*3.4.3. Monokine induced by interferon-γ*

to become a mature active form. In the human eye, there are three known TGF-β isoforms

PDR patients (2634 ± 1652 pg/mL) compared to control patients (1305 ± 972 pg/mL) [61]. This result is also consistent with a McAuley et al. study about vitreous biomarkers in diabetic reti-

Pro-inflammatory cytokines are usually secreted by inflammatory cells in response to hypoxia or hyperglycemia [64]. Well-known pro-inflammatory cytokines, such as tumor necrosis factor, interleukin, interferon, and receptor tyrosine kinase are found to be elevated in the vitreous of diabetic retinopathy patients, suggesting their important role in the pathogenesis of this disease [5, 64, 65]. Cytokines can induce the progression of diabetic retinopathy directly and indirectly. Direct mechanisms include the direct engagement with target cells to induce neovascularization [64]. While indirect mechanisms induce leukocytes and endothelial cells to produce pro-angiogenic mediators, which in turn induce neovascularization [64, 65]. Therapy targeting these cytokines may be

Tumor necrosis factors-α (TNF-α), a pro-inflammatory cytokine, is primarily synthesized by macrophages and T cells. Its expression is regulated by NF-κβ and it has been associated with the pathogenesis of several chronic inflammatory diseases including type 2 diabetes. Its function is primarily as an immune-modulator and it also plays a role in neovascularization and fibroplasia [3]. Costagliola et al. suggest that TNF-α is a potent mediator of leukostasis and contributes to blood-retinal barrier breakdown [3, 66]. TNF-α concentration is found elevated in the vitreous of PDR patients and the vitreous/serum ratio of TNF-α is also found higher compared to non-diabetic patients. Costagliola et al. found that TNF-α levels were lower in controls (1.9 pg/mL) than the PDR group (13.5 pg/mL) and increased with the severity of the disease [3, 66]. TNF-α has a short half-life (∼4 min), making its analyzation prone to producing false negative results. Soluble TNF-α receptors (sTNF-α-Rs) have a longer half-life, mak-

Several studies have shown that there is involvement of interleukins in the development of PDR. The most common interleukins found in DR patients are IL-6 and IL-8, where their concentrations were found increased in the vitreous of patients with PDR and prolonged hyperglycemia [3, 42, 47, 72–82]. Their role in the pathogenesis of PDR is still under investigation but evidence suggests the possibility of a rather direct contribution. IL-6 controls immune cells responses by shifting T-helper cell populations, inhibiting the production of Th1 cells, promoting the differentiation of Th2 and Th17 cells, and infiltration of monocytes and T cells [9, 10, 83].

beneficial, but we need better understanding about the cytokine roles to do so [5].

ing it a more reliable marker of the activation of TNF-α system [29, 31, 67–71].

as the dominant form [61–63]. Hirase et al. found an increase in total vitreous TGF-β2

increase correlates with the disease severity, suggesting that TGF-β2

), where the posterior segment of the eye mainly contains TGF-β2

levels are also increased in PDR patients. This

levels in

angiogenesis properties

(TGF-β<sup>1</sup>

, TGF-β2

, and TGF-β<sup>3</sup>

78 Early Events in Diabetic Retinopathy and Intervention Strategies

nopathy [62]. The mature active form of TGF-β2

play a role in the progression of PDR [61].

**3.4. Pro-inflammatory cytokines**

*3.4.1. Tumor necrosis factor-α*

*3.4.2. Interleukin*

Monokine induced by interferon-γ (Mig) attracts activated T cells and has potent angiostatic activity. Several studies suggest that Mig correlates with VEGF and contributes to the progression of neovascularization in DR patients. The main function of Mig in the progression of DR might be related to its leukostasis function [88, 89]. Wakabayashi et al. found significant increases in vitreous concentration of Mig in active (148 pg/mL) and inactive (82.3 pg/mL) DR patients compared with non-diabetic patients who had macular disease (21 pg/mL). However, there was no significant difference in serum Mig concentration between DR patients (85.9 pg/mL) and control subjects (70.4 pg/mL) [87]. Takeuchi et al. also found an increase in Mig vitreous concentration in PDR patients compared to epiretinal membrane patients, idiopathic macular hole patients, and uveitis patients [88].
