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PubMed1988

Decrease in pyrogenicity of muramyl dipeptide after coupling with luteinizing hormone-releasing hormone.

Muramyl dipeptide (MDP) and its adjuvant active derivative lysine-MDP (Lys-MDP) have been demonstrated to be pyrogenic and to induce endogenous pyrogen (EP) production in vivo and in vitro. It has recently been shown that immunologic castration can be achieved in mice by immunization with luteinizing hormone-releasing hormone (LHRH) directly conjugated by carbodiimide to Lys-MDP, termed LHRH-Lys-MDP (cdi), or with a linear monomeric MDP-linked molecule obtained by total synthesis, termed LHRH-Lys-MDP (s). These preparations were tested in the rabbit for their capacity to induce fever and were found to be devoid of pyrogenicity at dosage levels of Lys-MDP that induced fever. This decrease of pyrogenicity of Lys-MDP after coupling to LHRH seems to be related to the structure of the conjugate because the derivative LHRH-LysNH2-MDP exhibited the same pyrogenic activity as the free glycopeptide. Surprisingly, nonpyrogenic LHRH-Lys-MDP induced production of EP and interleukin-1 (IL-1) in vitro and increased in vivo modifications of metal levels attributed to the action of IL-1. Moreover, LHRH-Lys-MDP reduced the pyrogenic effect of an exogenous dose of EP.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1978

Heterogeneity of group A streptococcal pyrogenic exotoxin type B.

Streptococcal pyrogenic exotoxin type B purified from culture filtrates of either the NY-5 or T-19 strain of group A streptococcus was found to be heterogeneous in charge. Three protein fractions with isoelectric points of 8.0, 8.4, and 9.0 were isolated by differential solubility in ethanol and acetate-buffered saline followed by isoelectric focusing and shown to be antigenically identical to streptococcal pyrogenic exotoxin type B. The molecular weights of all three fractions were approximately 17,500, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with aggregates forming in the presence of hyaluronic acid. Only the pI 8.4 fraction showed the characteristic activities of streptococcal pyrogenic exotoxin in rabbits: pyrogenicity and ability to enhance susceptibility to lethal endotoxin shock. The pI 8.0 and pI 9.0 fractions were not pyrogenic, but could be used to immunize against pyrogenicity. These two fractions failed either to enhance lethal endotoxin shock or to immunize against enhancement activity. When the isolated fractions were electrofocused again they appeared heterogeneous, suggesting an instability of the B toxin molecular forms.

Amino Acids↗

PubMed1986

Inability of pyrogenic, purified Bordetella pertussis lipid A to induce interleukin-1 release by human monocytes.

Free lipid A of Bordetella pertussis, Neisseria meningitidis, and Escherichia coli lipopolysaccharide (LPS) was prepared by hydrolysis in acetate buffer (pH 4.5); in addition, lipid A from B. pertussis and E. coli was prepared by hydrolysis in mineral acid (HCl). The precipitates obtained were purified by extraction methods in toluene-methanol and are referred to as crude lipid A. Purified lipid A from N. meningitidis and B. pertussis was obtained by extraction in a mixture of chloroform-methanol-water-triethylamine. The different preparations were tested for their pyrogenicity (endogenous pyrogen; EP) and their capacity to trigger the release of interleukin-1 (IL-1; previously known as lymphocyte-activating factor; LAF) by human monocytes. Crude lipid A from E. coli and N. meningitidis were both IL-1 inducers. Crude B. pertussis lipid A (acetate buffer; pH 4.5), which contains a beta-1-6-linked D-glucosamine disaccharide, two phosphoryl groups, and five fatty acids, was pyrogenic and an IL-1 inducer (EP+/LAF+); but crude B. pertussis lipid A (0.25 N HCl), which lacked the glycosidic phosphoryl group, was 1,000-fold less pyrogenic than the diphosphorylated lipid A, yet it retained its IL-1-inducing capacity (EP-/LAF+). Purified N. meningitidis lipid A was not an inducer of IL-1 release and purified B. pertussis lipid A exhibited identical pyrogenicity as the parent LPS but was devoid of any IL-1-release inducing capacity (EP+/LAF-). These results demonstrate that for some endotoxins, purified lipid A is unable to induce IL-1 release by human monocytes; however, it is pyrogenic, supporting the hypothesis that IL-1 and EP are induced by different determinants on the LPS molecule.

Bordetella pertussis↗

PubMed1987

Effects of endogenous pyrogen and prostaglandin E2 on hypothalamic neurons in rat brain slices.

