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A mutant protein of human interleukin-1 beta with immunostimulatory but not pyrogenic potency.

Interleukin-1 (IL-1) mediates a variety of immune and inflammatory responses. In order to understand the mechanisms involved in multiple biological functions, it is important to define the active sites of IL-1. Using the technique for site-specific mutagenesis, we tested whether the arginine residue at the 4th position in human IL-1 beta is essential for multiple biological activities. In our experiments, the fourth position is replaced by a non-basic amino acid--either glycine or aspartic acid. The resulting mutant protein shows both immunostimulatory activity and the ability to induce hematopoietic growth factors similar to native IL-1 beta, but has a markedly reduced pyrogenic potency. Therefore, the mutant protein of IL-1 beta may represent a good candidate for use in vivo as an adjuvant for poor immunogenic vaccines.

Adjuvants, Immunologic↗

Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells.

Endotoxin, interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1 beta- and TNF alpha-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1 beta and TNF alpha. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.

Alkaloids↗

Preliminary assessment of removal of pyrogenic lipopolysaccharides with colloidal zirconia adsorbents.

Preliminary evaluation of bare or polymer-coated colloidal monoclinic zirconia of nominal particle size 100 nm indicated that it is an effective adsorbent for pyrogenic lipopolysaccharides (LPS) as measured by chemical and Limulus amebocyte lysate (LAL) assays. Zirconia at 50 micrograms ml-1 adsorbed 99.95% of added E. coli O128 LPS. Residual LPS levels below 0.1 ng ml-1 were easily attained. Colloidal zirconia was able to remove LPS from solution in the presence of bovine albumin (BSA). Some LPS contaminating BSA lacked affinity for zirconia. Preadsorption of phosphate onto bare zirconia blocked LPS adsorption. However, phosphated-oligomeric glycidyl (epoxy) pentaerythritol-coated colloidal zirconia could be derivatized with imidazole-containing ligands to produce an LPS-binding surface. Preliminary results of adsorption of LPS by the coated particles indicated a reduced level of LPS binding compared to bare zirconia, probably because the particles aggregated during the derivatization process, reducing the effective surface available for LPS adsorption.

Adsorption↗

Effect of bacterial pyrogen on three lizard species.

1. Three lizard species (Callopistes maculatus, Gerrhosaurus major, and Varanus exanthematicus) were tested for their response to intraperitoneal injection of alcohol-killed Aeromonas sobria. 2. A paired experimental design, in which each animal received an injection of sterile saline and 1 x 10(10) A. sobria, was utilized. 3. C. maculatus demonstrated a statistically significant increase in mean selected body temperature (MSBT) after bacteria injection. 4. G. major and V. exanthematicus did not demonstrate a statistically significant increase in MSBT. 5. C. maculatus is the first lizard species outside of the family Iguanidae to exhibit a febrile response to bacterial pyrogen.

Aeromonas↗

Inhibition of pyrogen Escherichia coli fever with intracerebral administration of prazosin, dihydrobenzperidol and nifedipin in the rabbits.

1. The thermoregulatory, effector processes were investigated after treatment with prazosin (PRA), dihydrobenzperidol (DHBP) and nifedipin (ADA) applied to the thermosensitive zone of the anterior hypothalamus (PO/AH) on normothermic and feverish rabbits (LPS, lipopolysaccharide E. coli; 1 meg/kg, i.v.). 2. The alpha 1-noradrenergic receptor antagonists, PRA and DHBP, applied to the PO/AH produced an abolishment of fever elicited by pyrogen i.v. injection mainly because of vasodilation of ear skin vessels and attenuation of metabolic rate. 3. Calcium channel blocker, ADA, also induced a decline in the rabbit's core temperature in the same manner. 4. All these drugs given to the PO/AH did not change the body temperature in normothermic rabbits. 5. These results, therefore, strongly suggest that alpha 1-noradrenergic receptors subserve the coordinated thermoregulatory mechanisms in PO/AH which are required for antipyresis. The inhibition of Ca2+ turnover is discussed as a possible mechanism of antipyretic action of these drugs given to the PO/AH.

Animals↗

Hypothalamic Na+ and Ca++ ions and temperature set-point: new mechanisms of action of a central or peripheral thermal challenge and intrahypothalamic 5-HT, NE, PGEi and pyrogen.

