Distribution and characterization of tumor necrosis factor‐α‐like immunoreactivity in the murine central nervous system

Abstract

Tumor necrosis factor-alpha (TNF alpha) is a protein released from macrophages during infection and inflammation. Recent studies suggest that it has several effects within the central nervous system, including generation of fever, enhancement of slow wave sleep, and stimulation of pituitary hormone secretion. We have proposed that TNF alpha may be synthesized by neurons in the CNS and used as a neuromodulator in the pathways involved in the central control of these activities. To test this hypothesis, we have used an antiserum raised against recombinant murine (rm) TNF alpha with an indirect immunoperoxidase technique to stain the murine CNS immunohistochemically. Western blot analysis of mouse brain homogenates revealed one band with electrophoretic mobility identical to that of rmTNF alpha. We identified TNF alpha-like immunoreactive (ir) neurons in the hypothalamus, in the bed nucleus of the stria terminalis, in the caudal raphe nuclei, and along the ventral pontine and medullary surface. TNF alpha ir innervation was widespread within the CNS, particularly in areas involved in autonomic and endocrine regulation, including the hypothalamus, amygdala, bed nucleus of the stria terminalis, parabrachial nucleus, dorsal vagal complex, nucleus ambiguus, and thoracic sympathetic preganglionic cell column. Our data suggest that TNF alpha may serve as a neuromodulator in central pathways involved in the regulation of the autonomic, endocrine and behavioral components of the acute-phase response to inflammation and infection.

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

“…Although absolute levels of TNF-␣ protein or mRNA were not altered measurably, elevated release of preexisting TNF-␣ from either neurons or more likely from astrocytes or glial cells might be sufficient to account for the activation of the HPA axis that is apparent during acute local inflammation. Indeed, immunocytochemical evidence indicates that TNF-␣ protein is distributed discretely in the mouse CNS, particularly in areas involved in autonomic and endocrine regulation, including the hypothalamus, amygdala, and bed nucleus of the stria terminalis (Breder et al, 1993). Whether a similar distribution is apparent in the rat CNS is not known, although clearly the levels of TNF-␣ protein are below the detection limits of the methodology used in the present work (L929 bioassay of brain homogenates).…”

Cytokine production in the nervous system of mice during acute and latent infection with herpes simplex virus type 1.

“…It is therefore noteworthy that many neurons in the normal ganglion constitutively express TNF receptors (Cunningham et al, 1997). A homeostatic function has been suggested for TNF-α from glial cells in the CNS (Breder et al, 1993) and IL-1 from Schwann cells in the PNS (Bergsteinsdottir et al, 1991).…”

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

“…48 Although TNF and IL-1 interact with receptors that are structurally unrelated, both cytokines share a significant overlap in functional and postreceptor intracellular cascades. The potent neurotoxic effects of IL-1 have been shown to be synergistically enhanced in the presence of TNF, suggesting that these crucial cytokines mediate post-traumatic inflammation and secondary brain damage.…”