We investigated the effects of endogenous pyrogen and prostaglandin E2 (PGE2) on the preoptic and anterior hypothalamic (POAH) neurons using brain slice preparations from the rat. Partially purified endogenous pyrogen did not change the activities of most of the neurons in the POAH region when applied locally through a micropipette attached to the recording electrode in proximity to the neurons. This indicates that partially purified endogenous pyrogen does not act directly on the neuronal activity in the POAH region. The partially purified endogenous pyrogen, applied into a culture chamber containing a brain slice, facilitated the activities in 24% of the total neurons tested, regardless of the thermal specificity of the neurons. Moreover, PGE2 added to the culture chamber facilitated 48% of the warm-responsive, 33% of the cold-responsive, and 29% of the thermally insensitive neurons. The direction of change in neuronal activity induced by partially purified endogenous pyrogen appears to be almost the same as that induced by PGE2 when these substances were applied by perfusion to the same neuron in the culture chamber. These results suggest that partially purified pyrogen applied to the perfusate of the culture chamber stimulates some constituents of brain tissue to synthesize and release prostaglandin, which in turn affects the neuronal activity of the POAH region.

Animals↗

PubMed1975

Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic neurons in the cat.

Leukocytic pyrogen and sodium acetylsalicyclate (NaASA) were microinjected into the preoptic/anterior hypothalamic (PO/AH) area of cats to examine the direct effects of these agents on identified thermoregulatory neurons. The pyrogen and NaASA were administered under thermoneutral conditions to preparations that displayed peripheral or peripheral and central thermoreceptor input. The majority of neurons studied with proximate injection of pyrogen responded in a manner consistent with the set-point hypothesis; i.e., units responding to heating with increased activity were depressed and those showing a decreased discharge with the heat test were excited by the pyretic agent. Injection of NaASA without pyrogen pretreatment caused no significant modification of thermoregulatory neuron discharge in most cases. However, when NaASA was administered after pyrogen, it uniformly antagonized the pyretic effect causing a return of the discharge to the control rate. It may be concluded that pyrogen and NaASA act directly in the PO/AH area to produce fever and antipyresis, respectively, by appropriately offsetting the activity of thermoregulatory neurons.

Animals↗

PubMed1979

Effects of pyrogen on the medullary temperature-responsive neurone of rabbits.

Effects of intravenously injected endogenous pyrogen on the unit activity of temperature-responsive neurones (TR neurones) of medulla oblongata were investigated in urethanized rabbits with an intact or lesioned preoptic/anterior hypothalamic area (PO/AH). TR neurones of the medulla responded to pyrogen in the same manner as did those of the PO/AH; the firing rate in the warm-responsive neurones were depressed and the cold-responsive neurones augmented. However, one-fourth of the medullary TR neurones did not respond to pyrogen in the PO/AH intact group (the control group). Following lesion of the PO/AH, the relative frequencies of TR neurones affected by pyrogen decreased as compared with those in control, and such was suggested to be more apparent in TR neurones discharging at rates of 10 imp./sec or more. Effects of the PO/AH-lesion were also seen in that the magnitude of the facilitatory or inhibitory effect of pyrogen was reduced in the PO/AH-lesioned group as compared with the control group. In some TR neurones an antipyretic agent (Sulpyrine, 48--151 mg/kg) was found to abolish responses to pyrogen.

Action Potentials↗

PubMed1975

[Pyrogen testing in vitro using the Limulus test].

The applicability of the Limulus test for the pyrogen test was checked in comparison to the pyrogen test in rabbits. In 6 out of 24 lots of raw materials and drugs pyrogens could be detected by means of the pyrogen test in rabbits. 2 of these 6 lots showed positive reaction in the Limulus test, there were no false positive results. Testing 7 bacterial strains in modified quantity of germs the Limulus test turned out to be more sensitive than the pyrogen test in rabbits. The application of this in vitro test as a complement to the pyrogen test in rabbits for a certain kind of problems is discussed.

Animals↗

PubMed1989

[Ultrastructural organization of the hypothalamic medial preoptic area and its changes under the effect of pyrogens].

In order to study structural bases of central mechanisms of thermoregulation, a comparative electron microscopic analysis of various cellular groups in one of thermosensitive zones of the cat hypothalamic area--the medial preoptic area--have been carried out under conditions of experimental fever. The latter is produced by injection of pyrogen of bacterial origin--pyrogenal--to the animals. Pyrogenal, increasing the body temperature, produces a stimulatory effect on various cellular elements, first of all on leucocytes, monocytes and macrophages in the medial preoptic area, as well as on endotheliocytes of the terminal vessels. Under pyrogenal effect activation of microglial cells and pericytes also takes place, and as a result of the rearrangements, occurring in the structure, they change into macrophages. This is an evidence of their active participation in the immune protection of the brain. According to the data from other investigations, all these activated cells produce peptide interleukin-1, one of the mediators of fever and stimulator of the immune system. Pyrogenal is stated to produce a stimulating effect on the astroglia and on some neurons of the medial preoptic area, that respond with cytoplasm increase and accumulation of numerous organelles. The reactive changes at fever in some neurons of the medial preoptic area can demonstrate that they belong to the thermosensitive pool. A conclusion is made, concerning a complex effect of pyrogenal, that results in a cooperative response of a number of cellular systems of the organism.

