Exogenous Pyrogens Research Articles

Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1

Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The aim of this study was to characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH2-terminal sequence of a lipoprotein from M. salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 microg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 microg/kg. The maximal fever (a peak of 1.5 degrees C above baseline) was caused by the 100 microg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma. Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses.

Hypothalamic Neuronal Histamine Modulates Febrile Response but Not Anorexia Induced by Lipopolysaccharide

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats. To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.

Role of endogenous macrophage inflammatory protein‐2 in regulating fever induced by bacterial endotoxin in normal and immunosuppressed rats

During myelosuppressive chemotherapy, Gram-negative bacterial infection with consequent exposure to lipopolysaccharide (LPS) is one of the most important causes of persistent fever. The classical model of the pathogenesis of fever suggests that pro-inflammatory cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens such as bacterial LPS, represent the distal mediators of the febrile response. Neutrophils are the first effectors cells and the most prominent leucocyte population involved in acute bacterial infection. Macrophage inflammatory protein (MIP)-2 plays a crucial role in influencing early cell trafficking and neutrophil activation during pathophysiological processes and serves the same chemotactic function as human interleukin-8. In the present study, we investigated the role of MIP-2 in the development of a febrile response induced by LPS in immunocompetent and leukopenic rats. Intraperitoneal injection of LPS in leukopenic rats elicited a biphasic febrile response of rapid onset, the magnitude and duration of which were significantly greater than in immunocompetent animals. The febrile responses to LPS were accompanied by a pronounced induction of serum MIP-2 levels at 1, 2 and 4 h compared with their respective controls. In both normal and leukopenic rats, neutralization of endogenous MIP-2 bioactivity by systemic administration of antirat MIP-2 antibody caused a significant attenuation of the early phase of LPS fever. However, in contrast with normal rats, the second phase of fever was unimpaired by anti-MIP-2 in leukopenic rats. These findings suggest that circulating MIP-2 is involved in the generation of the early phase of LPS fever that contributes to the maintenance of the later phase of fever in immunocompetent, but not leukopenic, rats. Our data support a regulatory role for endogenous MIP-2 in initiating the fever responses to LPS. Furthermore, these results provide evidence that different cellular and humoral mechanisms are implicated in the development of a febrile response triggered by Gram-negative bacterial infections in leukopenic hosts.

Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed.

For many years, it was thought that bacterial products caused fever via the intermediate production of a host-derived, fever-producing molecule, called endogenous pyrogen (EP). Bacterial products and other fever-producing substances were termed exogenous pyrogens. It was considered highly unlikely that exogenous pyrogens caused fever by acting directly on the hypothalamic thermoregulatory center since there were countless fever-producing microbial products, mostly large molecules, with no common physical structure. In vivo and in vitro, lipopolysaccharides (LPSs) and other microbial products induced EP, subsequently shown to be interleukin-1 (IL-1). The concept of the 'endogenous pyrogen' cause of fever gained considerable support when pure, recombinant IL-1 produced fever in humans and in animals at subnanomolar concentrations. Subsequently, recombinant tumor necrosis factor-alpha (TNF-alpha), IL-6 and other cytokines were also shown to cause fever and EPs are now termed pyrogenic cytokines. However, the concept was challenged when specific blockade of either IL-1 or TNF activity did not diminish the febrile response to LPS, to other microbial products or to natural infections in animals and in humans. During infection, fever could occur independently of IL-1 or TNF activity. The cytokine-like property of Toll-like receptor (TLR) signal transduction provides an explanation by which any microbial product can cause fever by engaging its specific TLR on the vascular network supplying the thermoregulatory center in the anterior hypothalamus. Since fever induced by IL-1, TNF-alpha, IL-6 or TLR ligands requires cyclooxygenase-2, production of prostaglandin E2 (PGE2) and activation of hypothalamic PGE2 receptors provides a unifying mechanism for fever by endogenous and exogenous pyrogens. Thus, fever is the result of either cytokine receptor or TLR triggering; in autoimmune diseases, fever is mostly cytokine mediated whereas both cytokine and TLR account for fever during infection.

