The role of cytokines in fever.
The history of the discovery of cytokines is inextricably entwined with investigations into the triggers for the febrile response — so much so that two years before the laboratories of Charles Dinarello and Steven Mizel independently cloned IL-1 and found that it was the same as the fever-inducing factor produced by leukocytes and known as leukocyte pyrogen (6
), Dinarello had outlined in a review article the mechanism by which he thought leukocyte pyrogen was likely to initiate fever. He also predicted the likely mechanism whereby antipyretics prevent the synthesis of COX metabolites and therefore reduce fever (9
). These proposed mechanisms still hold true today, explaining the roles of IL-1 in the genesis of fever and how antipyretics work to reduce fever.
Thus, there is a wonderful congruence in the history of molecular immunology that the primary and perhaps quintessential manifestation of inflammation and fever is mediated by the very first cytokine to be cloned (IL-1). Indeed, as Dinarello hypothesized for leukocyte pyrogen (9
), IL-1 alerts the hypothalamus that there is “danger” in the periphery (1
), as do other pyrogenic signals, such as TNF-α and IL-6 (1
). There is strong evidence of a humoral route of transmission for these pyrogenic cytokines from the periphery to the thermoregulatory neurons in the hypothalamus (Figure ). According to this humoral hypothesis, pyrogenic cytokines such as IL-1, IL-6, and TNF-α activate the febrile response indirectly, by inducing the secretion of PGE2
. Exactly where the PGE2
is produced and where it then goes to trigger neurons is a subject of intense research.
Comparison of the humoral and neuronal hypotheses for fever induction.
acts upon local endothelial cells or closely situated glial cells just inside the brain in the region surrounding the brain’s ventricular system. These cells in turn activate neurons in the preoptic area of the anterior hypothalamus (10
). The cells in this region of the brain surround portals in the blood-brain barrier (BBB) and are collectively known as the circumventricular organs. In these circumventricular organs, highly specialized fenestrations in the BBB allow transmission of cytokines to precise sites located in the hypothalamus of the brain. Signaling is via cytokine receptors for IL-1, TNF-α, and IL-6 on microglia cells. These receptors then activate the arachidonic acid pathway, causing release of PGE2
. The PGE2
then acts on neurons in the preoptic area of the hypothalamus, which receive the signal via prostaglandin E receptor 3 and respond by regulating temperature (11
). Other researchers have provided evidence that there are active transport mechanisms for moving cytokines such as IL-1, TNF-α, and IL-6 across the BBB (12
). These transport mechanisms may augment the effect of these pyrogenic cytokines by providing yet another route for them to access the hypothalamic centers (12
These schemes are useful for explaining how fever arises after exposure to IL-1 and how salicylates (such as aspirin) and other antiinflammatory drugs might act to block prostaglandins and thus inhibit fever (11
). The neurons in the preoptic area of the hypothalamus that are at the culmination of the cytokine/PGE2
cascade are also connected with neurons that regulate sleep and eating. This helps explain, in part, why fever is associated with somnolence and loss of appetite.
Recently, Bartfai and colleagues have refined the humoral hypothesis for fever generation (11
). There is a very rapid rise in core body temperature that occurs prior to the generation of PGE2
, which requires NF-κB induction of transcription of COX2
, a process that takes around 30 minutes (11
). They showed that IL-1β–mediated induction of sphingomyelinase via the receptor for IL-1 mediates a rapid febrile response that circumvents the need for PGE2
). Ceramide produced by the sphingomyelinase acts as the second messenger in place of PGE2
and triggers the rapid activation of preoptic neurons in the hypothalamus. Thus, the initial rapid rise in core body temperature is mediated via ceramide, and only after about 30–45 minutes, during which transcription of COX2
is activated, does the PGE2
pathway become responsible for the febrile response (10
). Both the PGE2
pathway and the sphingomyelinase pathway are triggered via IL-1β and are orchestrated in the rapid and prolonged response manifest as fever.
There is also a second hypothesis to explain how fever is generated. As fever can occur independently of IL-1, IL-6, and TNF-α, the alternative scheme is known as the neuronal hypothesis (13
). According to the neuronal hypothesis, stimulation of Kupffer cells in the liver via LPS can signal a cascade of events mediated by complement component C5a (14
). C5a stimulates PGE2
production in the liver, and signaling to the hypothalamus occurs via a neural pathway mediated by the vagus nerve and the nucleus tractus solitarius. The neuroanatomical circuit projects to the ventromedial preoptic nerves in the hypothalamus. Such a pathway triggers febrile responses and may act independently or in concert with the humoral pathways discussed above (13
Whether one or the other hypothesis is correct or whether both merge together to explain the physiology of fever needs to be resolved with further research. What is clear, however, is that anti-cytokine therapy has been used successfully to block particularly vexing conditions involving fever. In some patients with various infectious diseases, including louse-borne relapsing fever, secondary syphilis, brucellosis, leptospirosis, and Lyme disease, treatment with antibiotics is followed by a rise in TNF-α, IL-6, and IL-8 levels and then a devastating fever (16
). This is known as the Jarisch-Herxheimer reaction, and it is thought to occur when large quantities of toxins are released into the body when the antibiotics kill the disease-causing bacteria. For example, individuals with louse-borne relapsing fever (which is caused by infection with Borrelia recurrentis
), when treated with antibiotics, sometimes develop a devastating reaction manifest by fever, rigor, and hypotension. These violent reactions can be blocked with TNF-α–specific antibodies (17
). The role of IL-1, TNF-α, and other cytokines in fever can certainly be dramatically demonstrated in this scenario. Amelioration of fever, rigor, and shock-like hypotension with cytokine-specific antibodies demonstrates the importance of the role these cytokines play in the most severe clinical variants of the febrile response.