Upregulation of p55 and p75 receptors mediating TNF-alpha transport across the injured blood-spinal cord barrier.
Tumor necrosis factor (TNF-alpha) is involved in the inflammation and tissue regeneration occurring after spinal cord injury (SCI). This study tests the specific role of p55 and p75 receptors in mediating the transport of TNF-alpha across the blood-spinal cord barrier (BSCB) after SCI by compression. Transcytosis of 125I-TNF-alpha across a monolayer of the cerebral endothelial cells that compose the blood-brain barrier was significantly reduced in the absence of functional p55 and p75 receptors. At 3 d after SCI, double receptor knockout mice had a significantly reduced increase in TNF-alpha uptake from blood to injured lumbar spinal cord as compared with their inbred controls, despite the similar extent of BSCB disruption (measured by 99mTc-albumin). The p75 single receptor knockout mice had a reduced increase in 125I-TNF-alpha uptake, whereas the p55 receptor knockout mice had no significant increase of 125I-TNF-alpha uptake after SCI, suggesting that the p55 receptor plays a major role. Hence, the increased uptake of TNF-alpha 3 d after SCI is not explained by nonspecific barrier disruption but by receptor-mediated upregulation of transport. Quantitative RT-PCR analysis further showed that upregulation of TNF-alpha transport was related to increased expression of mRNA for p55 and p75 receptors. The increase of p55 receptor expression was more robust and seen between 12 h and 1 wk after SCI, whereas the increase of p75 receptor expression occurred later and involved fewer regions. Thus, the differential upregulation of p55 and p75 receptors indicates that permeation of TNF-alpha across the injured BSCB remains a regulated process. Knowledge of receptor-mediated regulation could facilitate effective therapeutic manipulation of BSCB permeation of vascular cytokines important to CNS regeneration.
Department of Medicine, Tulane University Health Science Center and the VA Medical Center, New Orleans, Louisiana 70112-1262, USA. wpan@tulane.edu
Weihong
W
Pan
Balazs
B
Csernus
Abba J
AJ
Kastin
D000818:Animals; D021461:Animals, Outbred Strains; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D007457:Iodine Radioisotopes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009187:Myelitis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D015703:Antigens, CD; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha