For many years, scientists have debated where fever originates. Though they understood prostaglandins are the messenger signals which begin the cascade of bodily changes resulting in fever, they could not figure out where this signal is created.

Some scientists theorized prostaglandins circulate in blood, while others argued immune cells create prostaglandins. However, a new study from researchers at Linköping University in Sweden proves prostaglandins are formed in the blood-brain barrier. “Knowledge of this type can be useful when developing drugs that ease certain symptoms, but not all of them," said Dr. David Engblom, senior lecturer in neurobiology.

Fever is a reaction to inflammation, your body's natural response to the entry of a harmful pathogen. When you take an aspirin, this analgesic drug suppresses the production of prostaglandins in the body and all the symptoms of inflammation cease simultaneously — fever, pain, and loss of appetite all end at once. But you might not want to get rid of all your symptoms. "Perhaps you want to inhibit loss of appetite but retain fever,” Engblom said. “In the case of serious infections, fever can be a good thing."

To learn how to better modulate the body's inflammation response, Engblom returned to an investigation he had begun 11 years ago. At that time, he uncovered the mechanism behind the formation of prostaglandin E2 when he observed how these signaling molecules could not pass through the blood-brain barrier, which protectively prevents harmful materials in the blood from entering the brain. Engblom showed in his original study how prostaglandin E2 could be synthesized from COX-2 and mPGES-1, two enzymes in the blood vessels on the inside of the brain, before moving to the hypothalamus, another region in the brain where the body's thermostat is located. In other words, prostaglandin E2 did not have to pass through the blood-brain barrier to enter the brain because it was already there.

Taking this research one step further, Engblom and his co-authors recently ran tests on mice that lacked the enzymes COX-2 and mPGES-1 in their brains’ blood vessels. When the mice were infected with bacterial toxins, the fever did not appear even though all the other signs of inflammation occurred. "This shows that those prostaglandins which cause fever are formed in the blood-brain barrier — nowhere else,” Engblom said. He and his colleagues believe their latest discovery will pave the way for smarter, more precise drugs.

Source: Wilhelms DB, Kirilov M, Mirrasekhian E,  et al. Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever. Journal of Neuroscience. 2014.