Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

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.