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.
Pan
Weihong
W
Department of Medicine, Tulane University Health Science Center and the VA Medical Center, New Orleans, Louisiana 70112-1262, USA. wpan@tulane.edu
Csernus
Balazs
B
Kastin
Abba J
AJ
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