Immune-to-Brain Signaling in Fever : The Brain Endothelium as Interface

Fever is a brain-regulated elevation of body temperature that occurs in response to infectious and non-infectious stimuli. During inflammatory episodes, circulating cytokines that are released by activated immune cells, trigger the induction of cyclooxygenase (COX)-2 in the ventromedial preoptic area of the hypothalamus (the thermoregulation center). COX-2-dependent-prostaglandin (PG)E2 synthesis is essential for the generation of fever and upon an immune challenge, it is induced in several cells within the brain including the brain endothelial cells and perivascular macrophages. However, due to lack of experimental models with cell type-specific modulation of PGE2 synthesizing enzymes, the cellular source of pyrogenic PGE2 and its induction mechanism(s) remained obscure. Using such technology, we showed that the brain endothelium is the cellular source of pyrogenic PGE2 and that activation of brain endothelial IL-6 receptors by circulating IL-6 is critical for the PGE2 induction. Inhibition of PGE2 synthesis is assumed to be the mode of action of many antipyretic drugs, possibly including paracetamol. Given that paracetamol at a high dose has been shown to induce hypothermia by activation of the transient receptor potential ankyrin 1 (TRPA1) ion channel, we examined whether the antipyretic effect of paracetamol is also TRPA1 dependent. Our findings revealed that the antipyretic effect of paracetamol is independent of TRPA1 and associated with inhibition of the PGE2 synthesis in the brain. This thesis provides new insight into the molecular mechanism behind the febrile response in which the peripheral circulating IL-6 communicates with the brain by induction of pyrogenic PGE2 in the brain endothelium. It also demonstrates that the antipyretic effect of paracetamol is exerted by inhibition of the PGE2 synthesis in the brain.Minor corrections are made in the electronic version of the thesis (Page 10).