Action of cyclosporine on fever induced in rats by intrahypothalamic injection of macrophage inflammatory protein-1 (MIP-1)

Abstract

In order to examine the central mechanism of pyrexic action of macrophage inflammatory protein-1 (MIP-1), guide cannulae for injections were implanted stereotaxically just above the anterior hypothalamic, pre-optic area of the rat. Following post-operative recovery, the body temperature ( t b) of each rat was monitored by a colonic thermistor probe over a test interval of 4hr. Injected in a 0.5 μ1 volume into the anterior hypothalamic pre-optic area, MIP-1, in a dose of 5.6 or 28 pg, evoked an intense fever with a latency of 15–30 min. Pretreatment of the anterior hypothalamic pre-optic area with 1.0 μg cyclosporine A (CsA), delivered in a volume of 0.5 μ1, delayed the onset of the fever induced by 5.6 pg MIP-1, injected at the same site. Similar injections of CsA also attenuated significantly the magnitude of the fever, following either the 5.6 or 28 pg dose of MIP-1. As a systemic control, 15 mg/kg CsA was administered intraperitoneally, 2.0 hr before the injection of MIP-1 in the anterior hypothalamic pre-optic area. By this route, CsA also delayed the rise in temperature but the fever induced by 5.6 pg MIP-1 reached the same magnitude as that after MIP-1 alone. Conversely, intraperitoneal administration of CsA did not antagonize the pyrexic response evoked by 28 pg MIP-1, injected into the anterior hypothalamic pre-optic area, but rather enhanced the fever. These results demonstrate that CsA was effective in suppressing the fever induced by MIP-1 when it was applied directly to the thermosensitive-pyrogen-reactive neurons of the anterior hypothalamic pre-optic area, prior to the cytokine. However, the nature of the systemic action of the immunosuppressant agent was dependent on the concentration of the cytokine present in the anterior hypothalamic pre-optic area and, by this route, did not inhibit the fever of MIP-1. In terms of the mechanism of action of MIP-1, these findings with CsA suggest that the febrile response to the cytokine depends in part on the activity in the diencephalon of an interleukin, thought to underlie the acute phase of the response of fever. It is envisaged that the initial thermogenic action on neurons of the anterior hypothalamic pre-optic area of MIP-1, in a trace amount, is brought about by the local synthesis or release of another cytokine, which appears to be an obligatory mediator for the fever evoked by MIP-1.