Animals↗

PubMedDate not supplied

Studies on the production of endogenous pyrogen by rabbit monocytes: the role of calcium and cyclic nucleotides.

Rabbit monocytes stimulated with endotoxin produced endogenous pyrogen, even under conditions of high or low extracellular calcium concentrations. Maximal production occurred when the concentration was in the near-physiological range. Prolonged incubation of cells with a calcium chelator prevented subsequent activation with endotoxin, an effect which was rapidly reversible by re-addition of calcium but not other cations. Addition of small amounts of lanthanum, which acts as a calcium channel blocker, prevented the restoration of pyrogen production, indicating that entry of the added calcium into the monocyte was required. Incorporation of a calcium ionophore into the cell membrane did not stimulate pyrogen production, and no measurable influx or efflux of calcium occurred during stimulation with endotoxin. These observations suggest that a slowly exchangeable calcium pool is necessary for the production of endogenous pyrogen, but that a rise in intracellular calcium is not by itself a necessary or sufficient stimulus. This stands in contrast to other biological systems in which Ca2+ directly couples stimulus and hormone secretion. Incubation of cells with agents shown to increase cyclic 3',5' AMP or cyclic 3',5' GMP levels in monocytes similarly did not stimulate pyrogen production or modulate its production by endotoxin stimulation. Thus, cyclic nucleotides also did not play a detectable role as intracellular messengers in this system. Future work is required to define more clearly the mechanism for the production of endogenous pyrogen, given its marked effects on the immune system through lymphocyte activation and temperature regulation.

Animals↗

PubMed1977

Pyrogen tests of infusions, blood anticoagulant solutions, plastic materials and rubber products.

The methods of the pyrogen test in rabbit as adopted by the authors are presented. The test includes positive and negative controls. The conditions of using the same rabbits on two consecutive days are discussed. Methods of sampling of sterile infusions and the preparation for pyrogen test of anticoagulant solutions containing citrate, phosphate and/or edetate ions are presented. The necessity of pyrogen control of distilled water is stressed. Attention is called on the importance of testing for pyrogenicity of the plastic materials and the rubber-wares to be applied during the production of anticoagulant solutions and infusions. A pyrogen test highly sensitive for detecting traces of detergent is applied for washed glassware. It is emphasized that sensitive pyrogen tests are indispensable not only when new derivatives are being introduced, but also during routine control, because occasional changes in the manufacturer's technology may sometimes be demonstrable in this way.

Animals↗

PubMed1985

Differences in endogenous pyrogen fevers induced by iv and icv routes in rabbits.

We have compared the characteristics of fevers produced by endogenous pyrogen administered by the intravenous (iv) and by the intracerebroventricular (icv) routes in conscious rabbits. Fevers induced by the intracerebroventricular route have a longer latency to onset, a less steep rise in body temperature, and a longer time to peak elevation in body temperature than do fevers induced by the intravenous route. Furthermore, a dose of indomethacin (2 mg/kg) administered intravenously, which is effective in markedly attenuating fevers produced by the intravenous route, was completely without effect on fevers induced by the intracerebroventricular route. On the other hand, when indomethacin (500 micrograms) was infused intracerebroventricularly, it markedly reduced fevers induced by the subsequent injection of endogenous pyrogen into the contralateral cerebral ventricle, but such pretreatment had little effect on fevers elicited by intravenous injections of endogenous pyrogen. It is concluded that the sites of action of endogenous pyrogen in response to intravenous injections of pyrogen are different from those responding to intracerebroventricular injections of pyrogen and that this is manifest in several distinct differences in the characteristics of the two fevers. These results indicate that the intracerebroventricular model of fever production is not appropriate for the study of the normal pathogenesis of fever.

Animals↗

PubMed1990

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit.

Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic tolerance between brain and peripheral tissues, however, has not been ascertained.

Animals↗

PubMed1991

Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1976

Colchicine stimulation of pyrogen production by human blood leukocytes.

The effect of colchicine, an anti-inflammatory agent, on endogenous pyrogen (EP) production by human blood leukocytes in vitro was examined. Colchicine not only failed to suppress EP production by human leukocytes stimulated by phagocytosis, but, in the absence of other stimuli, micromolar concentrations of the drug induced pyrogen production and release by both polymorphonuclear (PMN) and mononuclear leukocytes. The response was dose related, occurring at concentrations above 0.1 muM. Colcemid and vinblastine, other agents which bind to microtubular protein, also induced pyrogen release from human leukocytes, whereas lumicolchicine, a light-alerted derivative of colchicine without affinity for microtubules, was ineffective. Colchicine did not induce EP production by rabbit leukocytes, even at 100 muM concentration. Studies of the mechanism of PMN leukocyte activation by Colcemid indicated that although the time required for contact between drug and leukocyte was brief, pyrogen production and release did not begin for 6 or more hours. If added during this time, puromycin prevented subsequent production and release of pyrogen. These results indicated that agents which interfere with the assembly of microtubules induce EP production and secretion by human leukocytes in vitro.