Review: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed

For many years, it was thought that bacterial products caused fever via the intermediate production of a host-derived, fever-producing molecule, called endogenous pyrogen (EP). Bacterial products and other fever-producing substances were termed exogenous pyrogens. It was considered highly unlikely that exogenous pyrogens caused fever by acting directly on the hypothalamic thermoregulatory center since there were countless fever-producing microbial products, mostly large molecules, with no common physical structure. In vivo and in vitro, lipopolysaccharides (LPSs) and other microbial products induced EP, subsequently shown to be interleukin-1 (IL-1). The concept of the `endogenous pyrogen' cause of fever gained considerable support when pure, recombinant IL-1 produced fever in humans and in animals at subnanomolar concentrations. Subsequently, recombinant tumor necrosis factor-α (TNF-α), IL-6 and other cytokines were also shown to cause fever and EPs are now termed pyrogenic cytokines. However, the concept was challenged when specific blockade of either IL-1 or TNF activity did not diminish the febrile response to LPS, to other microbial products or to natural infections in animals and in humans. During infection, fever could occur independently of IL-1 or TNF activity. The cytokine-like property of Toll-like receptor (TLR) signal transduction provides an explanation by which any microbial product can cause fever by engaging its specific TLR on the vascular network supplying the thermoregulatory center in the anterior hypothalamus. Since fever induced by IL-1, TNF-α, IL-6 or TLR ligands requires cyclooxygenase-2, production of prostaglandin E2 (PGE 2) and activation of hypothalamic PGE2 receptors provides a unifying mechanism for fever by endogenous and exogenous pyrogens. Thus, fever is the result of either cytokine receptor or TLR triggering; in autoimmune diseases, fever is mostly cytokine mediated whereas both cytokine and TLR account for fever during infection.

The effects of drugs on thermoregulation.

Body temperature is a balance of the hypothalamic set point, neurotransmitter action, generation of body heat, and dissipation of heat. Drugs affect body temperature by different mechanisms. Antipyretics lower body temperature when the body's thermoregulatory set point has been raised by endogenous or exogenous pyrogens. The use of antipyretics may be unnecessary or may interfere with the body's resistance to infection, mask an important sign of illness, or cause adverse drug effects. Drugs may cause increased body temperature in five ways: altered thermoregulatory mechanisms, drug administration-related fever, fever from the pharmacologic action of the drug, idiosyncratic reactions, and hypersensitivity reactions. Certain drugs cause hypothermia by depression of the thermoregulatory set point or prevention of heat conservation. By affecting the balance of thermoregulatory neurotransmitters, drugs may prevent the signs and symptoms of hot flashes.

Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain.

Ciliary neurotrophic factor (CNTF) and leptin decrease food intake and body weight. Lipopolysaccharide (LPS) is a potent exogenous pyrogen and produces anorexia via cytokine production. CNTF-, leptin-, and LPS-induced cytokines all act on type I cytokine receptors. However, it is not known if these cytokines engage similar central nervous system (CNS) pathways to exert their effects. To assess mechanisms by which these cytokines act, we examined the patterns of immediate early gene expression (SOCS-3, c-fos, and tis-11) in the brain following intravenous administration. CNTF and LPS induced gene expression in circumventricular organs; ependymal cells of the ventricles, meninges, and choroid plexus; and the arcuate nucleus of the hypothalamus. CNTF administration also induced fever and cyclooxygenase-2 mRNA expression. In contrast, we found no evidence of leptin-induced inflammation. CNTF and leptin are being assessed as potential therapeutic anti-obesity agents, and both potently reduce food intake. Our findings support the hypothesis that CNTF and leptin engage distinct CNS sites and CNTF possesses inflammatory properties distinct from leptin.

Thermal homeostasis in systemic inflammation: modulation of neuronal mechanisms.

