TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway

Abstract

Nuclear factor-kappa B (NFKB), a pivotal player in inflammatory responses, is constitutively expressed in the pineal gland. Corticosterone inhibits pineal NFKB leading to an enhancement of melatonin production, while tumor necrosis factor (TNF) leads to inhibition of Aa-nat transcription and the production of N-acetylserotonin in cultured glands. The reduction in nocturnal melatonin surge favors the mounting of the inflammatory response. Despite these data, there is no clear evidence of the ability of the pineal gland to recognize molecules that signal infection. This study investigated whether the rat pineal gland expresses receptors for lipopolysaccharide (LPS), the endotoxin from the membranes of Gram-negative bacteria, and to establish the mechanism of action of LPS. Here, we show that pineal glands possess both CD14 and toll-like receptor 4 (TLR4), membrane proteins that bind LPS and trigger the NFKB pathway. LPS induced the nuclear translocation of p50/p50 and p50/RELA dimers and the synthesis of TNF. The maximal expression of TNF in cultured glands coincides with an increase in the expression of TNF receptor 1 (TNFR1) in isolated pinealocytes. In addition, LPS inhibited the synthesis of N-acetylserotonin and melatonin. Therefore, the pineal gland transduces Gram-negative endotoxin stimulation by producing TNF and inhibiting melatonin synthesis. Here, we provide evidence to reinforce the idea of an immune-pineal axis, showing that the pineal gland is a constitutive player in the innate immune response.

Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

“…All procedures were approved by the Catalan Ethical Committee for Animal Use (CEAA/DMAH 4049 and 5664). Pinealocytes were prepared from rat pineal glands as described previously by da Silveira Cruz-Machado et al (51). Briefly, pinealocytes were obtained by trypsinization (0.25%, 37°C, 15 min) followed by mechanical dispersion in the presence of fetal bovine serum.…”

Prognostic Value of Genetic Markers for Efficacy Estimation of Induction Treatment Including Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients

“…mCD14 является рецептором распознавания молекулярных образцов, который играет цен-тральную роль в реализации врожденного иммуни-тета и последующей активации приобретенного им-мунитета [78]. Рецепторный комплекс, включающий в себя CD14 и TLR4, связываясь с бактериальным липополисахаридом [79][80][81], способен тем самым ак-тивировать NF-κB путь передачи сигнала через белок миелоидной дифференцировки первичного ответа 88 (MyD88). NF-κB регулирует транскрипцию многих генов, важных для реализации иммунного ответа, и участвует в развитии многих заболеваний у человека [82].…”

The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy

“…This transient change in the source of melatonin has important functional implications during the time course of an inflammatory response. Accordingly, pathogen- or danger-associated molecular patterns, such as lipopolysaccharides, zymosan or the proinflammatory cytokine tumor necrosis factor (TNF), interact with their respective receptors in the membrane of glial cells or pinealocytes, resulting in the inhibition of melatonin synthesis [3,4,5]. Because melatonin in the nanomolar range impairs the migration of leukocytes to the lesion site [6], this initial suppression of the nocturnal melatonin synthesis by the pineal gland improves the efficiency of the transmigration.…”