Attenuation of hypoxia-ischemia-induced monocyte chemoattractant protein-1expression in brain of neonatal mice deficient in interleukin-1 convertingenzyme
Ry. Xu et al., Attenuation of hypoxia-ischemia-induced monocyte chemoattractant protein-1expression in brain of neonatal mice deficient in interleukin-1 convertingenzyme, MOL BRAIN R, 90(1), 2001, pp. 57-67
Interleukin-1 beta (IL-1 beta) upregulates expression of the chemokine mono
cyte chemoattractant protein-1 (MCP-1) in many experimental models. In neon
atal rodent brain, hypoxia-ischemia rapidly stimulates expression of this c
hemokine, although the role of IL-1 beta in regulating this response is unk
nown, Interleukin-1 converting enzyme (ICE) is a cysteine protease that cle
aves inactive pro-IL-1 beta to generate mature IL-1 beta. Neonatal mice wit
h a homozygous deletion of ICE (ICE -/-) are resistant to moderate, but not
to severe cerebral hypoxic-ischemic insults, relative to their wild-type c
ontrols. We hypothesized that their resistance to moderate hypoxic-ischemic
insults is mediated by suppression of the acute inflammatory response to b
rain injury in the absence of IL-1 beta, and that hypoxia-ischemia induced
MCP-1 expression would be attenuated in ICE -/- animals. To test this hypot
hesis, paired litters of 9-10-day-old ICE -/- and wild-type mice underwent
right carotid ligation, followed by 40, 70 or 120 min exposure to 10% O-2 a
nd ischemia-induced changes in MCP-1 mRNA and protein were compared, using
a semi-quantitative reverse-transcription polymerase chain reaction assay a
nd an ELISA, respectively. With a lesioning protocol that elicits minimal i
njury in wild-types (ligation + 40 min 10% O-2), there was an attenuation o
f hypoxia-ischemia-induced MCP-1 production at 8 h post-hypoxia; in contras
t, in animals that underwent longer periods of hypoxia-ischemia the magnitu
de of injury-induced induced MCP-1 production did not differ between wild-t
ype and ICE -/- animals. These results demonstrate both that the acute infl
ammatory response to hypoxia-ischemia is attenuated in ICE -/- animals, and
also that hypoxic-ischemic brain injury stimulates MCP-1 expression even i
n the absence of IL-1 beta activity. (C) 2001 Elsevier Science B.V. All rig
hts reserved.