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PubMed1984

Chemotactic cytokines: the role of leukocytic pyrogen and epidermal cell thymocyte-activating factor in neutrophil chemotaxis.

Macrophage-derived leukocytic pyrogen (LP) is thought to be similar if not identical to interleukin 1 (IL 1). In addition to macrophages, keratinocytes produce a factor that has similar biologic and biochemical characteristics to IL 1, called epidermal cell thymocyte-activating factor (ETAF). Because many diseases affecting the skin are characterized by infiltration of polymorphonuclear leukocytes (PMN) and some of these disorders are associated with fever, we investigated whether ETAF like LP had pyrogenic activity, and whether ETAF or LP were chemoattractants. ETAF or LP purified by column chromatography and isoelectric focusing were found to have chemotactic activity for PMN. The fractions containing maximal chemotactic activity corresponded to maximal fever-inducing activity and maximum thymocyte-activating activity. Furthermore, the chemotactic activity of ETAF and LP could be blocked by an antibody directed against LP. The results of this study indicate that these mediators, which arise from distinct cell populations, are closely related and may play a vital role in skin as well as distant inflammatory and immunologic events.

Animals↗

PubMed1964

PATHOGENESIS OF INFLAMMATION. I. THE PRODUCTION OF AN INFLAMMATORY SUBSTANCE FROM RABBIT GRANULOCYTES IN VITRO AND ITS RELATIONSHIP TO LEUCOCYTE PYROGEN.

Material obtained from the in vitro incubation of granulocytes from saline-induced peritoneal exudates of rabbits has been shown to produce inflammation and fever in rabbits. The supernatant material from cells incubated in saline has been termed granulocytic substance (GS) and is heat-labile. Its production is temperature dependent, occurring at 37 degrees C but not at 4 degrees C, requires viable cells, and is inhibited by potassium ions. A similar material is liberated when cells are incubated in a more physiologic medium. Freezing and thawing of granulocytes does not release GS and the active principle cannot be obtained from the incubation of lymphocytes. GS produces a delayed inflammatory response as measured by leucocyte sticking and emigration in the rabbit ear chamber and the leakage of protein-conjugated dye at the site of intradermal injection. The former response can be accurately quantitated by calculation of the inflammatory index from reactions observed in the ear chamber. The inflammatory reaction and the properties of GS distinguish it from a variety of previously described mediators of inflammation, but GS appears to be identical with leucocytic pyrogen. The possible role of GS in delayed and protracted inflammation and its relationship to the pathogenesis of fever are discussed.

Animals↗

PubMed2002

Comparison and validation of novel pyrogen tests based on the human fever reaction.

The Limulus amoebocyte lysate (LAL) test has replaced about 80% of the use of the rabbit pyrogen test. Ideally, human-based in vitro tests are needed, to replace the remaining use of the rabbit test and the use of the LAL test. The progress of an EU-funded project is described, in which a number of in vitro tests, based on the human fever reaction are passing through a prevalidation study on the way to evaluation in a formal validation study.

Animal Testing Alternatives↗

PubMed1996

Definition of the mitogenic factor (MF) as a novel streptococcal superantigen that is different from streptococcal pyrogenic exotoxins A, B, and C.

Human T cell activation by recombinant mitogenic factor (rMF) was investigated in comparison with that by recombinant streptococcal pyrogenic exotoxins (rSPE) A, B, and C. Recombinant MF, rSPEA, and rSPEC were mitogenic for peripheral blood mononuclear cells (PBMC), whereas rSPEB was not. Recombinant MF required only HLA-DR for the stimulation of PBMC, as determined using monoclonal antibodies (mAb) to HLA class II molecules and the mouse L cells transfected with HLA class II molecules. Recombinant SPEA and rSPEC required HLA-DR or HLA-DQ molecule. Recombinant MF selectively stimulated V beta 2, V beta 7, V beta 8, V beta 18 and V beta 21-bearing T cells, whereas rSPEA and rSPEC activated V beta 2 and V beta 6-bearing T cells as evaluated by the quantitative T cell receptor (TCR) analytical method. No clonality was observed in the nucleotide sequences of complementarity determining region 3 of TCR V beta in T cells responding to rMF. The profiles of cytokine production by PBMC in response to rMF, rSPEA, and rSPEC were quite similar. In summary, these results demonstrate that both HLA class II molecules and the TCR V beta required for rMF-mediated T cell activation are distinct from those required for rSPEA or rSPEC-mediated activation. Therefore, the MF is a novel streptococcal super-antigen which is different from SPEA, SPEB, and SPEC.

