title: Regulation of interleukin-1beta by the interleukin-1 receptor antagonist in the glutamate-injured spinal cord: endogenous neuroprotection.
abstract: Elevation of extracellular glutamate contributes to cell death and functional impairments generated by spinal cord injury (SCI), in part through the activation of the neurotoxic cytokine interleukin-1beta (IL-1beta). This study examines the participation of IL-1beta and its regulation by the endogenous interleukin-1 receptor antagonist (IL-1ra) in glutamate toxicity following SCI. Glutamate, glutamatergic agonists and SCI had similar effects on levels of IL-1beta and IL-1ra. Following spinal cord contusion or exposure to elevated glutamate, concentrations of IL-1beta first increased as IL-1ra decreased, and both then changed in the opposite directions. Applying the glutamate agonists NMDA and S-AMPA to the spinal cord caused changes in IL-1beta and IL-1ra levels very similar to those produced by contusion and glutamate. The glutamate antagonists MK801 and NBQX blocked the glutamate-induced changes in IL-1beta and IL-1ra levels. Administering IL-1beta elevated IL-1ra, and administering IL-1ra depressed IL-1beta levels. Infusing IL-beta into the spinal cord impaired locomotion, and infusing IL-1ra improved recovery from glutamate-induced motor impairments. We hypothesize that elevating IL-1ra opposes the damage caused by IL-1beta in SCI by reducing IL-1beta levels as well as by blocking binding of IL-1beta to its receptor. Our results demonstrate that IL-1beta contributes to glutamate damage following SCI; blocking IL-1beta may usefully counteract glutamate toxicity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Xu
authors.forename: Kathia M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Clement
authors.initials: C
authors.lastname: Echetebu
authors.forename: Zaiming Sam
authors.initials: ZS
authors.lastname: Ye
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hulsebosch
authors.forename: David J
authors.initials: DJ
authors.lastname: McAdoo
mesh_terms: D000818:Animals; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy; D018698:Glutamic Acid / Q000633:toxicity; D053590:Interleukin 1 Receptor Antagonist Protein / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017472:Receptors, Interleukin-1; D018698:Glutamic Acid