Fever can be defined as a specific model of body temperature control, modified by action of humoral substances released due to bacterial infection. Under laboratory conditions exogenous and endogenous pyrogens affect nervous endings in the body periphery, as well as thermosensitive neurons in the hypothalamus, which first manifests as a shock reaction and then as shifts of temperature thresholds for activation of thermoregulatory effectors (cold thermogenesis, vasomotion, sweating or panting) to higher body temperatures. During the later phase of fever, the temperature threshold for cold thermogenesis starts to move downwards, while the thresholds for other thermoregulatory outputs remain elevated, the result being enlarging of the interthreshold zone. This creates conditions for cooling of the body and for termination of the fever. During different phases of fever cytokines, prostaglandins, neuropeptides and catecholamines participate in modulation of mechanisms regulating thermoregulatory functions. This paper aims to specify the role of individual cytokines in induction of fever, as well as in activation of thermoregulatory centers as well as individual thermoregulatory effectors and to define differences in their mode of action. The paper further attempts to summarize our knowledge on humoral modulation of the cytokine release. It is concluded that cytokines are not the primary factors responsible for setting of the body thermostat during fever.

Influence of Pregnancy on Plasma Cytokines and the Febrile Response to Intraperitoneal Administration of Bacterial Endotoxin in Rats

Rats have an attenuated febrile response to exogenous (e.g. bacterial endotoxin) and endogenous pyrogen (e.g. interleukin-1beta) near the term of pregnancy, the mechanism of which is unknown. The present experiments were carried out on 71 non-pregnant and 181 pregnant Sprague-Dawley rats to determine if basal levels of the endogenous antipyretic substance, interleukin-1 receptor antagonist (IL-1ra), change relative to interleukin-1beta (IL-1beta) throughout gestation. Furthermore, we have constructed complete Escherichia coli lipopolysaccharide (LPS) dose-core temperature response curves in non-pregnant and pregnant rats on days 10, 15 and 20 of gestation (term of gestation approximately 21 days) to determine if the attenuated febrile response near the term of pregnancy results from a simple shift of the dose-response relationship or results from a dampening of the overall dose-response relationship. Basal IL-1beta, as determined by ELISA on trunk blood from non-pregnant and pregnant rats on days 10, 15 and 20 of gestation (d10, d15, d20), did not change significantly during pregnancy. Basal IL-1ra, however, was increased significantly in d15 rats as compared to non-pregnant, and d10 and d20 rats. The attenuated febrile response near the term of pregnancy, as determined by biotelemetry, did not result from a simple shift of the E. coli LPS dose-core temperature response curve but rather a dampening of the overall dose-response relationship. The febrile responses to EC(50) and EC(100) doses of E. coli LPS were preceded by a period of hypothermia, and were delayed and attenuated near the term of pregnancy as compared to that observed early in pregnancy and in non-pregnant rats. Our data provide evidence that pregnant rats are more sensitive to the hypothermia-producing effects of E. coli LPS than are non-pregnant rats and allow us to speculate that elevated basal IL-1ra may play a role in mediating the attenuated febrile response to pyrogen on day 15 but not on day 20 of gestation in rats.

Interleukin 1beta modulates rat subfornical organ neurons as a result of activation of a non-selective cationic conductance.

The circumventricular organs (CVOs) are ideal locations at which circulating pyrogens may act to communicate with the CNS during an immune challenge. Their dense vasculature and fenestrated capillaries allow direct access of these pyrogens to CNS tissue without impediment of the blood-brain barrier (BBB). One such CVO, the subfornical organ (SFO), has been implicated as a site at which the circulating endogenous pyrogen interleukin 1beta (IL-1beta) acts to initiate the febrile response. This study was designed to determine the response of rat SFO neurons to IL-1beta (1 nM to 100 fM) using whole-cell current-clamp and voltage-damp techniques. We found that physiological(subseptic) concentrations of IL-1beta (1 pM, 500 fM, 100 fm) induced a transient depolarization in SFO neurons accompanied by a significant increase in spike frequency. In contrast,pharmacological (septic) concentrations of IL-1beta (1 nM) evoked a sustained hyperpolarization. While depolarizations in response to IL-1beta were abolished by treatment of cells with the IL-1 receptor antagonist (IL-1ra), hyperpolarizations were still observed. Voltage-clamp analysis revealed that the majority (85 %) of SFO neurons responding to IL-1beta with depolarization (29 of 34 cells) exhibited an electrophysiological profile characterized by a dominant delayed rectifier potassium current (DIK), a conductance that we also found to be reduced to 84.4 +/- 3.3 % of control by bath application of IL-1beta. In addition, using slow voltage ramps we demonstrated that IL-1beta activates a non-selective cationic current (INSC) with a reversal potential of -38.8 +/- 1.8 mV. These studies identify the cellular mechanisms through which IL-1beta can influence the excitability of SFO neurons and, as a consequence of such actions, initiate the febrile response to exogenous pyrogens.