Animals↗

PubMed1986

Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1.

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1978

The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues.

The pyrogenic efect of the synthetic adjuvant N-acetylmuramyl-L-alanine-D-isoglutamine, also known as muramyl dipeptide (MDP), was studied in rabbits. MDP induced biphasic fevers in rabbits, but two structural analogues, N-acetylmuramyl-L-alanine-D-glutamic acid (MDPA) and the dimethylester of MDPA, were 10 times less pyrogenic. This finding was supported by studies in which MDP and its analogues released leukocytic pyrogen (LP) from rabbit phagocytic cells in vitro. In addition, MDP released LP from human phagocytes. Human phagocytes, however, required a 10-fold greater concentration of MDP than did rabbit cells. The structural analogues were similarly less effective than the parent molecule in releasing LP from human cells. All preparations of MDP were negative in the limulus amebocyte lysate test and failed to show pyrogenic cross-tolerance with bacterial endotoxin. Thus MDP, which is a pyrogenic molecule, is also able to release LP from rabbit phagocytes and to a lesser degree from human phagocytes, but does not cause gelation of limulus amebocyte lysate.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1977

The production of antibody against human leukocytic pyrogen.

Human peripheral blood leukocytes were stimulated with killed staphylococci in vitro to release leukocytic pyrogen (LP). Supernates from these stimulated leukocytes were concentrated, emulsified in Freund's complete adjuvant, and injected intradermally into rabbits. After seven monthly booster injections, rabbit antiserum destroyed the pyrogenic activity of human LP, and the titer of this neutralizing ability increased in the subsequent 7 mo. The pyrogen-neutralizing capacity of the rabbit antiserum was recovered in the globulin fraction, the IgG and IgM peaks of Sephadex G-200, and the acid-eluted fraction of a goat anti-rabbit IgG immunoadsorbant. The neutralizing antibody was specific for human LP inasmuch as it had no effect on rabbit, guinea pig, or monkey LP. When coupled to Sepharose, this antibody bound human LP; after acid elution from this immunoadsorbant, LP was recovered without loss of biologic or chemical characteristics. The antiserum was also absorbed with stimulated leukocyte supernates which did not contain LP, and this had no effect on the titer of anti-LP. Crude human LP, eluted from immunoadsorbant columns prepared from absorbed antiserum, contained significantly reduced contaminating protein when evaluated by polyacrylamide gel electrophoresis. These studies have established that specific antibody to human leukocytic pyrogen can be produced. This antibody is useful in the further study and purification of leukocytic pyrogen and its role in the pathogenesis of human fever.

Animals↗

PubMed1986

Characterization of the pyrogenicity of two different lipopolysaccharides and their lipid A-bovine serum albumin complexes.

In order to elucidate the dependency of pyrogenicity of lipopolysaccharide (LPS) on the lipid A structure, we investigated the pyrogenicity of both LPS and lipid A prepared from Mima polymorpha var. oxidans which is deficient in 3-hydroxymyristic acids linked to the 3-hydroxy group of other fatty acids. LPS and lipid A were also prepared as reference compounds from Escherichia coli UKT-B. Furthermore, the establishment of reliable indices for pyrogenicity was undertaken. The following results were obtained. The correlation in linearity was demonstrated between maximal increase in body temperature (delta Tmax) and dose of LPS or lipid A complexed with bovine serum albumin (BSA). The dose-response curves based on delta Tmax were more reliable statistically than the Fever Index-4h representing the area under fever curves for 4 h. The minimum pyrogenic dose (MPD) of E. coli LPS was 1.6 X 10(-3) micrograms/kg i.v. In contrast, the MPD of M. polymorpha LPS was 7.0 X 10(-3) micrograms/kg i.v. By intracisternal injection, the MPD of E. coli LPS was 2.5 X 10(-6) micrograms/kg and that of M. polymorpha LPS 1.0 X 10(-4) micrograms/kg. The end points of Limulus amoebocyte lysate gelation were 10(-5) micrograms/ml in E. coli LPS and 10(-3) micrograms/ml in M. polymorpha LPS. The MPDs of lipid A/BSA complexes by i.v. injection were 0.15 micrograms/kg in E. coli and 2.5 micrograms/kg in M. polymorpha. The rabbits immunized with E. coli lipid A/BSA complex acquired pyrogenic tolerance to the parent LPS but the cross tolerance to M. polymorpha LPS was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acinetobacter↗