65,66 It is of interest to note that differential methylation may perhaps also be re lated to differential demethylation brought on by demethylase,67 glycosylase,68 or other related enzymatic pursuits. 69 It appeals further studies to find out if detected methylation distinctions inside the TNFAIP3 promoter could possibly represent an epige netic modication that might modify a individuals response to TNF mediated processes in glaucoma. Various Consequences of TNF Signaling in Glaucoma By highlighting diverse proteins linked to TNF /TNFR1 signal ing while in the glaucomatous human retina,ndings of this examine support that a complicated cross speak romance in between multi ple signaling pathways determines diverse consequences of TNF signaling. three Things figuring out opposing results of TNF signaling also incorporate the sort of receptor preferentially made use of.
Two cell surface receptors, p55 and p75, mediate biological activities of TNF . These two receptors are co expressed on most cell varieties and feed into various signaling pathways in accordance to distinctions inside their intracellular domains. A death domain in TNFR1, not present in TNFR2, prospects to apoptotic cell death, whereas signaling as a result of TNFR2 leads principally to cell proliferation. Similarly, selleck inhibitor TNFR1 is located to augment neuronal death and TNFR2 has been discovered to promote neuroprotection in a retinal isch emia model in knockout mice. 70 No boost was detectable in the expression of TNFR2 during the glaucomatous specific VEGFR2 inhibitor human retina. A recent study71 of an experimental rat glaucoma model has supported that signaling by way of TNFR2 may perhaps be neurotoxic by a paracrine mechanism by increasing the glial produc tion of neurotoxic proteins, such as TNF .
An additional study72 has similarly shown that activation of this receptor may well set off RGC death by

a non cell autonomous signaling pathway by inducing TNF production in Mu ller cells. Thesendings collectively suggest that our proteomic information supportive of TNF mediated cell death signaling in human glaucoma may predominantly reect TNFR1 signaling. Regarding inamma tion signaling, research working with receptor specic antibodies,73 li gands,74 and knockout mice75 77 have indicated that TNFR1 is the main signaling receptor on most cell types by which the majority of inammatory responses classically attrib uted to TNF arise. Additionally, soluble TNF , greater than its membrane bound kind, is required to make neuroinam mation,78 which is the principal ligand for TNFR1. 79 As a result, TNFR1 appears to become the primary receptor for each neurode generative and inammatory consequences of TNF signaling in glaucoma.