Increased Serum Levels of Brain-Derived Neurotrophic Factor Contribute to Inflammatory Responses in Patients with Rheumatoid Arthritis

Ning-Sheng Lai,Hsien-Yu Huang Tseng,Hsien-Bin Huang,Ming-Chi Lu,Hui-Chun Yu,Chia-Wen Hsu

doi:10.3390/ijms22041841

Abstract

The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF) in the inflammatory responses in patients with rheumatoid arthritis (RA). Serum levels of BDNF and the precursor form of BDNF (proBDNF) from 625 RA patients and 40 controls were analyzed using enzyme-linked immunosorbent assay. Effects of BDNF on the mitogen-activated protein kinase pathway were analyzed by Western blotting. Microarray analysis was conducted to search BDNF regulated gene expression in Jurkat cells, and the differentially expressed genes were validated using T cells from patients with RA and controls. Serum BDNF levels were significantly elevated in patients with RA compared with the controls. Low serum BDNF levels were found in RA patients with anxiety or receiving biologics treatment. BDNF (20 ng/mL) enhanced the phosphorylation of ERK, JNK, and c-Jun, but suppressed the phosphorylation of p38, whereas BDNF (200 ng/mL) enhanced the phosphorylation of ERK and p38. After validation, the expression of CAMK2A, MASP2, GNG13, and MUC5AC, regulated by BDNF and one of its receptors, NGFR, was increased in RA T cells. BDNF increased the IL-2, IL-17, and IFN-γ expression in Jurkat cells and IL-2 and IFN-γ secretion in activated peripheral blood mononuclear cells.

Highlights

Rheumatoid arthritis (RA) is a chronic systemic disease characterized by persisting joint inflammation
For the possible effect of extracellular kinases (ERK) activation, we found that the addition of a low or high concentration brain-derived neurotrophic factor (BDNF) did not affect the Jurkat cell viability and proliferation (Figure 3C)
We found that the expression of 77 protein-coding genes was significantly decreased, and 142 protein-coding genes were significantly increased in Jurkat cells after cocultured with BDNF 200 ng/mL for 48 h compared with the controls (Figure 4A)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic systemic disease characterized by persisting joint inflammation. In addition to articular manifestations, patients with RA have an increased incidence of developing depression, which is itself a risk factor for developing. Decreased brain-derived neurotrophic factor (BDNF) expression is well-known to play a critical role in the pathogenesis of depression [2]. Previous research suggested that the increased serum levels of proBDNF or decreased. BDNF/proBDNF ratio could be a serum marker for depression [4,5]. Few studies have investigated the serum levels of BDNF in patients with RA, and the results were conflicting. Low serum BDNF levels were observed in RA patients with depression compared to RA patients without depression [6]. Grimsholm et al found that serum BDNF was elevated in 18 patients with RA compared with controls, and their BDNF levels were declined after receiving anti-TNF treatment [7].

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