INTERLEUKIN-1 RECEPTOR ANTAGONIST SUPPRESSES NEUROTROPHIN RESPONSE ININJURED RAT-BRAIN

Traumatic brain injury (TBI) induces astrocytic and microglial activat ion and proliferation and augmented production of the cytokine interle ukin-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-1 ra) on microglial proliferation and NGF production in rat cortex, foll owing 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 hou rs after a weight drop-induced trauma. Both microglial proliferation a nd NGF up-regulation were decreased significantly in animals receiving IL-1ra-expressing cells compared with animals receiving naive (untran sfected) 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 suppr ession of an NGF-mediated reparative response. Such blockade of inflam mation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.