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

TNF-α 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-α 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-α 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-α was lower in PDR patients than in disease (P = 0.04) and healthy controls (P < 0.005), contrasting with a higher production of TNF-α by lipopolysaccharide (LPS)-activated MNC from PDR patients (P = 0.013). Inhibition of TNF-α by TNF-R in plasma supernatants of activated blood from PDR patients was demonstrated by increase of TNF-α activity in the presence of anti-TNF-RI and anti-TNF-RII antibodies. These observations suggest that abnormalities in TNF-α production and control may operate during the development of microvascular complications of diabetes mellitus