. The myeloma cells have enhanced expression of CD138. CD138 is a transmembrane heparin sulfate glycoprotein expressed on different types of adherent and nonadherent cells. CD138 is used as a standard marker for identification of tumor cells. By fine-tuning the function of regulatory proteins and cell signaling, CD138 regulates cell behavior in normal and pathological processes, such as tumor growth and metastasis, by sequestering chemokines and growth factors.,, Its expression is enhanced on myeloma and many other tumor cells. Enhanced CD138 expression is associated with cell proliferation. CD138 is also expressed by human plasma cells, while its expression is lost in cells undergoing apoptosis. In addition to CD138, several cytokines and growth factors have been suggested to stimulate the growth of human myeloma cells, and among them interleukin-6 (IL-6) seems to be a major growth factor for myeloma cells which can inhibit apoptosis of these malignant cells.,,, IL-6, produced by different types of cells, is a cytokine with pleiotropic activities such as regulation of cell growth, differentiation, and maturation. Severalin vitro andin vivo studies have shown that IL-6 is one of the major growth factors involved in the pathogenesis of human MM and mouse plasmacytoma cells.,, Previous studies have demonstrated that there are both an autocrine and paracrine IL-6-mediated growth and survival in MM cells and derived cell lines in vitro.,,,,,
Exogenous addition of IL-6 is shown to be vital for the proliferation of freshly isolated myeloma cells cultured in vitro., Serum levels of IL-6 have been shown to be associated with disease activity in myeloma, with high levels indicating severity., In addition, IL-6 appears to have broad antiapoptotic activity in several B-cell tumors including MM. In view of its effects on tumor cell growth, survival, adhesion, and invasion, CD138 and IL-6 may be potential beneficial regulators of myeloma pathobiology. Therefore, drugs that affect CD138 and IL-6 function are expected to be useful as therapeutic agents in patients with this lethal disease. The effect of levamisole was seen on the expression of CD138 and secretion of IL-6. Levamisole is an anticancer agent.,,, It has the property of inhibiting alkaline phosphatase (APase). Levamisole has been shown to induce apoptosis in cultured endothelial cells. APase is a membrane-bound glycoprotein expressed in B lymphocytes upon activation.,,, The enhancement of APase activity correlates with proliferation , and in phosphorylation/dephosphorylation reactions. APase also hydrolyzes the mineralization inhibitor, pyrophosphate. Hypoxia induces the expression of CD138 in MM cells.Strychnos nux-vomica L. root extract was screened using the human MM-cell line, U266B1, which demonstrated antiproliferative effect and apoptosis with the expression of IL-6 and CD138 (Syndecan-1). NFjB inhibitors,, Hsp90 inhibitors, PI3 K/mTor inhibitors, and PPARc inhibitors  inhibit IL-6 signaling in MM cells. Therefore, in this study, the expression of CD138 and IL-6 in the presence of levamisole was investigated and presented.
| » Materials And Methods|| |
Cell lines and culture conditions
U266B1 and RPMI 8226 cell lines were obtained from National Center for Cell Sciences, Pune, India. They were maintained in RPMI-1640 tissue culture medium (Sigma) supplemented with l-glutamine (2 mM) and 10% heat-inactivated fetal calf serum (FCS; HiMedia) in 25-cm 2 tissue culture flasks (Orange Scientific), followed by incubation at 37°C in a humidified atmosphere of 95% air and 5% CO2 in a CO2 incubator (Forma Scientific). Each day, the cultures were examined for microbial contamination using an inverted microscope (Unico, USA).
APase activity assay
Myeloma cells (5 × 104) were cultured with varied concentrations of levamisole in 200 μL of complete medium in triplicate. APase activity was determined by p-nitrophenyl phosphate (p-NPP) hydrolysis. The absorbance of p-nitrophenol (p-NP) produced was measured at 405 nm. Cells were dispensed into wells of microtiter plate and centrifuged at 450g for 10 min at 4°C. The cells were suspended in 0.9% saline, and centrifugation step was repeated. About 180 μL of 1 mg/mL p-NPP in 0.1 M bicarbonate buffer with 2 mM MgCl2 was added to the pellet. It was then incubated at 37°C in a humidified incubator. After 30 min, the reaction was stopped by the addition of 20 μL of 1 N NaOH, and the absorbance was measured at 405 nm using ELISA plate reader. The amount of p-NP released was calculated from a standard graph. The results were then expressed as nanomoles of p-NP released per culture.
