Molecular basis for defining the pineal gland and pinealocytes as targets for tumor necrosis factor

• Published in: Frontiers in endocrinology (Lausanne) Vol. 2; p. 10
• Main Authors: Carvalho-Sousa, Claudia Emanuele, da Silveira Cruz-Machado, Sanseray, Tamura, Eduardo Koji, Fernandes, Pedro A C M, Pinato, Luciana, Muxel, Sandra M, Cecon, Erika, Markus, Regina P
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 2011; Frontiers Media S.A
• Subjects: astroglya; Endocrinology; Immune-pineal axis; Melatonin; Microglia; Nitric Oxide; Pineal Gland; tumor necrosis factor; melatonin; immune-pineal axis; pineal gland; nuclear factor kappa B
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2011.00010

The pineal gland, the gland that translates darkness into an endocrine signal by releasing melatonin at night, is now considered a key player in the mounting of an innate immune response. Tumor necrosis factor (TNF), the first pro-inflammatory cytokine to be released by an inflammatory response, suppresses the translation of the key enzyme of melatonin synthesis (arylalkylamine-N-acetyltransferase, Aanat). Here, we show that TNF receptors of the subtype 1 (TNF-R1) are expressed by astrocytes, microglia, and pinealocytes. We also show that the TNF signaling reduces the level of inhibitory nuclear factor kappa B protein subtype A (NFKBIA), leading to the nuclear translocation of two NFKB dimers, p50/p50, and p50/RelA. The lack of a transactivating domain in the p50/p50 dimer suggests that this dimer is responsible for the repression of Aanat transcription. Meanwhile, p50/RelA promotes the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide, which inhibits adrenergically induced melatonin production. Together, these data provide a mechanistic basis for considering pinealocytes a target of TNF and reinforce the idea that the suppression of pineal melatonin is one of the mechanisms involved in mounting an innate immune response.