Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-α on this pathway

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Characteristics of dengue virus‐infected peripheral blood mononuclear cell death that correlates with the severity of illness

“…DHF plasma samples containing TNF‐α at a concentration ≥ 20 pg/ml were selected for the apoptotic induction experiment, as previously described (20). Briefly, 3 × 10 6 PBMCs from healthy donors were pre‐incubated with 100 μl DHF plasma in the presence or absence of 20 pg etanercept, an anti‐TNF‐α antibody (Wyeth, Philadelphia, PA, USA), at 37°C for 2 hr.…”

Proteomic analysis for the anti‐apoptotic effects of cystamine on apoptosis‐prone macrophage

“…Recently, transglutaminase 2 (TG2) has been implicated in the pathogenesis of SLE [Szondy et al, 2003; Pitidhammabhorn et al, 2006]. TG2 is known as a multi‐functional enzyme that is expressed in the majority of tissues and implicated in numerous biological functions, including remodeling of the extracellular matrix [Aeschlimann et al, 1995], stimulus‐secretion coupling [Bungay et al, 1986], receptor‐mediated endocytosis [Davies et al, 1980], cell differentiation [Aeschlimann et al, 1993], tumor growth [Johnson et al, 1994], and apoptosis [Fesus et al, 1987].…”

Gene Expression Profiles in a Rabbit Model of Systemic Lupus Erythematosus Autoantibody Production

“…Recent reports from human studies have also directly or indirectly indicated upregulation of many of these pathways including NF-kB (58); death receptor signaling (59); integrin signaling (60); IL-4 signaling (61), PDGF signaling (62); and Glucocorticoid receptor signaling (63). …”