About 5 × 104 cells were treated with varied concentrations (0.0, 0.5, 1.0, and 2.5 mM) of levamisole in 200 μL of complete culture medium in triplicate. IL-6 in the culture supernatants was determined by ELISA. Microwells were coated with 100 μL of capture antibody per well (antihuman IL-6) diluted in coating buffer, and the plate was sealed, followed by incubation overnight at 4°C. The solution was aspirated and washed thrice with 200 μL of wash buffer per well. The wells were blocked with 200 μL of assay diluent per well and then incubated at room temperature for 1 h. The wells were aspirated and washed thrice with 200 μL of wash buffer per well. The samples were diluted in assay diluent, and about 100 μL was pipetted into wells and incubated for 2 h at room temperature. The wells were aspirated and washed five times with 200 μL of wash buffer per well. Approximately 100 μL of working detector (antihuman IL-6 antibody + streptavidin–avidin–horseradish peroxidase mixed just before addition) was added to each well and incubated for 1 h at room temperature. The wells were aspirated and washed seven times with 300 μL of wash buffer per well. About 100 μL of substrate solution was added to each well followed by incubation for 30 min at room temperature in dark. Then, 50 μL of stop solution was added to each well and the absorbance was read at 450 nm within 30 min of stopping the reaction.
CD138 expression on myeloma cells by flow cytometry
The myeloma cell lines RPMI 8226 and U266B1 were cultured in T-25 flasks in RPMI-1640 medium supplemented with 10% FCS and treated with varied concentrations of levamisole (control, 0.5, 1, and 2.5 mM), and the cells were harvested after 48 h. The number of CD138-positive cells was determined by fluorescence-activated cell sorting (FACS) using FITC-conjugated anti-human CD138 antibody. About 1 × 106 treated cells were centrifuged at 200g for 10 min and washed with wash buffer. The cells were then resuspended in 50 μL of staining buffer to this suspension; 20 μL of fluorescein-conjugated anti-CD138 antibody was added and incubated for 45 min on ice. Afterward, the suspension was centrifuged at 200 g for 10 min at 4°C. The supernatant was removed and the cells were suspended in 1 mL of cold buffer and centrifuged as above. This step was repeated twice. The pellet was resuspended in 0.5 mL of phosphate-buffered saline and stored at 4°C until analyzed. The expression of CD138 was assessed using a FACS flow cytometer using a gating protocol set for measuring the mean FITC fluorescence intensity of labeled cells. About 10,000 events were counted and the data are presented as scatter plots. Appropriate isotype controls were prepared and processed in an identical manner.
| » Results|| |
Effect of levamisole on CD138 expression in myeloma cells
CD138 expression on untreated and levamisole-treated myeloma cells at different concentrations for 48 h of culture period was determined using FITC-conjugated anti-CD138 monoclonal antibody. Flow cytometric analysis showed that in case of untreated cells, 63% of U266 and 51% of RPMI 8226 cells were CD138-positive. The percentage of CD138-positive cells decreased significantly with increasing concentrations of levamisole [Figure 1]a, [Figure 1]b and [Figure 2]a, [Figure 2]b; P < 0.05].
|Figure 1: Effect of levamisole on CD138 expression of myeloma cells using fluorescence-activated cell sorting analysis. (A) Results are those of one experiment representative of three independent experiments. Cell population in red color represents unstained cells. Cell population in green color represents cells stained positive for CD138. (a) Isotype control, (b) without levamisole, (c) 0.5 mM levamisole, (d) 1.0 mM levamisole, (e) 2.5 mM. (B) Results are those of one experiment representative of three independent experiments. Cell population in red color represents unstained cells. Cell population in green color represents cells stained positive for CD138. (a) Isotype control, (b) without levamisole, (c) 0.5 mM levamisole, (d) 1.0 mM levamisole, (e) 2.5 mM|
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|Figure 2: CD138 expression on levamisole treated (a) U266B1 myeloma cells (b) RPMI8266 myeloma cells. Each value represents the mean ± standard error of mean of three experiments. *P < 0.05, treated versus untreated |
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Quantitation of IL-6 in U266 B1 cell culture supernatant
The supernatant from myeloma cells cultured with and without levamisole was harvested at intervals of 24 h over a period of 72 h. IL6 was assayed using sandwich ELISA. There was a dose- and time-dependent increase in the concentration of IL-6 in the supernatant at 0.5 and 1.0 mM concentrations of levamisole, respectively [Figure 3].
