Circulating Cytokines as Mediators of Fever

Abstract

The febrile response is thought to be mediated by endogenous mediators, generically called "endogenous pyrogens." In the classical model of pathogenesis, induction of fever is mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons into the bloodstream in response to exogenous pyrogens. These mediators act at the level of the organum vasculosum of the lamina terminalis in the central nervous system (CNS), inducing synthesis of prostaglandins, which are the central mediators of the coordinated responses leading to fever. However, analysis of recent data suggests that multiple pathways may be involved in the induction of fever by cytokines, such as local cytokine production leading to signaling through vagal fibers, release of cytokine-induced circulating mediators at the tissue level, the use of membrane-bound cytokines as mediators, or the local release of cytokines in the hypothalamus by circulating activated monocytes. In addition, certain bacterial products can stimulate cytokine production directly at the level of hypothalamus, probably by activation of Toll-like receptors. A multipathway mechanism for the induction of fever is therefore suggested.

Tumor Necrosis Factor-α Allele Lymphotoxin-α+250 Is Associated with the Presence and Severity of Placental Inflammation among Preterm Births

“…Several other investigators had reported elevated levels of TNF-␣ in the presence of TNF-␣Ϫ308, TNF-␣Ϫ238, and LT-␣ϩ250 alleles (22,40,41). However, several intrapartum events, such as fetal distress, maternal fever, and/or intrapartum administration of antibiotics, may affect cord blood TNF-␣ levels (42)(43)(44).…”

Behavioral fever in ectothermic vertebrates

“…These PRR are expressed by innate immune cells including macrophages, dendritic cells and neutrophils and upon activation, trigger proinflammatory and antimicrobial reactions (Mogensen, 2009). Notably, their activation induces the release of pyrogenic cytokines called endogenous pyrogens such as interleukin (IL) 1b, IL6, tumor necrosis factor a (TNFa), and interferons (IFN) (Dinarello, 1999;Netea et al, 2000). Both IL1b and TNFa can induce the expression of each other (Dinarello et al, 1986;Ikejima et al, 1990) and are potent inducers of IL6 (Zetterstrom et al, 1998), which on contrary tends to be an inhibitor of IL1b and TNFa production (Netea et al, 2000;Schindler et al, 1990).…”

“…Notably, their activation induces the release of pyrogenic cytokines called endogenous pyrogens such as interleukin (IL) 1b, IL6, tumor necrosis factor a (TNFa), and interferons (IFN) (Dinarello, 1999;Netea et al, 2000). Both IL1b and TNFa can induce the expression of each other (Dinarello et al, 1986;Ikejima et al, 1990) and are potent inducers of IL6 (Zetterstrom et al, 1998), which on contrary tends to be an inhibitor of IL1b and TNFa production (Netea et al, 2000;Schindler et al, 1990). IL6 seems to be the major mediator for sustaining fever; indeed, IL6-knockout mice or IL6-neutralizing antibodiesinjected mice were not able to develop LPS-induced fever, even if TNFa and IL1b upregulation was unaltered (Chai et al, 1996;Hamzic et al, 2013;Kozak et al, 1998).…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…6 EPs are produced from stimulated leukocytes (or other cell types) once pathogens invade into the bloodstream. Among all EPs, IL-1␤ and TNF-␣ are 2 of the most important cytokines to induce fever in host.…”

“…Among all EPs, IL-1␤ and TNF-␣ are 2 of the most important cytokines to induce fever in host. 6,7 In addition to its fever-causing ability, IL-1␤ can regulate local and systemic inflammation by activating lymphocytes and promoting leukocytes infiltration to the inflammation site. 8 Unlike TNF-␣, the production of IL-1␤ requires the activation of dual pathways: the priming signals to induce the transcription and synthesis of pro-IL-1␤, and the subsequent secondary signals to activate inflammasome and caspase-1.…”