The effects of changes in ambient and central temperature, amines, PGEu and pyrogen were investigated with respect to the mechanism of Na+-Ca++ ratio in the posterior hypothalamus of the unrestrained cat. Guide tubes were implanted bilaterally above the posterior hypothalamic area of 23 cats so as to accommodate push-pull cannulae. After a Na+ or Ca++ sensitive site was identified by perfusion at 50 mul/min of an artificial CSF containing 10.4 mM excess Ca++ ions or 13.6 mM excess Na+ ions, several types of experiments were undertaken with the results summarized as follows: if the cat was exposed to a cold or warm environmental temperature as the posterior hypothalamus was perfused with excess cation, the typical hypothermia was produced by Ca++ and hyperthermia by Na+ ions. However, if the cat was exposed to peripheral cooling or warming 30 min prior to the perfusion, the fall or rise produced by Ca++ or Na+ was attenuated or prevented. In other experiments, 1.0 muCi 45Ca++ was injected in the ion sensitive site in the posterior hypothalamus to label stores of the cation. Raising of ambient temperature caused a retention of 45Ca++ in this hypothalmic area, whereas a cold environmental temperature enhanced the efflux of 45Ca++ at the same perfusion site. The magnitude of change in 45Ca++ efflux depended upon the intensity of the thermal challenge. Similarly, warming of the anterior hypothalmic, preoptic area by means of implanted thermodes caused an immediate diminution in 45Ca++ efflux in the posterior hypothalamus, whereas cooling of this anterior region augmented the extrusion of 45Ca++ ions from the posterior area. When substances which produce a temperature change were applied to the same thermosensitive zone, the direction of shift in 45Ca++ flux in the posterior area corresponded to the signal for heat production or heat loss. That is, the microinjection of 5-HT, PGE1 or Salmonella typhosa into the anterior hypothalamus enhanced the efflux of 45Ca++ in the posterior hypothalamus as hyperthermia developed, whereas a similar microinjection of norepinephrine reduced the 45Ca++ output from the same sites. Finally, locally anesthetizing the cells of the anterior hypothalamus by the nerve blocker, procaine, prevented the cold and heat-induced 45Ca++ eflux and retention, respectively. These results suggest that if the Na+-Ca++ ratio in the posterior hypothalamus establishes and maintains the set-point for body temperature of 37 degrees -38 degrees C, the mechanism of lability of Ca++ through changes in binding characteristics, transport, or metabolism of the cation serves two purposes: (1) the active defense of the set-point temperature through gradations in ion shifts; and (2) the upward or downward change in set-point value, pathological or normal, triggered by virtue of impulses relayed from the anterior hypothalamus.

Animals↗

Arachidonate-induced hydrocephalus and hyperthermia: "dilutional tolerance" to centrally injected pyrogen and PGE1.

Conscious, unrestrained cats given multiple injections of sodium arachidonate into a lateral cerebral ventricle responded with prolonged increases in both temperature. Development of tolerance was indicated by a gradual reduction in the response to successive doses. Cross-tolerance developed to hyperthermic actions of intraventricular bacterial endotoxin and prostaglandin E1 but not to leukocytic pyrogen given IV. Tolerance to the centrally administered agents was associated with enlargement of the cerebral ventricles and was therefore at least partially due to dilution of injected solutions by the increased volume of cerebrospinal fluid. The lateral ventricles were the most affected, particularly on the side of injection. There was no indication of physical obstruction within the ventricular system. Light microscopic examination revealed regions of chronic granulomatous inflammation of the subependymal zone of the periventricular tissues. The hydrocephalus was not secondary to the large number of intraventricular injections per se, to alkalinity of the arachidonate solution or to intermittent development of hyperthermia and was apparently a specific response to arachidonate. Intraventricular administration of arachidonate provides a means of inducing hydrocephalus with minimal morbidity and mortality.

Alprostadil↗

Comparison of R- and S-form lipopolysaccharides fractionated from Escherichia coli UKT-B lipopolysaccharide in pyrogen and Limulus tests.

Different LPS was shown to have a relatively different proportion of O-specific chain-less (R-form) LPS by polyacrylamide gel electrophoresis (PAGE) with sodium deoxycholate (DOC). By using DOC-PAGE, S-form LPS having O-chain with approximately 11 repeating units on average (S-Fr) and O-chain-less LPS (R-Fr) were separated from Escherichia coli UKT-B S-form LPS. Significantly stronger pyrogenicity was observed in R-Fr than in S-Fr when measured on the weight basis. Similar result was observed in Limulus test. Comparing biological activities of different S-form LPS, attention should be given to the amounts of co-existing R-form LPS.

Deoxycholic Acid↗

Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8.

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.

Animals↗

In vitro pyrogenicity of the diphtheria, tetanus and acellular pertussis components of a trivalent vaccine.

