Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist
1 Department of Neurochemistry and Neurotoxicology, Arrhenius Laboratories for Natural Sciences, Stockholm University, S-106 91 Stockholm; and 2 Division of Geriatric Medicine, Department of Clinical Neuroscience and Family Medicine, Novum, S-141 86 Huddinge, Sweden The interleukin-1 (IL-1) recept...
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Published in | American journal of physiology. Regulatory, integrative and comparative physiology Vol. 276; no. 3; pp. 644 - R651 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.03.1999
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Subjects | |
Online Access | Get full text |
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Summary: | 1 Department of Neurochemistry
and Neurotoxicology, Arrhenius Laboratories for Natural Sciences,
Stockholm University, S-106 91 Stockholm; and
2 Division of Geriatric Medicine,
Department of Clinical Neuroscience and Family Medicine, Novum, S-141
86 Huddinge, Sweden
The
interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous
antagonist that blocks the effects of the proinflammatory cytokines
IL-1 and IL-1 by occupying the type I IL-1 receptor. Here we
describe transgenic mice with astrocyte-directed overexpression of the
human secreted IL-1ra (hsIL-1ra) under the control of the murine glial
fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains
have been generated and characterized further: GILRA2 and GILRA4. These
strains show a brain-specific expression of the hsIL-1ra at the mRNA
and protein levels. The hsIL-1ra protein was approximated to ~50
ng/brain in cytosolic fractions of whole brain homogenates, with no
differences between male and female mice or between the two strains.
Furthermore, the protein is secreted, inasmuch as the concentration of
hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4)
times higher in the transgenic mice than in the control animals. To
characterize the transgenic phenotype, GILRA mice and nontransgenic
controls were injected with recombinant human IL-1 (central
injection) or lipopolysaccharide (LPS, peripheral injection). The
febrile response elicited by IL-1 (50 ng/mouse icv) was abolished in
hsIL-1ra-overexpressing animals, suggesting that the central IL-1
receptors were occupied by antagonist. The peripheral LPS injection (25 µg/kg ip) triggered a fever in overexpressing and control animals.
Moreover, no differences were found in LPS-induced (100 and 1,000 µg/kg ip; 1 and 6 h after injection) IL-1 and IL-6 serum levels
between GILRA and wild-type mice. On the basis of these results, we
suggest that binding of central IL-1 to central IL-1 receptors is not
important in LPS-induced fever or LPS-induced IL-1 and IL-6 plasma levels.
glial fibrillary acidic protein promoter; lipopolysaccharide; interleukin-1; cytokine |
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ISSN: | 0363-6119 0002-9513 1522-1490 |
DOI: | 10.1152/ajpregu.1999.276.3.R644 |