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Volume 17, Number 9, Issue of May 1, 1997 pp. 3262-3273
Copyright ©1997 Society for Neuroscience

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

Received Jan. 8, 1997; revised Feb. 6, 1997; accepted Feb. 10, 1997.

Andrew V. Turnbull¹, Fernando J. Pitossi², Jean-Jacques Lebrun¹, Soon Lee¹, Jon C. Meltzer³, Dwight M. Nance³, Adriana del Rey², Hugo O. Besedovsky², and Catherine Rivier¹

¹ The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, ² Institute for Normal and Pathological Physiology-Immunophysiology, Philipps-Universitat Marburg, 35037 Marburg, Germany, and ³ Department of Pathology, University of Manitoba, Winnipeg, Manitoba, R3E 0W3, Canada.

The present study tested the hypothesis that the cytokine tumor necrosis factor- (TNF-) is an important CNS mediator of the hypothalamo-pituitary-adrenal (HPA) axis response to local inflammation in the rat. Recombinant murine TNF- administered directly into the cerebroventricles of normal rats produced a dose-dependent increase in plasma adrenocorticotropin (ACTH) concentration. Local inflammation induced by the intramuscular injection of turpentine (50 µl/100 gm body weight) also produced an increase in plasma ACTH, peaking at 160-200 pg/ml at 7.5 hr after injection (compared with 10-30 pg/ml in controls). Intracerebroventricular pretreatment with either 5 µl of anti-TNF- antiserum or 1-50 µg of soluble TNF receptor construct (rhTNFR:Fc) reduced the peak of the ACTH response to local inflammation by 62-72%. In contrast, intravenous treatment with the same doses of anti-TNF- or rhTNFR:Fc had no significant effect on the ACTH response to local inflammation. Although these data indicated an action of TNF- specifically within the brain, no increase in brain TNF- protein (measured by bioassay) or mRNA (assessed using either in situ hybridization histochemical or semi-quantitative RT-PCR procedures) was demonstrable during the onset or peak of HPA activation produced by local inflammation. Furthermore, increased passage of TNF- from blood to brain seems unlikely, because inflammation did not affect plasma TNF- biological activity. Collectively these data demonstrate that TNF- action within the brain is critical to the elaboration of the HPA axis response to local inflammation in the rat, but they indicate that increases in cerebral TNF- synthesis are not a necessary accompaniment.

Key words: tumor necrosis factor-; corticotropin-releasing factor; local inflammation; adrenocorticotropin; CNS; intraventricular

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