Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level.
The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.
Sairanen
T R
TR
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, U.S.A.
Lindsberg
P J
PJ
Brenner
M
M
Sirén
A L
AL
D000818:Animals; D001923:Brain Chemistry; D002339:Carotid Arteries; D003250:Constriction; D015870:Gene Expression; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D016548:Prosencephalon / Q000098:blood supply*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000032:analysis / Q000235:genetics*
D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1