Bacterial Proteins↗

PubMed1990

Preparative separation of pyrogens from proteins by isoelectric focusing using a multicompartment electrolyser with Immobiline membranes.

Due to the nature of lipopolysaccharide endotoxin structures of bacterial pyrogens, their removal from solutions containing therapeutic proteins is often a problem in the pharmaceutical industry. In this report we describe the application of electromotive force to dislodge lipopolysaccharide endotoxins from proteins. This was performed by employing a multicompartment electrolyzer fitted with Immobiline membranes of specified pIs. A thousand-fold reduction of endotoxin could be achieved in the model test system described. This contribution describes the use of a new recycling isoelectric focusing approach without the use of carrier ampholytes.

Isoelectric Focusing↗

PubMed1998

Identification of domains involved in superantigenicity of streptococcal pyrogenic exotoxin F (SpeF).

A series of 11 synthetic peptides of 30 amino acids, each with 10 amino acids overlap which spanned the entire sequence of streptococcal pyrogenic exotoxin F (SpeF), were employed in proliferation studies on human peripheral blood mononuclear cells (PBMCs). Regions 41-70, 141-170 and 181-210 were identified as important for SpeF-induced lymphocyte activation. Secondary structure predictions of these peptides showed similarities to regions in other superantigens known to be important for T cell mitogenicity. Furthermore, antisera specific to peptides covering amino acids 1-70 and 181-228 were able to inhibit SpeF-induced mitogenicity by 25% when pre-incubated with SpeF prior to PBMC activation.

Adjuvants, Immunologic↗

PubMed1987

Dexamethasone pre-treatment is antipyretic toward polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen.

The effect of intravenously injected dexamethasone on the febrile response of rabbits to Polyinosinic: Polycytidylic acid (Poly I:C), lipopolysaccharide (LPS) and interleukin 1/endogenous pyrogen (IL1/E.P.) was studied. Dexamethasone (1 mg/kg) attenuated the febrile response to Poly I:C (5 micrograms/kg) but only if administered between 0.5 to 2 h before Poly I:C. If it was given after Poly I:C this resulted in a potentiation of the fever. Antagonism of the febrile response to Poly I:C by dexamethasone pre-treatment was dose-dependent and a maximal effect was observed with 3 mg/kg, a higher dose (6 mg/kg) resulted in a lesser effect on the Poly I:C fever. DEX injected alone (0.5-6 mg/kg) did not have any effect on body temperature. Fevers in response to LPS (50 ng/kg) and IL1/E.P. were also attenuated by dexamethasone. It is concluded that Poly I:C, LPS and IL1/E.P. induce fever by a common mechanism which is either directly or indirectly inhibited by dexamethasone.

Animals↗

PubMed1994

Major histocompatibility complex class II binding site for streptococcal pyrogenic (erythrogenic) toxin A.

Streptococcal pyrogenic exotoxin A (SPEA) is an important pathogenicity factor of group A streptococci. It is a member of the family of "superantigens" produced by Staphylococcus aureus and Streptococcus pyogenes and its T lymphocyte stimulating activity is involved into the pathogenesis of certain diseases caused by pyogenic streptococci. In this study we have produced and characterized recombinant SPEA molecules in Escherichia coli. These molecules are indistinguishable from natural SPEA in both T cell stimulatory and HLA class II binding activities. Human class II molecules are more efficient than mouse class II molecules in presenting SPEA to T cells. In binding tests to major histocompatibility complex class II-positive cells SPEA competes with staphylococcal enterotoxin B and A but not with toxic shock syndrome toxin-1.

Animals↗

PubMed1988

Cloning and characterization of the gene, speC, for pyrogenic exotoxin type C from Streptococcus pyogenes.

The structural gene of streptococcal pyrogenic exotoxin type C (SPE C) was cloned from the chromosome of Streptococcus pyogenes strain T18P into Escherichia coli using pBR328 as the vector plasmid. Subcloning enabled the localization of the gene (speC) to a 1.7 kb fragment. Partially purified E. coli-derived SPE C and purified streptococcal-derived SPE C, were shown to have the same molecular weight (23,800) and biological activities. A DNA probe, prepared from cloned speC, cross-hybridized with the structural genes of SPE A and SPE B indicating relatedness at the nucleotide level. The speC-derived probe also hybridized to a fragment of CS112 bacteriophage DNA containing the phage attachment site.

Bacterial Proteins↗

PubMed1992

Production of pyrogenic exotoxins in group A streptococci isolated from patients in Zagreb, Croatia.

