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Brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration. Tissue regeneration is characterized by inflammation that directs the quality of tissue repair. In this study, we investigated the anti-apoptotic effect of BDNF against the toxicity of tumor necrosis factor α (TNFα), which is known for its pro-apoptotic action in human microvascular endothelial cells (HMVECs). We demonstrate that BDNF attenuates TNFα-increased Annexin V-positive cells, lactic dehydrogenase (LDH) release, and intercellular adhesion molecule 1 (ICAM-1) mRNA and cleaved caspase-3 expression. In addition, biochemical analyses indicate that TNFα increases phosphatase and tensin homolog (PTEN) expression; however, it decreases phosphorylated PTEN. BDNF did not affect PTEN expression, but it did increase the phosphorylation of PTEN. BDNF-induced Akt phosphorylation was inhibited by TNFα. Terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay showed that the PTEN inhibitor bpV(pic) rescues HMVECs from TNFα-induced apoptosis. In conclusion, BDNF protects HMVECs from toxicity of TNFα through the regulation of the PTEN/Akt pathway. Key words: brain-derived neurotrophic factor, tumor necrosis factor-α, apoptosis, vascular endothelial cells, periodontal therapy. Le facteur neurotrophique derive du cerveau BDNF (Brain-derived neurotrophic factor) accroit la regeneration du tissue parodontal [Takeda et al, 2005 et 2011]. La regeneration tissulaire est caracterisee par une inflammation qui dicte la qualite de la reparation du tissu. Dans cette etude, nous avons examine l'effet anti-apoptotique du BDNF envers le facteur necrosant des tumeurs-a (TNF-α) qui est bien connu pour son action pro-apoptotique sur les cellules endotheliales microvasculaires (HMVEC). Nous demontrons que le BDNF attenuait l'accroissement induit par le TNF-α du nombre de cellules positives a l'annexine V, la liberation de deshydrogenase lactique (LDH), et l'expression de l'ARNm de la molecule d'adhesion intercellulaire ICAM-1 et de la caspase-3 clivee. De plus, les analyses biochimiques indiquaient que le TNF-α augmentait l'expression de PTEN (phosphatase and tensin homolog) mais diminuait la PTEN phosphorylee. Fait interessant, le BDNF n'affectait pas l'expression de PTEN, mais augmentait sa phosphorylation. La phosphorylation 'd'Akt induite par le BDNF etait inhibee par le TNF-α. Le dosage TUNEL montrait que le bpv(PIC), un inhibiteur de PTEN, protegeait les HMVEC de l'apoptose induite par le TNF-α. En conclusion, le BDNF protege les HMVEC de la toxicite du TNF-α par la regulation de la voie PTEN/Akt. [Traduit par la Redaction] Mots-cles : facteur neurotrophique derive du cerveau, facteur necrosant des tumeurs-a, apoptose, cellules endotheliales vasculaires,therapie periodontique., Introduction Brain-derived neurotrophic factor (BDNF) plays a role in the survival and differentiation of central and peripheral neurons by binding to the tropomyosin receptor kinase B (TrkB) receptor [Barbacid 1994; [...]

The p75 neurotrophin receptor (p75NTR) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75NTR interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75NTR signaling are trimeric (i.e., TNFRassociated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75NTR is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75NTR activation in a growth cone retraction functional assay. However, monomersare capable of inducing acute morphological effects in neurons. We propose that p75NTR activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75NTR confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system. [ABSTRACT FROM AUTHOR]

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The p75 neurotrophin receptor (p75(NTR)) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75(NTR) interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75(NTR) signaling are trimeric (i.e., TNFR-associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75(NTR) is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75(NTR) activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75(NTR) activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75(NTR) confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system., Significance Statement: The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including apoptosis, neuronal processes remodeling, and synaptic plasticity. The goal of our work was to inquire whether oligomers of the receptor are required for function. Here we report that p75(NTR) predominantly assembles as a trimer, similar to other tumor necrosis factor receptors. Interestingly, monomers and trimers coexist at the cell surface, but trimers are not required for p75(NTR) activation in a functional assay. However, monomers are capable of inducing acute morphological effects in neurons. Identification of the oligomerization state of p75(NTR) begins to provide insights to the mechanisms of signal initiation of this noncatalytic receptor, as well as to develop therapeutic interventions to diminish its activity., (Copyright © 2015 the authors 0270-6474/15/3511911-10$15.00/0.)