This evidence suggests that the opposite effects of TNFRs on survival or death of motor neurons depend on the cell population involved.
We previously reported that the high levels of TNFRs in the spinal cord of mutant SOD1 mice were associated with activation of signaling involving MKK3-6, MKK4, ASK1, and phosphorylated p38MAPK (P-pMAPK) in motor neurons and glial cells [52,74].
Unexpectedly, the significant increase in phospho-ASK1 (P-ASK1) immunoreactivity in transgenic large motor neurons was prevented by inhibition of each of TNFRs separately (Figure 3).
Table 1: Effects of the activation of TNFRs on different cell types.
TNF and TNF receptors (TNFR) are growing members of ligand and receptor superfamily that regulate several complex signaling pathways leading to apoptosis, inflammation, cellular differentiation, and antiviral state.
TNFR superfamily includes TNFR1, TNFR2, LT-betaR, OX40, CD27, CD40, CD30, 41-BB (CD137), Fas, TRAILR1 (DR4), TRAILR2 (DR5), TRAILR3, TRAILR4, OPG, RANK, Decoy (DC) R3, TWEAKR, NGFR, Transmembrane Activator and CAML interactor (TACI), BAFFR, LIGHTR (HVEM), DR3, glucocorticoid induced TNF receptor (GITR), EDAR, XEDAR, TROY, RELT, DR6, and B-cell maturation protein (BCMA) [4, 7].
In this review, we will focus on TNF and TNFR and their family members in context to HIV infection and potentially how to modulate them by TNF inhibitor therapy.
These potentially different responses are affected by the percentage of TNFR positive cells in the context of the absolute number of TNF[alpha] receptors (Table 2).
Association of SNPs -1207G/C, -1709A/T, and -3609C/T of TNFR genes promoters with expression levels of membrane-bound TNF[alpha] receptors types I and II in the absence of association with level of soluble TNF[alpha] receptors is established what testifies to existence of different mechanisms of regulation of soluble and membrane-bound receptors expression.
Abbreviations CD: Cluster of differentiation ELISA: Enzyme-linked immunosorbent assay IgG: Immunoglobulin G LPS: Lipopolysaccharide MFI: Mean fluorescence intensity PBMC: Peripheral blood mononuclear cell PCR: Polymerase chain reaction PE: Phycoerythrin RFLP: Restriction fragment length polymorphism SNP: Single nucleotide polymorphism TAE: Tris-acetate-EDTA TNF[alpha]: Tumor necrosis factor alpha TNFR: Tumor necrosis factor receptor sTNFR: Soluble tumor necrosis factor receptor.
This would imply that proteolytic shedding of cytokines like TNF[alpha] also regulates immune cell migration, and this activity could be counterregulated by receptor shedding of TNFR, IL1R, or IL6R [97, 99, 100].
Interestingly, ADAM17 may exert both positive and negative effects on angiogenesis by timely release of TNF[alpha]  or its receptor TNFR. TNF[alpha] stimulation increased ADAM17 expression accompanied by increased shedding of TNFR, which could be a self-protective mechanism during prolonged immunostimulation .