|Figure 3: Effect of levamisole on interleukin-6 secretion by U266 cells. Each value represents the mean ± standard error of mean of three experiments. *P < 0.05, treated versus untreated|
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Effect of levamisole on APase activity of cell lines
Both the myeloma cell lines (RPMI 8226 and U266 B1) constitutively express APase activity. In the presence of levamisole, APase activity was inhibited in a dose-dependent manner. The assay was performed at the end of 48 and 72 h; the results are presented in [Figure 4]a and [Figure 4]b.
|Figure 4: Concentration- and time-dependent effects of levamisole on MM cell alkaline phosphatase activity. (a) U266 B1. (b) RPMI 8226. Control: no levamisole addition. Each value represents the mean ± standard error of mean of experiments. *Values significantly differ from the respective control, P < 0.05|
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| » Discussion|| |
CD138 and IL-6 play a major role in regulating the pathobiology of myeloma. The defining characteristic of the syndecan family is a highly conserved transmembrane and cytoplasmic domain which contains four conserved tyrosines and a variable number of serines/threonines that may serve as phosphorylation sites. Activation leads to phosphorylation of the receptors themselves and initiation of a cascade of phosphorylation events that activate or deactivate a wide variety of other kinases and regulatory molecules, ultimately resulting in changes in cellular behavior. In this study, the authors observed that on culturing with increasing concentrations of levamisole, there was a significant decrease in the percentage of CD138-positive cells. It has been reported earlier that the membrane-bound CD138 has a turnover and that the ectodomain of it is shed constitutively by cultured cells.,, In murine mammary gland cells, NMuMG cells, it has been shown that CD138 is constitutively phosphorylated at low levels and orthovandate inhibits a phosphatase which rapidly dephosphorylates the protein. This inhibition of cellular phosphatase leads to activation of a cytoplasmic kinase that recognizes and phosphorylates CD138, leading to its subsequent shedding from the membrane. The shedding of CD138 is highly regulated by the activation of at least two distinct receptor classes, G-protein-coupled and protein tyrosine kinases. The shedding of CD138 has been shown to increase with tyrosine phosphorylation of its cytoplasmic domain. Similar findings were reported in myeloma cells. In this study, it was found that the expression of CD138 in myeloma cell lines RPMI 8226 and U266 B1 was inhibited by levamisole in a dose-dependent manner in both the cell lines. The decreased expression of CD138 in levamisole-treated cells could be because of its accelerated shedding from the membrane. The authors propose that such a shedding of syndecan-1 on myeloma cells might be because of the inhibition of APase by levamisole. On inhibition of APase, there is probably a reduced dephosphorylation of the receptors resulting in phosphorylation of CD138 and its subsequent shedding from the membrane.
The shedding or loss of CD138 is associated with apoptosis and inhibition of cell growth in vitro. Loss of CD138 may also contribute to the mechanism of induction of apoptosis in myeloma cells, and it may be because of loss of interaction of heparan sulfate chains with a cellular receptor or growth factor. The CD138 functions as a receptor or coreceptor for different factors including growth factors which are proven to have possible effects on the biology of MM. Earlier, it was reported that in murine B lymphoid cells, CD138 expression was regulated by IL-6 through posttranslational mechanisms. It was also reported that CD138 was lost by primary myeloma cells induced to apoptosis when cultured without IL-6. With dexamethasone, virtually all myeloma cells were apoptotic and had lost CD138. Addition of exogenous IL-6 partially prevented apoptosis in association with an increase in CD138-positive cells. IL-6 has multiple effects including regulation of cell growth, differentiation, and maturation, in a wide variety of cell types. For example, IL-6 secreted by T-helper cells stimulates terminal differentiation and growth of B cells., In addition, IL-6 appears to have broad antiapoptotic activity in several B-cell tumors including MM. IL-6 is a potent survival factor for myeloma cells and probably prevents them from undergoing apoptosis under drug exposure. It was shown that U266 cells secrete and require IL-6 for growth and survival. It was earlier reported that U266 proliferation was inhibited by neutralizing anti-IL-6 mAb or IL-6 antisense oligonucleotides.,, In an earlier published work, the authors have reported an antiproliferative activity of levamisole on myeloma cell lines. Here, they report that levamisole-mediated growth inhibition of myeloma cellsin vitro is associated with a loss of CD138 and increased IL-6 secretion. The increased secretion of IL-6 by myeloma cells could be an attempt to protect themselves from apoptosis.
| » Conclusion|| |
The effect of an alkaline phosphatase inhibitor, levamisole on expression of CD138, and level of interleukin-6 (IL-6) in human MM cell lines RPMI 8226 and U266 B1 was investigated and was found that Levamisole inhibited CD138 expression and affected the levels of IL-6 in a dose-dependent manner.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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