Studies on the Pathogenesis of Fever

Moore, Douglas M.; Cheuk, S. Fai; Morton, Jonathan; Berlin, Richard D.; Wood, William B.

doi:10.1084/jem.131.1.179

Cited by 27 publications

(6 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…That these processes seem to be common to all modes of stimulation of human peripheral leukocytes for pyrogen release is suggested by the ability of cycloheximide to inhibit LP production by cells exposed to endotoxin, noted in the present investigation, and the ability of puromycin and actinomycin D to block release from cells incubated with etiocholanolone (33). Furthermore, similar findings have been observed for rabbit peripheral leukocytes stimulated by phagoeytosis or endotoxin, using cycloheximide and puromycin as the inhibiting agents (35).…”

Section: Discussionsupporting

confidence: 74%

Studies on the Origin of Human Leukocytic Pyrogen

Nordlund

Root

Wolff

1970

The Journal of Experimental Medicine

View full text Add to dashboard Cite

Granulocytes and monocytes derived from inflammatory exudates or the peripheral circulation of several mammalian species (1-5) can be stimulated to release a pyrogen, leukocytic pyrogen (LP) 1, which induces a characteristic febrile response in rabbits. Chemical characterization of LP has shown it to be a protein molecule (6-8) and since the original discovery of its production by rabbit peritoneal exudate cells (9), many attempts have been made to determine the mechanism of its synthesis by leukocytes. With one exception (10), preformed pyrogen has not been obtained from disrupted rabbit cells (11,12). Its release in vitro has been shown to take place over a several hour period (4, 11, 12), to be dependent upon the temperature of incubation (11), and inhibited by agents which bind sulfhydryl groups in enzymes (13). These findings suggest that LP is either synthesized de novo or activated from a precursor substance after contact with an appropriate stimulating agent.In the present studies, the role of RNA and protein synthesis and the energy requirements for pyrogen release by human peripheral leukocytes activated by the ingestion of heat-killed bacteria have been investigated. The results reported here indicate that both transcription of messenger RNA and its translation by ribosomes into

show abstract

Section: Discussionsupporting

confidence: 74%

Studies on the Origin of Human Leukocytic Pyrogen

Nordlund

Root

Wolff

1970

The Journal of Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…It does, however, provide a simple method of obtaining granulocytic pyrogen for experimental use (5), and detailed studies of its kinetics and cationic control have revealed additional information about the cellular physiology of pyrogen production (11).…”

Section: Discussionmentioning

confidence: 99%

Studies on the Pathogenesis of Fever

Hahn

Cheuk

Moore

et al. 1970

The Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Previous studies on the release of endogenous pyrogen from rabbit exudate granulocytes in vitro (1) have revealed: (a) that large amounts of pyrogen are released when the cells are incubated (37°C) in 0.15 M NaC1; (b) that the release is blocked if physiological concentrations of K + are added to the medium; and (c) that inhibition by ouabain of K + transport into the cells nullifies the blocking effect of K + on the release process. These results indicate that deprivation of K ions causes exudate granulocytes to release endogenous pyrogen. Other cellular proteins (e.g., aldolase) are also released with the pyrogen (1). Furthermore, it has been found that sulfhydryl reagents, such as iodoacetate, p-chloromercuribenzoate, and N-ethylmaleimide, which inhibit the energyrequiring N a -K transport system of the cells (2), also inhibit the release process (3). The present studies were undertaken to investigate further the mechanism whereby K + deprivation stimulates exudate granulocytes to release pyrogen. Material and MethodsThe methods used to exclude extraneous pyrogens, to obtain exudate granulocytes from rabbits, and to assay granulocytic pyrogen, have been described elsewhere (4, 5).Plasma was separated from rabbit blood after the addition of heparin (10 IU per ml of Liquaemin, Organon, Inc., West Orange, N. J.). Endotoxin from Escherlchla coli 0111:B4 was purchased from Difco Laboratories, Detroit, Mich.; inulin from Mann Research Laboratories, Inc., New York, N.Y.; and puromycin dihydrochloride from Nutritional Biochemicals Corp,, Cleveland, Ohio; modified Hanks' solution (MH) was prepared as described in reference (6).

show abstract

“…The first recognition of this collaboration resulted from the identification of pyrogens (molecules inducing fever), like pyrexin, in sterile extracts of damaged tissue (Menkin, 1944), later on to be named endogenous pyrogens (body's own produced pyrogens) of sterile tissue extracts and exudates, and of neutrophils (Bennett and Beeson, 1953). Subsequently, Atkins and Wood independently could show that upon stimulation, not only neutrofils but several types of immune cells released different molecules that induced fever (Atkins and Bodel, 1971;Moore et al, 1970;Wood, 1962). These endogenous pyrogens proved to be rather large proteins of 15-40 kDa (Bernheim et al, 1979;Dinarello et al, 1974).…”

Section: Immune-to-brain Signalingmentioning

confidence: 99%

“…The search for immune-to-brain signaling pathways started more than 40 years ago as the endogenous pyrogens (Atkins and Bodel, 1971;Moore et al, 1970;Wood, 1962) proved to be too large to penetrate the BBB (Dinarello et al, 1974). Complementary to the pro-inflammatory cytokines, PGE2 emerged at the same time as a critical mediator in inflammation as the mechanism behind aspirin was revealed (Vane, 1971).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

View full text Add to dashboard Cite

The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

show abstract

Studies on the Pathogenesis of Fever

Cited by 27 publications

References 14 publications

Studies on the Origin of Human Leukocytic Pyrogen

Studies on the Origin of Human Leukocytic Pyrogen

Studies on the Pathogenesis of Fever

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Contact Info

Product

Resources

About