Interleukin-6 (IL-6) is regarded as an endogenous mediator of lipopolysaccharide (LPS)-induced fever. IL-6 is thought to act on the brain at sites that lack a blood-brain barrier, the circumventricular organs (CVOs). Cells that are activated by IL-6 respond with nuclear translocation of the signal transducer and activator of transcription 3 molecule (STAT3) and can be detected by immunohistochemistry. We investigated whether the LPS-induced release of IL-6 into the systemic circulation was accompanied by a nuclear STAT3 translocation within the sensory CVOs. Treatment with LPS (100 microg/kg) led to a slight (1 h) and then a strong increase (2-8 h) in plasma IL-6 levels, which started to decline at the end of the febrile response. Administration of both pyrogens LPS and IL-6 (45 microg/kg) induced a febrile response with IL-6, causing a rather moderate fever compared with the LPS-induced fever. Nuclear STAT3 translocation in response to LPS was observed within the vascular organ of the lamina terminalis (OVLT) and the subfornical organ (SFO) 2 h after LPS treatment. To investigate whether this effect was mediated by IL-6, the cytokine itself was systemically applied and indeed an identical pattern of nuclear STAT3 translocation was observed. However, nuclear STAT3 translocation already occurred 1 h after IL-6 application and proved to be less effective compared with LPS treatment when analyzing OVLT and SFO cell numbers that showed nuclear STAT3 immunoreactivity after the respective pyrogen treatment. Our observations represent the first molecular evidence for an IL-6-induced STAT3-mediated genomic activation of OVLT and SFO cells and support the proposed role of these brain areas as sensory structures for humoral signals created by the activated immune system and resulting in the generation of fever.