Related Experiment Video

Updated: May 24, 2026

Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14+ Monocytes
11:52

Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14+ Monocytes

Published on: January 27, 2023

TNFα modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts

Alison M Connor1, Nizar Mahomed, Rajiv Gandhi

  • 1Arthritis and Immune Disorder Research Centre, University Health Network, Toronto Medical Discovery Tower, 10th Floor, Room 10-358, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

Arthritis Research & Therapy
|March 16, 2012
PubMed
Abstract

Insights

Tumor necrosis factor-alpha (TNFα) increases endoplasmic reticulum (ER) stress in rheumatoid arthritis (RA) synovial fibroblasts. Both autophagy and proteasome pathways are upregulated in RA, with TNFα primarily stimulating autophagy.

Area of Science:

  • Cell Biology
  • Immunology
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) is a chronic inflammatory joint disease.
  • Synovial fibroblasts and macrophages are key cells in RA pathogenesis.
  • Tumor necrosis factor-alpha (TNFα) drives RA synovial fibroblast proliferation and inflammatory mediator production.
  • Protein misfolding triggers cellular stress, managed by proteasome and autophagy pathways.

Purpose of the Study:

  • To investigate the hypothesis that protein degradation pathway activity increases in RA synovial fibroblasts upon TNFα stimulation.
  • To compare the response of autophagy and proteasome pathways to TNFα in RA synovial fibroblasts versus control fibroblasts.

Main Methods:

  • Examined endoplasmic reticulum (ER) stress markers using immunoblotting and PCR.
  • Assessed autophagy and proteasome pathway activity via chemical inhibition, LC3 immunoblotting, proteasome activity assays, and long-lived protein degradation measurements.
  • Determined cellular viability under different conditions.

Main Results:

  • RA synovial fibroblasts exhibit heightened basal ER stress, further exacerbated by TNFα.
  • Autophagy is the primary pathway for ER stress relief in unstimulated RA fibroblasts.
  • Both autophagy and proteasome pathways are more active in RA synovial fibroblasts than controls.
  • TNFα consistently stimulates the autophagy pathway, not the proteasome, in RA synovial fibroblasts.
  • RA synovial fibroblasts show increased reliance on the proteasome for viability when autophagy is inhibited under TNFα stimulation.

Conclusions:

  • TNFα stimulation elevates ER stress markers in synovial fibroblasts.
  • Synovial fibroblast survival in RA is contingent on both lysosome/autophagy and ubiquitin/proteasome pathways.
  • Both degradation pathways exhibit enhanced activity in RA synovial fibroblasts.
  • These findings offer insights into how TNFα promotes synovial fibroblast survival in RA tissue.

Related Concept Videos

T Cell Types and Functions01:24

T Cell Types and Functions

When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
NF-kB-dependent Signaling Pathway02:26

NF-kB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...