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Articles in PresS, published online ahead of print February 8, 2002
J Appl Physiol, 10.1152/jap.00822.2001
Submitted on August 6, 2001
Accepted on February 6, 2002
1 Veterinary-Physiology, Justus-Liebig-University Giessen, Giessen, Germany
* To whom correspondence should be addressed. E-mail: Thomas.Huebschle{at}vetmed.uni-giessen.de.
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 which 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 (100µg/kg) led to a slight (1h) and then a strong increase (2-8h) in plasma IL-6 levels, that started to decline at the end of the febrile response. Administration of both pyrogens LPS and IL-6 (45µg/kg) induced a febrile response with IL-6 causing a rather moderate fever as compared to 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) 2h 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 1h after IL-6 application and proved to be less effective as compared to 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 which are created by the activated immune system and result in the generation of fever.
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