The pyrogenic exotoxin profiles were determined of group A streptococci isolated from patients in Zagreb, Croatia in the period 1989-1990. A total of 12 strains were studied, five from patients with serious infections and seven from patients with uncomplicated infections. Serotypes M1 and M3 were found in seven (58%) patients. Seven strains produced exotoxin A and ten strains exotoxin B. The proportion of exotoxin A and B producing strains in patients with severe infections (3 patients respectively) was similar to that found in patients with uncomplicated infections (4 and 7 patients respectively).

Adult↗

PubMed1976

On the mechanism of pyrogenic action of ricin.

The incubation of rabbit white blood cells with ricin, the toxic protein of castor oil seeds, leads to the production of endogenous pyrogens. This induction can be inhibited by the antibiotics actinomycin D or cycloheximide. The results are discussed in terms of disturbed corticosteroid- and Mg2+-levels.

Animals↗

PubMed1979

Influence of antilymphocyte and antipolymorphonuclear sera on the pyrogenic effect of scarlet fever toxin.

The role played by lymphocytes in the pyretic response to scarlet fever toxin (ET) was studied in vivo using antilymphocyte serum (ALS). Two i.v. injections of ALS inhibited the pyretic response to a subsequent ET injection in rabbits. The course of endotoxin fever remained uninfluenced by ALS. Antipolymorphonuclear serum had no effect on the pyretic response to either of the toxins. Pretreatment with ALS also inhibited the skin reaction after i.d. injection of ET. These findings are further evidence a mediating role of lymphocytes in the biological effects of ET, among other things in the release of endogenous pyrogen.

Animals↗

PubMed2005

Release of TNF-alpha and IL-1beta from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin.

BACKGROUND: Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. OBJECTIVE: To determine if the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. RESULTS: Release of TNF-alpha and IL-1beta after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release.NF-kappaB expression, a transcriptional regulator for TNF-alpha and IL-1beta genes, corresponded to this secretion pattern. TNF-alpha release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1beta required 6 hours (p = 0.0009). CONCLUSION: Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-alpha.

Amphotericin B↗

PubMed2000

Involvement of CRH in fever induced by a distinct pre-formed pyrogenic factor (PFPF).

OBJECTIVE: This study investigated the role of corticotrophin-releasing hormone (CRH) in mediating the fever induced by a novel pre-formed pyrogenic factor (PFPF), using a CRF antagonist in vivo and evaluating the capacity of PFPF to stimulate CRH release from the hypothalamus in vitro. MATERIALS AND METHODS: Male Wistar rats were used. The PFPF, induced following brief incubation of rat peritoneal macrophages with LPS and retained on 10 or 20 kDa MW cut-off membranes, was injected intracerebroventricularly. Fever was monitored using a rectal probe. Hypothalamus tissue was incubated with PFPF to establish its ability to induce CRH release. The CRH was measured by ELISA. RESULTS: PFPF induced a dose-dependent fever that was abolished by boiling or pronase treatment. Whereas both dexamethasone and indomethacin were effective in reducing interleukin- (IL) 1beta-induced fever, only dexamethasone abolished the fever induced by PFPF. The CRH antagonist, a-helical CRH9-41, abolished the fever induced by synthetic CRH, IL-8 and PFPF but not tumour necrosis factor-a (TNF-alpha). Like IL-1, PFPF was able to induce the release of CRH from rat hypothalamic tissue in vitro. CONCLUSIONS: These results suggest that the fever induced by PFPF depends on CRH release but not prostaglandin synthesis.

Animals↗

PubMed1994

Polyunsaturated fatty acids reduce pyrogen-induced tissue factor expression in human monocytes.

Endotoxin (LPS) and interleukin-1 beta (IL-1 beta) increased the expression of tissue factor, a membrane-anchored glycoprotein that initiates blood coagulation on the surface of cultured human umbilical vein endothelial cells (HUVEC) and human monocyte/macrophages. On monocyte/macrophages, oleic acid strongly inhibited LPS-induced tissue factor expression, a similar activity also being obtained with regard to the pyrogenic effects of IL-1 beta. Other polyunsaturated fatty acids such as linoleic or linolenic acid also reduced tissue factor expression whereas palmitic acid was ineffective. In contrast, these compounds showed no effect on LPS- or IL-1 beta-induced tissue factor expression in HUVEC when tested at the concentration of 10 microM. These data therefore suggest that the well-recognized antithrombotic and antiatherogenic effect of polyunsaturated fatty acids may in part be mediated through an inhibition of tissue factor expression in monocyte/macrophages.

