EXPRESSION OF TNF AND TNF RECEPTORS (P55 AND P75) IN THE RAT-BRAIN AFTER FOCAL CEREBRAL-ISCHEMIA

Cerebral ischemia induces a rapid and dramatic up-regulation of tumor necrosis factor (TNF) protein and mRNA. but the cellular sources of TN F in the ischemic brain have not been defined. The diverse activities of TNF are mediated via ligand interaction with two distinct receptors , p55 and p75, which activate separate intracellular signal transducti on pathways, leading to distinct biological effects. Since the effects of cerebral ischemia on TNF receptor (TNFR) expression are unknown, w e examined the cellular localization and protein expression of TNF and its two receptors in the rat cerebral cortex in response to permanent middle cerebral artery (MCA) occlusion. The results indicate that foc al cerebral ischemia up-regulates expression of TNF and both TNFRs wit hin the ischemic cortex. The most abundant type ofTNF immunoreactivity (IR) was a punctate and filamentous pattern of transected cellular pr ocesses; however, cell bodies of neurons, astrocytes, and microglia, a s well as infiltrating polymorphonuclear (PMN) leukocytes also showed TNF IR. Brain vasculature displayed TNF IR not only within endothelial cells but also in the perivascular space. MCA occlusion induced signi ficant up-regulation of TNF receptors, with p55 IR appearing within 6 hr, significantly before the appearance of p75 IR at 24 hr after the o nset of ischemia. Since p55 has been implicated in transducing cytotox ic signalling of TNF, these results support the proposed injurious rol e of excessive TNF produced during the acute response to cerebral isch emia.