We have earlier found that a trivalent vaccine, containing antigenic components from both Gram-positive and Gram-negative bacteria, induced secretion of the endogenous pyrogen interleukin 6 (IL-6) when added to fresh human blood in vitro. The results of the present study showed that the IL-6 secretion was induced by toxoids derived from the Gram-positive bacterium Corynebacterium diphtheriae. However, fresh whole blood from different donors reacted differently to the stimulation. The blood from some donors induced secretion of large concentrations of IL-6, while the blood from other donors induced essentially no IL-6 secretion as a response to stimulation with diphtheria toxoid or a mixture of diphtheria and tetanus toxoids. Repeated testing over several years using blood from the same donor confirmed a donor-dependency of the reaction. This donor-dependency was only found for the toxoid, since blood from all donors reacted with approximately similar IL-6 production to stimulation by endotoxin from the Gram-negative bacterium Escherichia coli, known to be mediated via the toll-like receptor (TLR) 4. Also, no donor-dependecy was found to highly purified lipoteichoic acid from the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus, known to be mediated via TLR-2 and TLR-6. The receptors involved in stimulation by diphtheria toxoid are not known, but may differ from those used by endotoxin and lipoteichoic acid.

Antibodies, Bacterial↗

Pyrogenic reactions during haemodialysis caused by extramural endotoxin.

Between July 24 and Aug. 19, 1974, an outbreak of pyrogenic reactions occurred in patients at a private haemodialysis centre in a suburb of Washington, D.C. 49 reactions characterised by chills, fever, and hypotension occurred in twenty-three of the seventy patients dialysed during this period. No infections could be documented in any of the affected individuals. Despite the fact that only low levels of gram-negative bacterial contamination of the haemodialysis system were found, high levels of endotoxin contamination of dialysis fluid and endotoxaemia in patients experiencing overt reactions were recorded using the Limulus lysate test. The cause of these reactions was traced to an increase in endotoxin contamination of the tap water used to prepare dialysate, possibly caused by an increase in the algae levels in the local water source. The installation of a reverse osmosis system for water treatment may be a solution to the problem of endotoxin contamination of water used to prepare dialysis fluid.

Adult↗

Presence of streptococcal pyrogenic exotoxin A and C genes in human isolates of group G streptococci.

The bacteriophage-associated genes speA and speC encode streptococcal pyrogenic exotoxins of group A streptococci (GAS). Human isolates of group C and G streptococci (GCS and GGS) are commensals and the closest known genetic relatives of GAS; on occasion, GCS-GGS can cause infection that is clinically similar to GAS disease. Thirty-four human isolates of GCS-GGS were tested for speA and speC. Two GGS isolates harbored speA only, whereas a third GGS had both genes. All spe alleles found in GGS were identical to known spe alleles of GAS, except for one speA allele, which was unique. The presence of shared speA and speC alleles in GAS and GGS is highly suggestive of recent interspecies transfer. Acquisition of GAS-like virulence genes by GGS may lead to enhanced pathogenicity in this usually commensal-like organism.

Bacterial Proteins↗

Further analysis of ricin's pyrogenic effect.

Ricin (RIC) the toxic protein of castor oil seeds (Ricinus communis, Euphorbiaceae;) given intraperitoneally in sublethal doses causes fever in a dose-dependent manner in the following mammals: rabbit, cat, guinea pig, rat and vervet monkey. This hitherto unknown property of ricin calls attention to its use as a pyrogen-substance in the pharmacological screening of new antipyretic drugs.

Animals↗

Accumulation of unsaturated lipids in monocytes during early phase pyrogen tolerance.

This paper presents data that inspired a new explanation for the mechanism of early phase endotoxin tolerance. Rabbits injected intravenously with LPS from Salmonella abortus developed a two-phase fever (6 h) and monophasic hyperlipidemia of very low density lipoproteins (two consecutive days). If during these days rabbits were injected with the same dose of LPS at 24-h intervals, the second phase of fever disappeared, i.e. early phase pyrogenic tolerance was obtained. This was correlated with a decrease of lipoprotein hyperlipidemia (measured 1.5 h after LPS injection) and an accumulation of lipids rich in double bonds in monocytes (measured 3.5 h after LPS injection). Results showed that the degree of unsaturation of acyl chains (AC) in monocytes (AC/DB, DB=double bonds) is negatively correlated (r=-0.72) with fever response (fever index). The authors maintain that a gradual increase in monocyte membrane fluidity is an adaptation to repeated exposure of monocytes to lipid A and is responsible for the progressive desensitization of monocytes to endotoxin. It is suggested that disorders of this mechanism lead to an accumulation of abnormal quantities of saturated lipids and cholesterol within macrophages, which, as foam cells, are the starting point for atherosclerosis pathology.

Adipose Tissue↗

Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats.

