Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that are mainly used to treat pain, inflammation, and fever via cyclooxygenase-2 (COX-2) inhibition.
In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER<sup>T2</sup> under the <i>Slco1c1</i> promoter, PGE<sub>2</sub> levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE<sub>2</sub> synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever.
The febrile response is triggered by prostaglandin E2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1).
Finally, COX-2 transcription is also induced at febrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasing blood prostaglandin levels during fever.
As significant findings, compounds 1-3 demonstrated potent COX-2 inhibitory activities with high selectivities for COX-2 over COX-1 in human cells or whole-blood in vitro, and demonstrated orally potent anti-pyretic activity against lipopolysaccharide-induced systemic-inflammatory fever model in F344 rats.
Exposure to hyperthermia reduces IL-1beta-induced prostaglandin E2 release, suppresses activation of the adhesion molecules VCAM-1, ICAM-1, the cytokines TNFalpha, IL-1alpha, IL-1beta, IL-8 as well as COX-2 protein synthesis.
We conclude that in epithelial cells, IL-18 signal transduction is primarily via the MAPK p38 pathway rather than NF-kappaB, which may explain the absence of COX-2 and the failure of IL-18 to cause fever.