A recent study by Daniel Björk Wilhelms and colleagues from the Linköping University in Sweden identifies the exact source and location where prostaglandins (the mediators that trigger fever) are produced in the brain during inflammation-induced fever.
The prostaglandin E2 (PgE2) was first proposed some 3-4 decades ago as the key factor for fever generation. In fact, the inhibition of prostaglandin synthesis represents the major mechanism of action for common antipyretic drugs, such as aspirin.
Previous research has mapped the anterior preoptic hypothalamus as the brain’s target region for fever-inducing PgE2. It is known that PgE2 in this area initiates a complex neuro-endocrine response during fever, and that the hypothalamus regulates body’s temperature through both heat production and heat loss’ control.
The precise source of PgE2 during fever induction, and, specifically, which cells are the critical interface in transmitting the pyrogenic signal from the periphery to the brain still remain subjects of debate.
Prostaglandins circulating in the blood are thought to be the major source, but it remains controversial whether PgE2 can actually pass from the blood into the brain. The other option is that PgE2 is produced from immune cells in the brain or it is generated by other cells inside rather than outside the blood-brain barrier (BBB).
The brain endothelium is a strong candidate for being the critical site of prostaglandin production, as immune challenge induces the production in these cells of both cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) – the enzymes responsible for the generation of PgE2.
The Swedish team has used mice with targeted deletions of COX-2 and mPGES-1 in brain endothelial cells to show that these mice were not able to respond with fever upon immune challenge in the periphery. According to the researchers this indicates that prostaglandins are formed in the blood-brain barrier and demonstrates the crucial role of brain endothelial PgE2 production in the generation of fever.