Neuroimmune response to endogenous and exogenous pyrogens is differently modulated by sex steroids.

The objective of this study was to explore whether and how ovarian hormones interact with the febrile response to pyrogens. Estrogen and progesterone treatment of ovariectomized rats was associated with a reduction in lipopolysaccharide (LPS)-induced fever, compared with ovariectomized controls. LPS-fever reduction was accompanied by reduced levels of the inducible cyclooxygenase-2 (COX-2) protein expression in the hypothalamus as well as reduced plasma levels of IL-1beta. The amount of LPS-induced IL-6 in the plasma was not affected by ovarian hormone replacement. In contrast, hypothalamic COX-2 expression in response to intraperitoneal injection of IL-1beta was potentiated by the ovarian hormone replacement. IL-1beta induced a moderate increase in plasma levels of IL-6 that was suppressed by ovarian hormone replacement. These data suggest that ovarian hormone replacement attenuated the proinflammatory response to LPS by suppressing the LPS-induced IL-1beta production and COX-2 expression in the hypothalamus. The markedly different action of ovarian hormones on IL-1beta and LPS effects suggests that this sex hormone modulation of the immune response is a function of the nature of infection and provides further evidence that LPS actions are different from those of IL-1beta.

Clinical review: fever in intensive care unit patients.

Fever is a common response to sepsis in critically ill patients. Fever occurs when either exogenous or endogenous pyrogens affect the synthesis of prostaglandin E2 in the pre-optic nucleus. Prostaglandin E2 slows the rate of firing of warm sensitive neurons and results in increased body temperature. The febrile response is well preserved across the animal kingdom, and experimental evidence suggests it may be a beneficial response to infection. Fever, however, is commonly treated in critically ill patients, usually with antipyretics, without good data to support such a practice. Fever induces the production of heat shock proteins (HSPs), a class of proteins critical for cellular survival during stress. HSPs act as molecular chaperones, and new data suggest they may also have an anti-inflammatory role. HSPs and the heat shock response appear to inhibit the activation of NF-kappabeta, thus decreasing the levels of proinflammatory cytokines. The anti-inflammatory effects of HSPs, coupled with improved survival of animal models with fever and infection, call into question the routine practice of treating fever in critically ill patients.

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The actions of prostanoids in various physiological and pathophysiological conditions have been examined using mice lacking the prostanoid receptors. PGD2 was found to be a mediator of allergic asthma. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic and cardio-protective agent. Several important actions of PGE2 are brought out via the PGE2-receptor subtype EP3; PGE2 participated in the regulation of platelet function, and it worked as a mediator of febrile responses to both endogenous and exogenous pyrogens. These novel findings on the roles of the prostanoids would contribute to the development of drugs targeting the prostanoid receptors.

Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1β

Various lines of evidence have implicated cyclooxygenase (COX)-2 as a modulator of the fever induced by the exogenous pyrogen lipopolysaccharide (LPS). Thus, treatment with specific inhibitors of COX-2 suppresses the febrile response without affecting basal body (core) temperature ( T c). Furthermore, COX-2 gene-ablated mice are unable to develop a febrile response to intraperitoneal (i.p.) LPS, whereas their COX-1-deficient counterparts produce fevers not different from their wild-type (WT) controls. To extend the apparently critical role of COX-2 for LPS-induced fevers to fevers produced by endogenous pyrogens, we studied the thermal responses of COX-1- and COX-2 congenitally deficient mice to i.p. and intracerebroventricular (i.c.v.) injections of recombinant murine (rm) interleukin (IL)-1β. We also assessed the effects of one selective COX-1 inhibitor, SC-560, and two selective COX-2 inhibitors, nimesulide (NIM) and dimethylfuranone (DFU), on the febrile responses of WT and COX-1 −/− mice to LPS and rmIL-1β, i.p. Finally, we verified the integrity of the animals’ responses to PGE 2, i.c.v. I.p. and i.c.v. rmIL-1β induced similar fevers in WT and COX-1 knockout mice, but provoked no rise in the T cs of COX-2 null mutants. The fever produced in WT mice by i.p. LPS was not affected by SC-560, but it was attenuated and abolished by NIM and DFU, respectively, while that caused by i.p. rmIL-1β was converted into a T c fall by DFU. There were no differences in the responses to i.c.v. PGE 2 among the WT and COX knockout mice. These results, therefore, further support the notion that the production of PGE 2 in response to pyrogens is critically dependent on COX-2 expression.

