Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist

Abstract

The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous antagonist that blocks the effects of the proinflammatory cytokines IL-1α and IL-1β 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-1β (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response elicited by IL-1β (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-1β 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-1β and IL-6 plasma levels.

白介素1β 与学习和记忆

“…Besides, the IL-1rKO mice show impaired contextual fear conditioning, but normal auditory-cued fear conditioning 48 h after the conditioning trial [38] . Similar results are obtained in IL-1ra transgenic (IL-1raTG) mice, in which the human IL-1ra gene is overexpressed specifically within the CNS and the response to exogenous IL-1 administration is abolished [39] . These mice show descending learning ability in the spatial memory paradigm, but not in the non-spatial memory paradigm, and impaired contextual but normal auditory-cued fear conditioning [36] .…”

Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression

“…32 IL-1raTG mice have astrocyte-directed overexpression of the human IL-1ra gene under the control of the murine glial fibrillary acidic protein promoter, and are insensitive to the administration of exogenous IL-1, therefore, they over-express human IL-1ra only within the brain and spinal cord. [51][52][53] The physiological and behavioral phenotype of this strain is overall normal, besides a small, but significant, elevation in body weight and reduced bone density. 52 Similar to the IL-1rKO mice, IL-1raTG mice are insensitive to the administration of exogenous IL-1 51 and to some manipulations that induce brain IL-1, for example, closed-head injury.…”

“…[51][52][53] The physiological and behavioral phenotype of this strain is overall normal, besides a small, but significant, elevation in body weight and reduced bone density. 52 Similar to the IL-1rKO mice, IL-1raTG mice are insensitive to the administration of exogenous IL-1 51 and to some manipulations that induce brain IL-1, for example, closed-head injury. 54 Animals were housed in an air-conditioned room (22 þ 11C), with food and water ad libitum, except when specified otherwise.…”

Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

“…Newborn transgenic mice overexpressing secreted human IL-1ra in astrocytes within the brain and spinal cord , as well as their WT C57BL/6XCBA controls (a strain derived from the nontransgenic littermates of the transgenic offspring) (Lundkvist et al, 1999;Wolf et al, 2003;Bajayo et al, 2005) were used as a source for NPCs. The subjects in the experiments were 9-to 10-week-old WT C57BL/6 X CBA mice.…”

“…In the present study we developed a novel approach for long-term chronic blockade of brain IL-1 for at least 4 weeks, using intrahippocampal transplantation of neural precursor cells (NPCs), which have the capacity to proliferate and differentiate into all major cell types of the central nervous system (Alvarez-Buylla et al, 2001). NPCs were obtained from mice with transgenic overexpression of human IL-1ra under the glial fibrillary acidic protein (GFAP) promoter (Lundkvist et al, 1999). We assessed the ability of transplantation of these NPCs, compared to transplantation of either NPCs from WT mice or vehicle only, to rescue the effects of chronic isolation on memory functioning and hippocampal neurogenesis.…”