TY - JOUR

T1 - Ligand-regulated expression of TNF receptors 1 and 2 determines receptor-mediated functional responses

AU - Alshevskaya, Alina

AU - Koneva, Olga

AU - Belomestnova, Irina

AU - Lopatnikova, Julia

AU - Evsegneeva, Irina

AU - Zhukova, Julia

AU - Kireev, Fedor

AU - Karaulov, Aleksander

AU - Sennikov, Sergey

N1 - Funding Information: The study was supported by a grant from the Russian Science Foundation (Project No. 20-75-10051) Publisher Copyright: © 2021 S. Karger AG. All rights reserved.

PY - 2021/11/1

Y1 - 2021/11/1

N2 - 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.

AB - 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.

KW - Cellular immunology

KW - Cytokine receptor expression

KW - Immune regulation

KW - TNF-alpha

KW - Receptors, Tumor Necrosis Factor, Type II/metabolism

KW - Humans

KW - Recombinant Proteins/pharmacology

KW - Apoptosis/drug effects

KW - Receptors, Tumor Necrosis Factor, Type I/metabolism

KW - Cell Line, Tumor

KW - Tumor Necrosis Factor-alpha/genetics

KW - Cell Cycle/drug effects

UR - http://www.scopus.com/inward/record.url?scp=85107671279&partnerID=8YFLogxK

U2 - 10.1159/000516352

DO - 10.1159/000516352

M3 - Article

C2 - 34062547

AN - SCOPUS:85107671279

VL - 182

SP - 1077

EP - 1088

JO - International Archives of Allergy and Immunology

JF - International Archives of Allergy and Immunology

SN - 1018-2438

IS - 11

ER -