The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-lP, induce an intense fever in the rat when they are injected 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,) of MIP-1P with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T, continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 pl of pyrogen-free artificial CSF, recombinant murine MIP-lP, or recombinant human IL-6. MIP-1P in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in T, of 2.4 2 0.21"C reached by 3.7 2 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, JL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T, of 1.2 2 0.25"C, 1.8 2 0.15"C, and 2.1 2 0.22"C and duration of 6.2 2 1.28 hr, 6.7 2 0.49 hr, and 6.8 2 0.65 hr when given in doses of 25, 50, and 100 ng, respectively. These results show that MIP-1P and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-lP exerts its action in a much lower concentration. Thus, the de novo synthesis and subsequent action of the MIP-1 family of cytokines on neurons of the AH/POA in response to a pyrogen challenge apparently play a functional role in the pathogenesis of fever. Further, the endogenous activity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute phase response to a bacterial challenge.