Cell Line↗

PubMed1988

Comparative pyrogenic potency of endogenous prostanoids and of prostanoid-mimetics injected into the anterior hypothalamic/preoptic region of the cat.

In both pyrogen-induced fever and fever subsequent to acute hypothalamic trauma, pyrexia is believed to be mediated by cyclooxygenase products acting within the anterior hypothalamic/preoptic (AH/PO) region of the brain. The goal of the present study was to assess, through a potency analysis, the likely contributions of various prostanoids to pyrexia production. Prostanoids and prostanoid-mimetics were injected bilaterally into the AH/PO region of conscious, indomethacin pretreated cats, and partial dose-response curves for pyrexic activity were obtained. ED1 degrees doses (doses producing a 1 degree C fever) for PGE2, PGE1 and 6-keto-PGE1 (a metabolite of PGI2 and/or of the PGI2 hydrolysis product, 6-keto-PGF1 alpha) ranged between 2 and 15 pmol. PGF2 alpha and the stable PGI2-mimetics, iloprost and 6-beta-PGI1, required doses of 900-1100 pmol. PGD2 and 6-keto-PGF1 alpha had ED1 degrees doses of 2200-2400 pmol. PGI2, thromboxane (TX) B2 and the TXA2/PGH2-mimetics, SQ26655, 9,11-azo-PGH2 and U46619, were incapable of producing a 1 degrees C rise at the maximum dose of 30,000 pmol. The results offer no support for an involvement in fever of PGF2 alpha, PGD2, TXA2, TXB2, PGH2, PGI2 or 6-keto-PGF1 alpha. Only the 3 E-series prostaglandins were sufficiently potent to merit serious consideration as mediators of pyrexia. Of these, only PGE2 is known to be produced in abundance by cat brain; no information is available regarding PGE1 production, and our results with PGI2 and 6-keto-PGF1 alpha indicate that cat brain may not synthesize 6-keto-PGE1. The results thus suggest an important role for PGE2 in fever production in the cat and are compatible with an involvement of PGE1.

Animals↗

PubMed1988

Maturation of pyrogen-elicited fever in the kitten.

The febrile response to the endotoxin Salmonella typhosa was studied in developing kittens. We found that kittens younger than 30 days of age generated only a small rise in temperature in response to a standardized endotoxin challenge that consistently causes fever in adult cats. Some degree of febrile response was present at birth, but the dose of pyrogen necessary to elicit a fever was 10-15 times greater than that required in the adult. There was a gradual increase in both the magnitude and duration of fever as a function of age with the largest change occurring after 30 days of age. There was a direct relationship between the ability of the kitten to maintain its body temperature (Tbo) at the room ambient (Ta) and the magnitude of the elicited fever. However, increasing the Ta to thermoneutral (Ta = 30-32 degrees C) did not enhance the thermal response indicating that the failure to elicit the fever is not due to passive effects of Ta. These data suggest that the febrile response to an endotoxin develops over the first 6-7 weeks of the kitten's life and are discussed in relation to other physical variables of development.

Aging↗

PubMed1985

Purification of human interleukin 1 from human monocyte culture supernatants and identity of thymocyte comitogenic factor, fibroblast-proliferation factor, acute-phase protein-inducing factor, and endogenous pyrogen.

Human interleukin 1 (IL-1) in lipopolysaccharide and silica-stimulated human peripheral blood monocyte culture supernatants was purified to apparent homogeneity by sequential chromatography using DEAE-Sephacel, Sephacryl S-200, CM-high-performance liquid chromatography (HPLC), and hydroxyapatite-HPLC. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) yielded only one band detectable by silver staining with an apparent molecular weight (MW) of 19,000 under nonreducing conditions. IL-1 activity was eluted from a single site from PAGE performed in the absence of SDS. About 4.4 micrograms of IL-1 was purified from 5.0 liters of culture supernatant of lipopolysaccharide- and silica-stimulated human peripheral blood monocytes, with 46.6% recovery of biological activity. The specific activity of the purified IL-1 was 4.3 X 10(7) U/mg protein. Amino acid composition analysis of the purified human IL-1 was similar to that previously described for murine IL-1. The purified IL-1 exhibited the biological activities previously attributed to IL-1, including thymocyte comitogenic activity, fibroblast proliferation activity, acute-phase protein (haptoglobin)-inducing activity, and endogenous pyrogen activity.

Acute-Phase Proteins↗