Pain, fever and prostanoids

Although it has been known that prostanoids are involved in pain regulation and fever, the precise roles of their receptors and receptor subtypes are unclear. All prostanoid receptors have been cloned and mice deficient in each receptor have been developed. Recent studies using prostanoid-receptor-knockout mice are shedding some light on these issues. Nociceptive responses to an intraperitoneal injection of acetic acid and hyperalgesia induced by carrageenan were abolished by IP-receptor deficiency. In addition, the use of mice lacking prostanoid receptor is revealing an interesting role of prostanoid in neuropathic as well as inflammatory pain. With regard to pyrexia, PGE2 injected intracerebroventricularly induced the febrile response in wild-type mice, but it was without effect in mice lacking the EP3 receptor. Furthermore, febrile responses induced by IL-1 beta, an endogenous pyrogen, and LPS, an exogenous pyrogen, were specifically suppressed in mice lacking the EP3 receptor. These results indicate that PGE2 works as a common final mediator of the febrile response and that this action of PGE2 is mediated by the EP3 receptor. The determination of precise roles of prostanoids in pain and fever may provide novel targets for antipyretic analgesics with fewer side effects.

Circulating cytokines as mediators of fever.

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.

Evidence that platelet-derived growth factor may be a novel endogenous pyrogen in the central nervous system.

Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory actions in the mammalian central nervous system (CNS). Like the cytokines, PDGF primarily signals through tyrosine phosphorylation-dependent pathways that activate multiple intracellular molecules including Janus family kinases. We previously showed that microinjection of PDGF-BB into the lateral ventricle induced a febrile response in rats that was reduced by pretreatment with Win 41662, a potent inhibitor of PDGF receptors (Pelá IR, Ferreira MES, Melo MCC, Silva CAA, and Valenzuela CF. Ann NY Acad Sci 856: 289-293, 1998). In this study, we further characterized the role of PDGF-BB in the febrile response in rats. Microinjection of PDGF-BB into the third ventricle produced a dose-dependent increase in colonic temperature that peaked 3-4 h postinjection. Win 41662 attenuated fever induced by intraperitoneal injection of bacterial lipopolysaccharide, suggesting that endogenous PDGF participates in the febrile response to this exogenous pyrogen. Importantly, febrile responses induced by tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were unchanged by Win 41662. Both indomethacin and dexamethasone blocked the PDGF-BB-induced increase in colonic temperature, and, therefore, we postulate that PDGF-BB may act via prostaglandin- and/or inducible enzyme-dependent pathways. Thus our findings suggest that PDGF-BB is an endogenous CNS mediator of the febrile response in rats.

Fever Adults -In Approach to Diagnosis and Management

Fever is one of the most important and presenting symptoms in family practice. However making the correct diagnoses and selecting the most effectiye therapy poses a challenge to the busy family practitioner. Fever is defined as an elevation of body temperature above the normal daif variation and is found in a number of disease states as a result of the re-setting of the hypothalamic set point by various exogenous and endogenous cytokines and pyrogens. In family practice,fever is much more likely to be a manifestation of a common rather than a rare disease and key concepts, including pyrexia of unknown origin and factitious fever, should be understood, important life threatening conditions, e.g. malaria and meningococcal disease must always be considered when confronted by a patient with acute febrile illness and ill-defined localising signs. Antipyretics and other supportive therapy should be judiciously used, since they may obscure the effect of a specific therapeutic agent on the natural course ofthe disease and the focus of management should remain the underlying condition.

Roles of Prostanoids Revealed From Studies Using Mice Lacking Specific Prostanoid Receptors

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2α was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Roles of prostanoids revealed from studies using mice lacking specific prostanoid receptors.

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.