Evidence for control of tumour necrosis factor-alpha (TNF-α) activity by TNF receptors in patients with proliferative diabetic retinopathy

Abstract

TNF-alpha has been implicated in the pathogenesis of insulin- dependent diabetes mellitus (IDDM). At present there are no studies linking serum levels of soluble TNF receptors (sTNF-R) to the development of diabetic microvascular complications such as proliferative diabetic retinopathy (PDR), or to the production of TNF-alpha in these patients. We investigated serum levels of sTNF receptors (sTNF-RI and sTNF-RII) in IDDM patients with or without PDR, and related these to the in vitro production of TNF-alpha upon activation of whole blood and isolated mononuclear cells (MNC). We observed higher serum levels of sTNF-RI in IDDM patients with active (range 945-6630 pg/ml; P = 0.029) or quiescent PDR (range 1675-4970 pg/ml; P = 0.00092) than in individuals with IDDM without retinopathy (range 657-2617 pg/ml) or healthy controls (range 710-1819 pg/ml; P = 0.0092 and 0.0023, respectively). Increased serum levels of sTNF-RII were also seen in IDDM patients with active PDR (range 1749-5218 pg/ml; P = 0.034) or quiescent PDR (range 1494-5249 pg/ml; P = 0.0084) when compared with disease controls (range 1259-4210 pg/ml) or healthy subjects (range 1237-4283 pg/ml). Whole blood production of biologically active TNF-alpha was lower in PDR patients than in disease (P = 0.04) and healthy controls (P < 0.005), contrasting with a higher production of TNF-alpha by lipopolysaccharide (LPS)-activated MNC from PDR patients (P = 0.013). Inhibition of TNF-alpha by TNF-R in plasma supernatants of activated blood from PDR patients was demonstrated by increase of TNF-alpha activity in the presence of anti-TNF-RI and anti-TNF-RII antibodies. These observations suggest that abnormalities in TNF-alpha production and control may operate during the development of microvascular complications of diabetes mellitus.

Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors

“…The data do not confirm reports on increased systemic TNF-α concentrations in Type II diabetes compared with healthy control subjects [9,10,11,36]. Factors accounting for this difference might be the smaller sample size of these studies, possible selection bias, or the inclusion of patients with diabetic complications, because a rise in systemic TNF-α concentrations in the latter case is known [11,37,38].…”

Hyperglycemia-Induced Reactive Oxygen Species Toxicity to Endothelial Cells Is Dependent on Paracrine Mediators

“…Cytokines, such as TNF-␣, its soluble receptor, and IL-1␤, are increased in serum of diabetic patients, and increased TNF-␣ levels have been associated with the development of diabetes complications (34 -36). Furthermore, increases in TNF-␣ and IL-1␤ levels have been shown in vitreous fluid of diabetic patients and in retinas of streptozotocin-induced diabetic rats and mice (26,35,36).…”

Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy

“…[1][2][3][4][5][6][7] Interleukins play an important role in the regulation of immune mechanisms, and are also thought to be responsible for the development of PDR. Cytokines such as tumour necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-1b), and interferon-gama regulate cells and have immune and inflammatory properties.…”