Pyrogen Sensing and Signaling: Old Views and New Concepts

Blatteis, Clark M.; Sehic, Elmir; Li, Shuxin

doi:10.1086/317522

Cited by 108 publications

(64 citation statements)

References 75 publications

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“…PGE 2 is a well-known inductor of fever (16). In a rat model of LPS-induced fever (19), upregulation of the enzymes that me- diate its generation was shown.…”

Section: Discussionmentioning

confidence: 99%

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Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Sauvant¹,

Holzinger²,

Gekle³

2006

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is the principal mediator of fever and inflammation. Recently, evidence emerged that during febrile response, PGE 2 that is generated in the periphery enters the hypothalamus and contributes to the maintenance of fever. In a rat model of fever generation, peripheral PGE 2 is increased, whereas clearance by metabolism of peripheral PGE 2 is downregulated. The major route of PGE 2 excretion is via the renal proximal tubular organic anion secretory system, where basolateral uptake that is mediated by renal organic anion transporter 1 (rOAT1) and rOAT3 is rate limiting. Therefore, it was hypothesized that PGE 2 itself will abolish its excretion by rOAT1 or rOAT3. Fluorescein was used as a prototypic organic anion, and NRK-52E cells from rat served as a proximal tubular model system. PGE 2 time-dependently downregulates basolateral organic anion uptake, without affecting cell volume or cell protein, recirculation of counter ions, or proximal tubular transport systems in general. In addition, PGE 2 diminishes expression of both rOAT1 and rOAT3. Both organic anion uptake and expression of rOAT1 and rOAT3 are dose-dependently downregulated by PGE 2 . These findings suggest that during fever or inflammation, renal secretory transport of PGE 2 is reduced, contributing to elevated PGE 2 levels in blood. These data fit into the hypothetical concept of peripheral PGE 2 's playing a significant role in fever. The described regulatory mechanism may also be of relevance in chronic inflammatory events. Moreover, the data presented could explain why increased plasma urate levels occur in diseases that go along with increased levels of PGE 2 .J Am Soc Nephrol 17: 46 -53, 200646 -53, . doi: 10.1681 T he organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds. This system consists of organic anion exchangers that are located at the basolateral membrane and a less well-characterized transport step at the apical membrane. The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system, dependent on an inward-directed Na ϩ gradient to drive the uptake of ␣-ketoglutarate, which then is exchanged for organic anions. It has been shown that OAT1 represents characteristics of the basolateral, polyspecific transporter for organic anions, which had been functionally described for some time (1). Recently, new evidence has indicated that organic anion transporter 3 (OAT3) (2), which also is located in the basolateral renal proximal tubular membrane, also works as an appropriate exchanger for organic anions and dicarboxylates (3,4). Moreover, additional homologues have been cloned and were called OAT2 (5), OAT4 (6), OAT5 (7), and OAT6 (8). These clones show 40 to 60% homology in amino acid sequence compared with OAT1 or OAT3, and they differ in substrate specificity and expression pattern. Furthermore, these latter proteins are not anion exchangers like OAT1 or OAT3 but seem to work as fac...

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“…PGE 2 is a well-known inductor of fever (16). In a rat model of LPS-induced fever (19), upregulation of the enzymes that me- diate its generation was shown.…”

Section: Discussionmentioning

confidence: 99%

“…In general, fever-generating PGE 2 is thought to be produced in the brain (16). Nevertheless, it is shown that substantial amounts of peripheral PGE 2 enter hypothalamic structures (17), and recent data support the idea of blood-derived PGE 2 's playing an important role in fever (18,19).…”

mentioning

confidence: 99%

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Sauvant¹,

Holzinger²,

Gekle³

2006

Journal of the American Society of Nephrology

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“…It relies on the stimulation of peripheral sensory nerves, i.e. vagal (Blatteis et al, 2000;Romanovsky, 2000) and trigeminal (Navarro et al, 2006) afferences by PGE 2 . The presumed pathway consists of a first synapse in the nucleus of the solitary tract (NTS), followed by travelling of the signal via ventral noradrenergic bundle to the POA where it induces the release of NE, hence stimulating synthesis of PGE 2 .…”

Section: The Neural Pathwaymentioning

confidence: 99%

Behavioral fever in ectothermic vertebrates

Rakus

Ronsmans

Vanderplasschen

2017

Developmental & Comparative Immunology

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a b s t r a c tFever is an evolutionary conserved defense mechanism which is present in both endothermic and ectothermic vertebrates. Ectotherms in response to infection can increase their body temperature by moving to warmer places. This process is known as behavioral fever. In this review, we summarize the current knowledge on the mechanisms of induction of fever in mammals. We further discuss the evolutionary conserved mechanisms existing between fever of mammals and behavioral fever of ectothermic vertebrates. Finally, the experimental evidences supporting an adaptive value of behavioral fever expressed by ectothermic vertebrates are summarized.

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“…Nonetheless, evidence exists that these molecules reach the brain by at least two mechanisms: a) systemic circulation and b) neural pathways (reviewed by Banks and Quan and Banks) [5,97]. Cytokines within systemic circulation may affect blood-brain barrier (BBB) permeability, may bind to areas of the brain that lack a BBB such as circumventricular organs [10], may cross through fenestrated capillaries of the BBB or may use cytokine-specific transporters [11]. Cytokines may also activate brain endothelial and perivascular cells [106] to induce production of other signaling molecules such as nitric oxide (NO), prostanoids or other cytokines that in turn stimulate glial cells [54,63,97].…”

Section: Inflammation and Pro-inflammatory Cytokinesmentioning

confidence: 99%

Alzheimer's Disease and Peripheral Infections: The Possible Contribution from Periodontal Infections, Model and Hypothesis

Kamer¹,

Dasanayake²,

Craig³

et al. 2008

JAD

152

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Abstract. Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

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Pyrogen Sensing and Signaling: Old Views and New Concepts

Cited by 108 publications

References 75 publications

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Behavioral fever in ectothermic vertebrates

Alzheimer's Disease and Peripheral Infections: The Possible Contribution from Periodontal Infections, Model and Hypothesis

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