REGIONAL INDUCTION OF TUMOR-NECROSIS-FACTOR ALPHA EXPRESSION IN THE MOUSE-BRAIN AFTER SYSTEMIC LIPOPOLYSACCHARIDE ADMINISTRATION

Tumor necrosis factor alpha (TNF-alpha) is a cytokine that is responsi ble, in part, for several aspects of the acute-phase response to infla mmation, including the generation of fever. TNF-alpha has direct effec ts on central nervous system neurons deep within the hypothalamus that are involved in producing the febrile response, but the blood-brain b arrier prevents circulating TNF-alpha from having access to these site s. We therefore have hypothesized that TNF-alpha may be produced in th e brain and used as a mediator in the cerebral components of the acute -phase response. We used in situ hybridization to determine the distri bution of production of TNF-alpha mRNA in the mouse brain after system ic administration of lipopolysaccharide. During the initial phase of f ever, hybridization was observed in perivascular cells and neurons in circumventricular organs, including the vascular organ of the lamina t erminalis, median eminence, and area postrema, as well as along the ve ntral surface of the medulla; hybridization was also prominent over ma ny cell in the meninges. During the late phase of the response, hybrid ization was observed over neurons in the pericircumventricular nuclei such as the anteroventral periventricular and arcuate nuclei of the hy pothalamus and the nucleus of the solitary tract. TNF-alpha produced b y a cascade of neurons within the brain may participate in the complex autonomic, neuroendocrine, metabolic, and behavioral responses to inf ection and inflammation.