Febrile response can be initiated by the presence of foreign pathogens, known as “exogenous pyrogens”. Exogenous pyrogens can be produced by a variety of types of pathogens including viruses, yeast, and both Gram-positive and Gram-negative bacteria—one of the most commonly experimentally used exogenous pyrogen is lipopolysaccharide (LPS), purified from the surfaces of E. coli bacteria (2). Specific to pathogens and typically not found in normal host cells, they can consist of any class of biological macromolecule: proteins, nucleic acids, carbohydrates, or lipids.
These substances can alert host immune cells to the presence of foreign invaders in a rapid, acute manner through signaling of the Toll-like receptors (TLRs), a class of surface molecules evolutionarily conserved from insects to mammals and first identified in Drosophila melanogaster. This relationship was discovered when it was observed that mice with mutations in the Tlr4 gene had compromised ability to mount an immune response when exposed to LPS (3). Infected mice with dysfunctional copies of the Tlr-4 gene were resistant to LPS, showing no immune response, but would often experience shock and sepsis as a result of the inability to combat infection. From this, we can see that exogenous pyrogen alone cannot induce full-scale fever.
In an early experiment on fever production in rabbits, another type of pyrogen was identified as having an important role in causing fever in addition to that of exogenous pyrogen. Initially labeled “endogenous pyrogen”, this type substance was found to be produced by host organisms in response to injection of external pyrogen, and persisted in circulation for a significantly longer period of time (4). These soluble circulating endogenous pyrogens are now known to belong to a class of signaling molecules known as cytokines, and are produced by immune cells as a result of the TLR activation by exogenous pyrogen.
One of the most notable cytokines involved in febrile response are interleukins 1 and 6 (IL-1 and IL-6), both of which have been implicated in signaling the hypothalamus to induce thermoregulatory set point increase in response to injection of pathogen (5). In a review of several knockout experiments performed on IL-1, IL-6, and both of their receptors, it was proposed that these two cytokines, in addition to tumor necrotic factor (which also acts as an antipyretic) work together to communicate with the central nervous system.
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Phylogenetic Conservation of Febrile Response
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