FEVER AND FEEDING IN THE RAT - ACTIONS OF INTRAHYPOTHALAMIC INTERLEUKIN-6 COMPARED TO MACROPHAGE INFLAMMATORY PROTEIN-1-BETA (MIP-1-BETA)

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subu nit MIP-1 beta, induce an intense fever in the rat when they are injec ted directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (T-b) of MIP-1 beta with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Follo wing the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T-b contin uously were inserted intraperitoneally in each of 15 male Sprague-Dawl ey rats. Each micro-injection was made in a site in the AH/POA in a vo lume of 1.0 mu l of pyrogen-free artificial CSF, recombinant murine MI P-1 beta, or recombinant human IL-6. MIP-1 beta in a dose of 25 pg evo ked an intense fever characterized by a short latency, a mean maximum rise in T-b of 2.4 +/- 0.21 degrees C reached by 3.7 +/- 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/ POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T-b of 1.2 +/- 0.25 degrees C, 1.8 +/- 0.15 degre es C, and 2.1 +/- 0.22 degrees C and duration of 6.2 +/- 1.28 hr, 6.7 +/- 0.49 hr, and 6.8 +/- 0.65 hr when given in doses of 25, 50, and 10 0 ng, respectively. These results show that MIP-1 beta and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-1 beta e xerts its action in a much lower concentration. Thus, the de novo synt hesis and subsequent action of the MIP-1 family of cytokines on neuron s of the AH/POA in response to a pyrogen challenge apparently play a f unctional role in the pathogenesis of fever. Further, the endogenous a ctivity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute p hase response to a bacterial challenge. (C) 1994 Wiley-Liss, Inc.