Platelet expression of tumour necrosis factor-alpha (TNF-α), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy

Abstract

SUMMARYMicrovascular complications of insulin-dependent diabetes mellitus (IDDM) have been strongly associated with platelet abnormalities, whilst TNF-a has been implicated in the pathogenesis of this condition. However, at present it is not clear whether human circulating platelets express TNF-a or TNF receptors (TNF-R) or whether impaired expression of these molecules and of the TNF-reactive adhesion molecule ICAM-1 may be associated with platelet abnormalities in patients with IDDM. On this basis we investigated the platelet expression of these molecules in patients with IDDM complicated or uncomplicated by proliferative diabetic retinopathy (PDR) and in healthy subjects. We observed that the proportion of platelets staining for TNF-a was significantly higher in IDDM patients with active PDR than in patients without microvascular complications (P ¼ 0·0078), quiescent PDR (P ¼ 0·003) or healthy subjects (P ¼ 0·0013). Patients with active PDR also showed a higher proportion of platelets expressing TNF-RI (P ¼ 0·0052) and TNF-RII (P ¼ 0·015) than healthy controls or patients with quiescent PDR (P ¼ 0·009 and 0·0006, respectively). In addition, the percentage of ICAM-1 þ platelets was significantly higher in patients with active PDR than in patients with quiescent PDR (P ¼ 0·0065) or normal subjects (P ¼ 0·013). There was a direct correlation between platelet expression of TNF-a and that of TNF-R in PDR patients, indicating that platelet staining for TNF-a may be due to binding of this cytokine to its receptors. The results suggest that increased platelet expression of TNF-a, TNF-R and ICAM-1 in IDDM patients may constitute important markers of thrombocyte abnormalities during the development of microvascular complications of diabetes mellitus.

Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

“…This hypothesis is supported by the fact that local (including local vascular) Tnf-α levels are known to increase dramatically very early after an appropriate stimulus (47) - leading to the original classification of Tnf-α as an "immediate-early" gene (48). Our observation that acute Rantes production by VSMCs is governed by Tnf-α is consistent with an immediate-early local increase in Tnf-α following vascular injury, which may arise from several sources, including adherent monocytes (47) and platelets (49). Conversely, as compared with Tnf-α, Il-6 levels potentially fluctuate over a slower time course (43), with Il-6-dependent VSMC activation reliant on complex activation pathways involving exogenous soluble Il-6 receptor (43).…”

Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy

“…Elevated IL-6 and IL-8 have been documented in the vitreous fluid of patients with diabetic retinopathy (19), and TNF-␣ has been shown to be elevated in the serum (19) and epiretinal membranes (20) of patients with diabetic retinopathy. In addition, platelets from patients with active proliferative diabetic retinopathy express higher than normal levels of TNF-␣ and its receptors, TNF-RI and TNF-RII (21). The expression of intracellular adhesion molecule (ICAM)-1 is increased early in diabetic retinopathy and has been associated with increased TNF-␣, leukostasis, and subsequent endothelial cell death characteristic of the disease (2,21,22).…”

“…In addition, platelets from patients with active proliferative diabetic retinopathy express higher than normal levels of TNF-␣ and its receptors, TNF-RI and TNF-RII (21). The expression of intracellular adhesion molecule (ICAM)-1 is increased early in diabetic retinopathy and has been associated with increased TNF-␣, leukostasis, and subsequent endothelial cell death characteristic of the disease (2,21,22). Increased levels of IL-1␤ have also been measured in the retinas of STZ-induced diabetic rats and correlate with elevated levels of the inducible isoform of NO synthase (23).…”

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

“…[17][18][19][20] The biological effects of IL-1b depend on the target cell. Together with TNF-a, IL-1b is responsible for angiogenic activity.…”