Tumor necrosis factor-α (TNF) has been associated with ischemic and diabetic retinopathy in both human and animal models.
8–11 It elicits a broad spectrum of biological effects including proliferation, differentiation, and apoptosis.
12,13 These differences in the TNF-induced response are due, in part, to the presence of two distinct TNF-specific plasma membrane–localized receptors, type I 55 kDa TNFR (TNFR1) and type II 75 kDa TNFR (TNFR2).
14,15 TNFR1 is expressed ubiquitously. In contrast, basal TNFR2 expression is detected only in certain cell types, including vascular endothelial cells (EC), cardiac myocytes, and some neuronal cells.
16–18 It can also be induced in EC in pathological settings such as ischemia.
19,20 In vascular EC, TNFR1 primarily mediates inflammation and apoptosis whereas TNFR2 promotes cell activation, migration, growth, or proliferation.
19–23 TNFR1 via formation of TNFR1 signaling complex activates MAP kinase, NF-κB, and apoptotic signaling cascades.
24,25 Less is known regarding TNFR2 downstream signaling. TNFR2 through TRAF2 can activate Nuclear factor–κB (NF-κB).
26 We have previously identified nonreceptor tyrosine kinase, bone marrow kinase (Bmx) that plays an important role in cell survival and migration, as a TNFR2-specific tyrosine kinase that mediates TNFR2-induced EC migration and angiogenesis.
19–21 Mechanistically, we have shown that TNFR2 and Bmx form a complex to transactivate VEGFR2, a potent angiogenic receptor.
19–21,27,28