Ligand-Regulated Expression of TNF Receptors 1 and 2 Determines Receptor-Mediated Functional Responses.

INTRODUCTION: Modulating specific biological effects through the changes in cytokine receptors' expression level remains poorly understood. This study aimed to investigate the influence of the dose-dependent effect of TNF on the balance between proapoptotic and proliferation response depending on the parameters of TNFR1/2 expression density. METHODS: Tumor cell lines (HEp-2, K-562, MCF-7, ZR-75/1, MOLT-4, IM-9, and Raji) were characterized for TNFR1/2 co-expression using flow cytometry and were studied to reveal the dose-dependent effect of rhTNF on cell cycle and apoptosis parameters. The associations among the studied parameters were estimated by correlation and regression analysis. RESULTS: It was found for ZR-75/1 cells (the cell line characterized by high expression of both types) that a dose-dependent increase in expression of both types of TNF-α receptors on cells reduces the proliferative activity of cells. For MOLT-4 cells (which are characterized by lower expression), an increase in proliferative response of cells was positively associated with the percentage of both TNFR1+ and TNFR2+ cells. However, opposite effects on the cells were shown for the K-562 and MCF-7 lines having a similar expression profile. A similarity (a large percentage of double-positive cells) was revealed for the lines having similar effects (K-562 and ZR-75/1). CONCLUSIONS: High expression of TNF receptor type 1 is not always associated with predominant activation of proapoptotic pathways. However, in the case of simultaneous high expression of both types of receptors, the proportion of double-positive cells is crucial for the activation of either the proapoptotic or proliferation pathways.

Co-Expression of Membrane-Bound Tumor Necrosis Factor-Alpha Receptor Types 1 and 2 by Tumor Cell Lines.

INTRODUCTION: Density and co-expression of tumor necrosis factor (TNF) receptors may vary among cell populations. However, the role and potential of these changes remain unclear. This study aimed to determine the density of expression and co-expression of TNFR1/2 and the dose-dependent effect of soluble TNF on these parameters. METHODS: Epithelial-like (HEp-2, K-562, MCF-7, ZR-75/1) and lymphoblast-like (MOLT-4, HL-60, Raji, RPMI-8226, IM-9) cell lines were characterized for co-expression of TNFR1/2 using a modified flow cytometry protocol. The dose-dependent effects of rhTNF on TNF receptor expression in these lines were studied. RESULTS: This study reports a protocol for the simultaneous quantitative evaluation of the of TNF receptor number and co-expression of membrane-bound TNFR1/2. Cells within one tumor cell line were found to differ regarding their expression of type 1 and 2 TNFα receptors; simultaneously, cells with all 4 variants of co-expression may be present in culture. CONCLUSION: We demonstrated a dose-dependent effect of TNF on changes in the expression of TNFR1/2 by the percentage of positive cells and by the number of receptors, which may be used to control TNF-mediated processes in target cells.

Expression Density of Receptors as a Potent Regulator of Cell Function and Property in Health and Pathology.

The expression of cytokine receptors has a crucial role in many cellular processes. Recent studies reported that changes of receptor expression could control the action of mediators on target cells. The initiation of different signaling pathways and, therefore, specific effects on cells, depends on certain components forming the cytokine-receptor complex. These mechanisms control the immune response and affect both the course of diseases (oncological, autoimmune, inflammatory) and the effectiveness of therapy. This review describes the potential of immune mediator receptors to regulate the efficiency of cytokine activity during pathologic processes and ensure the variability of their biological effects. Our aim was to investigate the spectrum of potential roles of changes in mediator receptor expression for main classes of pathologies. For all major types of immune mediators (cytokines, interleukins, chemokines, growth factors, and tumor necrosis factors), it has been shown that changes in their receptor expression are associated with impaired functioning of the organism in chronic diseases.

Co-expression of membrane-bound TNF-alpha type 1 and 2 receptors differ in the subsets of immunocompetent cells.

The immunoregulatory cytokine tumor necrosis factor α plays crucial roles in the pathogenesis of a broad spectrum of disorders. However, its effect may depend on the expression and co-expression of receptors on the target cell. The aim of the present study was to evaluate the expression levels of type 1 and 2 tumor necrosis factor α receptors (TNFR1/2) on individual cell subsets from peripheral blood of healthy volunteers. Flow cytometry analysis was used to study whole populations as well as subsets (T regulatory cells, T memory cells, cytotoxic T cells, T helper cells). Significant differences in the co-expression of TNFR1/2 were seen within subsets and total pools. Further studies are necessary to explore the implications of the observed differences in the modulation of tumor necrosis factor α function in health and pathology.