TNF-a is one of most important inflammatory cytokines. It is produced primarily by monocytes and macrophages on which it exerts its endo-, para- and autocrine actions. It stimulates cytotoxic properties of monocytes and macrophages and simultaneously is a mediator of cytotoxicity. Its biological effects depends strongly on quantity and intensity of TNF-a secretion. Apart from taking part in inflammatory processes it also plays important role in neovascularisation (Wilson &Balkwill, 2002). TNF-a exerts versatile effects due to its ability to induce synthesis of other cytokines functionally related to TNF-a, extracellular matrix proteins, monocyte and fibroblast chemotaxis modulation and also influences the expression of adhesive molecules in retinal vessels (Doganay et al.,2002; Naldini & Carraro, 2005). Teflon implants soaked in 3.5 ng TNF-a and implanted into rat cornea caused a visible growth of new blood vessels after 7 days (Fajardo et al., 1992). A similar effect was achieved on chicken embryo membranes (Hooper et al., 2005). However, (Patterson et al., 1996) showed an antiangiogenic action of TNF-a using human endothelial cells. The authors showed that incubation of those cells with known proangiogenic factor VEGF for 24h augmented their proliferative activity more than two fold, whereas 12h pre-incubation abolished this effect. However, TNF-a alone revealed a weak cytotoxic effect towards endothelial cells. Inhibition of endothelial cell proliferation by TNF-a was associated with reduction in VEGFR-2 (KDR/Flt-1) receptor mRNA transcription level which depends on dose and the duration of cytokines. Low concentrations of TNF-a can trigger signalling pathways through p55 and p75 receptor, but in high concentrations only through p55 (Bigda et al., 1994). In young patients with newly diagnosed diabetes increased activity of TNF-a has been demonstrated (Mysliwiec et al, 2006). High levels of TNF-a have been detected also in type 1 diabetic children and adolescents with non-proliferative retinopathy (Mysliwiec et al, 2006, Zorena et al. 2007). TNF-a may become a relevant indicator of development and risk of diabetic retinopathy. Similar observations were made in adult patients with PDR (Gustavsson et al., 2008; Koleva-Georgieva et al., 2011). Levels of TNF-a in vitreous of Type 2 diabetic patients with PDR were higher than those found in control group. Furthermore a correlation between TNF-a and HbA1c is observed, suggesting that there is a close relation between glycaemic control and inflammatory factors in T2DM patients (Adamiec-Mroczek et al., 2008; Lee JH, 2008). TNFRI and TNFRII receptors' levels in vitreous of patients with PDR and proliferative vitreoretinopathy were much higher than in patients with perforation in macula (Limb et al., 2001). Attempts are being made to block TNF-a actions with monoclonal antibodies (Sfikkakis et al., 2010; Giganti et al., 2010; Biswas et al., 2010). In randomized studies, the intravenous use of infliximab has improved visual acuity in patients with diabetic macular edema (DME) (Sfikakis et al., 2010).
Etanercept is a soluble TNF-a receptor that acts as competitive inhibitor blocking effects of TNF-a binding to cells. Etanercept reduced leukocyte adherence in retinal blood vessels of diabetic rats for 1 week as compared to control. Etanercept did not reduce retinal VEGF levels, but it inhibited blood-retinal barrier breakdown and NF-kB activation in the diabetic retina (Joussen et al., 2002; Zheng et al., 2004).
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