Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain.
Traumatic brain injury (TBI) induces astrocytic and microglial activation and proliferation and augmented production of the cytokine interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF). The increase in NGF temporally follows the increase in IL-1 beta, suggesting that the IL-1 beta up-regulation after trauma directly induces the increase in NGF. We examined the effect of IL-1 receptor antagonist protein (IL-1ra) on microglial proliferation and NGF production in rat cortex, following two different models of TBI. Rabbit fibroblasts infected with a retroviral vector containing the human IL-1ra gene were implanted into the wound cavity immediately following a cortical stab wound or 6 hours after a weight drop-induced trauma. Both microglial proliferation and NGF up-regulation were decreased significantly in animals receiving IL-1ra-expressing cells compared with animals receiving naive (untransfected) fibroblasts. These data demonstrate that the increase in NGF after central nervous system trauma is directly mediated through IL-1 beta and that blocking IL-1 beta following brain injury leads to suppression of an NGF-mediated reparative response. Such blockade of inflammation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.
DeKosky
S T
ST
Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, PA, USA.
Styren
S D
SD
O'Malley
M E
ME
Goss
J R
JR
Kochanek
P
P
Marion
D
D
Evans
C H
CH
Robbins
P D
PD
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000637:transplantation; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012190:Retroviridae; D015854:Up-Regulation
D007375:Interleukin-1; D009414:Nerve Growth Factors; D017472:Receptors, Interleukin-1