Fever and feeding: Differential actions of macrophage inflammatory protein-1 (MIP-1), MIP-1? and MIP-1? on rat hypothalamus

Abstract

Changes in body temperature (T_b) and feeding were characterized in unrestrained rats following the micro-injection into the anterior hypothalamic preoptic area (AH/POA) of macrophage inflammatory protein-1 (MIP-1), MIP-1α or MIP-1β. After the rats recovered from the stereotaxic implantation of a single guide tube placed in the AH/POA, either one of the MIP-1 compounds or control CSF was micro-injected in a volume of 1.0 μl into this area. Changes in body temperature (T_b) and food and water intakes were monitored throughout each experiment. When micro-injected into the AH/POA in a dose of 28 or 280 pg, doublet MIP-1 and MIP-1β evoked a monophasic fever which increased above baseline to a mean maximum of 2.17±0.14°C and 2.1±0.24°C, respectively. MIP-1α micro-injected similarly evoked a biphasic fever, with the T_b declining transiently at the 30 min point ≥0.4°C lower than the congruent rises in T_b evoked by doublet MIP-1 or MIP-1β. The secondary rise in T_b induced by MIP-1α had a latency of 1.5–2.0 hrs and reached a maximum of 1.56±0.16°C. Although all three cytokines significantly attentuated the rats' mean intake of food during the 24 hr interval after their micro-injection into the AH/POA, doublet MIP-1 exerted the most potent anorexic effect in comparison to that of the saline control rats. However, neither body weight nor intake of water was altered significantly by the three cytokines. These results demonstrate a functional distinction between the febrile actions of MIP-1α and MIP-1β on cells of the AH/POA. It is envisaged that MIP-1β underlies the initial phase of a pyrogen-induced fever, whereas MIP-1α could mediate the secondary phase of a biphasic fever. Clearly, the localized elevation of either MIP-1α or MIP-1β in the AH/POA perturbs the neuronal mechanism underlying the “set-point” for body temperature. Thus, both MIP-1α and MIP-1β could play a functional role in the pathological events occurring in neurons of the AH/POA in response to an endotoxin or other pyrogen challenge.