title: Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor.
abstract: The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (-50%; p < 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1beta exacerbates damage (+45%; p < 0.05). Mice lacking IL-1RI [IL-1RI knock-out (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 +/- 6.1 and 46.2 +/- 6.2 mm3, respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1beta (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (+61%; p < 0.001) and in WT mice (+45%). This effect of IL-1beta was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1beta on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (+20%) animals. These data show that IL-1beta can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.
authors.affiliation: School of Biological Sciences, University of Manchester, M13 9PT, United Kingdom.
authors.forename: Omar
authors.initials: O
authors.lastname: Touzani
authors.forename: Herve
authors.initials: H
authors.lastname: Boutin
authors.forename: Rosalind
authors.initials: R
authors.lastname: LeFeuvre
authors.forename: Lisa
authors.initials: L
authors.lastname: Parker
authors.forename: Andy
authors.initials: A
authors.lastname: Miller
authors.forename: Giamal
authors.initials: G
authors.lastname: Luheshi
authors.forename: Nancy
authors.initials: N
authors.lastname: Rothwell
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D004435:Eating / Q000187:drug effects; D007276:Injections, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D053577:Interleukin-1 Receptor Accessory Protein; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D012795:Sialoglycoproteins / Q000008:administration & dosage
chemical_list: C507767:Il1rap protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D011506:Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D012795:Sialoglycoproteins