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

The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous anta gonist that blocks the effects of the proinflammatory cytokines IL-1 alpha and IL-1 beta by occupying the type I IL-1 receptor. Here we describe trans genic mice with astrocyte-direeted overexpression of the human secreted IL- 1ra (hsIL-1ra) under the control of the murine glial fibrillary acidic prot ein (GFAP) promoter. Two GFAP-hsIL-1ra strains have been generated and char acterized further: GILRA2 and GILRA4. These strains show a brain-specific e xpression of the hsIL-1ra at the mRNA and protein levels. The hsIL-1ra prot ein was approximated to similar to 50 ng/brain in cytosolic fractions of wh ole 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 animal s. To characterize the transgenic phenotype, GILRA mice and nontransgenic c ontrols were injected with recombinant human IL-1 beta (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response eli cited by IL-1 beta (50 ng/mouse icv) was abolished in hsIL-1ra-overexpressi ng animals, suggesting that the central IL-1 receptors were occupied by ant agonist. The peripheral LPS injection (25 mu g/kg ip) triggered a fever in overexpressing and control animals. Moreover, no differences were found in LPS-induced (100 and 1,000 mu g/kg ip; 1 and 6 h after injection) IL-1 beta and IL-6 serum levels between GILRA and wild-type mice. On the basis of th ese results, we suggest that binding of central IL-1 to central IL-1 recept ors is not important in LPS-induced fever or LPS-induced IL-1 beta and IL-6 plasma levels.