A pro‐inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor‐associated periodic syndrome (TRAPS)

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor‐associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand‐independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild‐type TNFR1 (WT), were expressed at near physiological levels in an SK‐Hep‐1 cell model. TNFR1‐associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y‐TNFR1‐expressing SK‐Hep‐1 cells and TRAPS patients’ PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients’ PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS‐associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine‐blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.     

Roles of ligands from the TNF superfamily in B cell development,function, and regulation

Most ligands from the tumour necrosis factor (TNF) superfamily play very important roles in the immune system, and particularly so in B lymphocyte biology. TNF ligands are essential to many aspects of normal B cell biology from development in the bone marrow to maturation in the periphery as well as for activation and differentiation into germinal centre, memory or plasma cells. TNF ligands also influence other aspects of B cell biology such as their ability to present antigens or regulate immune responses. Importantly, inadequate regulation of many TNF ligands is associated with B cell disorders including autoimmunity and cancers. As a result, inhibitors of a number of TNF ligands have been tested in the clinic, with some becoming very successful approved treatments alleviating B cell-mediated pathologies.     

Stanozolol promotes lipid deposition in the aorta through an imbalance in inflammatory cytokines and oxidative status in LDLr knockout mice fed a normal diet

The aim of the study was to evaluate the effect of an anabolic steroid, stanozolol, in a model of atherosclerosis and to investigate the involvement of the modulation of the inflammatory cytokines and oxidative stress in vascular lipid deposition. Low‐density lipid receptor‐deficient (LDLr?/?) mice were fed a standard chow diet and were each week injected subcutaneously either saline (control C group) or 20 mg/kg stanozolol (S group). After 8 weeks, the levels of cholesterol, oxidized LDL (OxLDL) and cytokines were measured in plasma, lipid deposition in aorta was evaluated by en face analysis, and thiobarbituric acid‐reactive substances and oxidation protein were determined in liver. The S group demonstrated increases in vascular lipid deposition, triglycerides and non‐HDL cholesterol levels. Stanozolol increased tumour necrosis factor alpha (TNF‐α) and decreased interleukin‐10 as well as increased the TNF‐α/IL‐10 ratio. Furthermore, oxidative stress was observed in the S group, as indicated by an increase in the plasma OxLDL, as well as by lipid peroxidation and oxidation of proteins in the liver. Chronic treatment with stanozolol promoted lipid deposition in the LDLr^?/? mice that could be attributed to a modification of the circulating cytokine levels and systemic oxidative stress. Our results suggest that the anabolic steroid stanozolol in the absence of functional LDL receptors by increasing systemic inflammation and oxidative stress may increase the risk of development and progression of atherosclerosis.