Vagal afferent signals, have been implicated in cytokine mediated interactions between the periphery and the central nervous system. Studies in experimental animals have shown that cytokine induced activation of brain mediated responses to infection such as fever, sickness behaviour and pituitary-adrenal activation, are inhibited by subdiaphragmatic vagotomy. We have previously proposed that the peripheral signal to the brain in fever is of a humoral nature while others have suggested that either neural afferents or a mixture of both humoral and neural signals may be involved. The objective of the present study was to examine further the role of vagal transmission, in mediating the febrile response to a systemic injection of IL-1beta in rats and to compare this with changes in social exploration behaviour. Intraperitoneal injection of IL-1beta (1.0-30.0 microg/kg) inhibited social exploration in rats and this was attenuated in vagotomized animals. Injection of increasing concentrations of IL-1beta (0.1-1.0 microg/rat) induced significant (P<0.001) increases in core body temperature. However, in contrast to effects on social exploration, the increase in temperature was not inhibited by vagotomy at any of the doses used. These observations demonstrate a dissociation between the two brain mediated events, one of which is dependent on the integrity of the vagus nerve (social exploration) while the other (fever) is apparently generated by different mechanisms which may include circulating pyrogens.

Animals↗

The pyrogenic and mitogenic actions of interleukin-1 are related.

Our present understanding of the pathogenesis of fever is that host macrophages, following activation by an appropriate stimulus such as Gram-negative lipopolysaccharide (LPS) immune complexes, or primed lymphocytes in the presence of specific antigen, synthesize and release endogenous pyrogen (EP). EP is carried in the blood circulation to the hypothalamic area of the brain where its action, involving a protein synthetic step, results in an increase of the level at which body temperature is maintained. Recently, it was shown that EP is very similar and possibly identical to another macrophage mediator previously called lymphocyte activating factor and now known as interleukin-1 (IL-1) which, in conjunction with lectin or specific antigen, induces clonal expansion of T lymphocytes. We show here that murine T-cell proliferation in response to IL-1 in vitro is greatly increased when the cells are exposed to a temperature typical of fever and that injection of the same IL-1 causes fever in mice. If this relationship exists in vivo, the resulting facilitation of a T-cell-dependent immune response may well confer survival value and contribute to the evolutionary conservation of fever--a phylogenetically ancient response to infection.

Animals↗

Association of pyrogenic exotoxin genes with pharyngitis and rheumatic fever/rheumatic heart disease among Indian isolates of Streptococcus pyogenes.

AIM: To monitor the presence of various pyrogenic exotoxin genes in strains of Streptococcus pyogenes isolated in India. METHODS & RESULTS: Isolates recovered from pharyngitis (52) and rheumatic fever (RF)/ rheumatic heart disease (RHD) (8) patients were analysed for the presence of toxin genes, speA, speB and speF, by PCR. The specificity of the products was confirmed by restriction enzyme digestion and Southern hybridization. Among the 60 isolates studied, the incidence of speA, speB and speF were 5(8.3%), 56(93.3%) and 53(88.3%), respectively. The expression of these genes was established in representative isolates by RT-PCR. CONCLUSIONS: Comparative analysis of frequency of the speA, speB and speF genes, among pharyngitis and RF/RHD associated isolates, showed higher incidence in RF/RHD (25%, 100%,100%) as compared to pharyngitis patients (5.8%, 92.3%, 86.5%), respectively. SIGNIFICANCE OF STUDY: The presence of the speA gene, which is usually associated with scarlet fever or toxic shock-like syndrome, within few Indian isolates may be indicative of new virulent strains circulating within the Indian community. High distribution of toxin genes among RF/RHD compared to pharyngitis isolates indicate their possible role in increased virulence.

Adolescent↗

Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1.

Interleukin 1 (IL-1) is a cytokine released during immune activation that mediates the host's response to infection and inflammation. Peripheral and central injections of IL-1 induce fever and sickness behavior, including decreased food motivation and reduced interest in social activities. To determine the receptor mechanisms responsible for these effects, rats were injected with IL-1 receptor antagonist (IL-1ra), an endogenous cytokine that acts as a pure antagonist of IL-1 receptors. IL-1ra blocked the increased body temperature and oxygen consumption induced by injection of recombinant human IL-1 only when both cytokines were administered i.p. In contrast, i.p. or intracerebroventricular administration of IL-1ra blocked the depressive effect of IL-1 beta on food-motivated behavior and social exploration when this cytokine was administered by the same route as the antagonist. In addition, intracerebroventricular IL-1ra blocked the reduction in social exploration produced by i.p. IL-1 beta but had only partial antagonist effects on the decrease in food-motivated behavior induced by i.p. IL-1 beta. In each case, the dose of IL-1ra was 100- to 1000-fold in excess of the biologically active dose of IL-1. These results suggest that the receptor mechanisms that mediate the behavioral and pyrogenic effects of IL-1 are heterogeneous.

Animals↗