Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.
Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP-treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.
Yatsiv
Ido
I
Pediatric Intensive Care Unit and Department of Pharmacology, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
Morganti-Kossmann
Maria C
MC
Perez
Daniel
D
Dinarello
Charles A
CA
Novick
Daniela
D
Rubinstein
Menachem
M
Otto
Viviane I
VI
Rancan
Mario
M
Kossmann
Thomas
T
Redaelli
Claudio A
CA
Trentz
Otmar
O
Shohami
Esther
E
Stahel
Philip F
PF
D000328:Adult; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D016489:Head Injuries, Closed / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C118370:interleukin-18 binding protein