INHIBITION OF TUMOR-NECROSIS-FACTOR-ALPHA ACTION WITHIN THE CNS MARKEDLY REDUCES THE PLASMA ADRENOCORTICOTROPIN RESPONSE TO PERIPHERAL LOCAL INFLAMMATION IN RATS

The present study tested the hypothesis that the cytokine tumor necros is factor-alpha (TNF-alpha) is an important CNS mediator of the hypoth alamo-pituitary-adrenal (HPA) axis response to local inflammation in t he rat. Recombinant murine TNF-alpha administered directly into the ce rebroventricles of normal rats produced a dose-dependent increase in p lasma adrenocorticotropin (ACTH) concentration. Local inflammation ind uced by the intramuscular injection of turpentine (50 mu l/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 mu l of anti-TNF -alpha antiserum or 1-50 mu g of soluble TNF receptor construct (rhTNF R:Fc) reduced the peak of the ACTH response to local inflammation by 6 2-72%. In contrast, intravenous treatment with the same doses of anti- TNF-alpha or rhTNFR:Fc had no significant effect on the ACTH response to local inflammation. Although these data indicated an action of TNF- alpha specifically within the brain, no increase in brain TNF-alpha pr otein (measured by bioassay) or mRNA (assessed using either in situ hy bridization histochemical or semi-quantitative RT-PCR procedures) was demonstrable during the onset or peak of HPA activation produced by lo cal inflammation. Furthermore, increased passage of TNF-alpha from blo od to brain seems unlikely, because inflammation did not affect plasma TNF-alpha biological activity. Collectively these data demonstrate th at TNF-alpha action within the brain is critical to the elaboration of the HPA axis response to local inflammation in the rat, but they indi cate that increases in cerebral TNF-alpha synthesis are not a necessar y accompaniment.