Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes

Objectives. To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. Design. Cross-sectional study. Setting. University hospital diabetes clinic. Subjects. A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. Outcome measures. Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. Results. Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r=0.41, P=0.012 and r=0.31, P =0.04, respectively), Tumour necrosis factor-a soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P=0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r=0.39, P=0.008), triglycerides (r=0.36, P=0.021) and diastolic blood pressure (r=0.35; P=0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r=0.46, P=0.002; r=0.32, P=0.034) and triglycerides (r=0.33, P=0.033; r=0.29, P=0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P<0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF- and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P<0.001). None of these interactions were apparent in control subjects. Conclusions. (i) IL-6, through effects on sICAM-1, and TNF-a via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF- are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.