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PubMed1992

Distinct T-cell receptor V beta gene usage by human T lymphocytes stimulated with the streptococcal pyrogenic exotoxins and pep M5 protein.

A number of streptococcal products, including the streptococcal pyrogenic exotoxin (SPE) types A, B, and C as well as a 22-kDa fragment of M type 5 protein (pep M5), are potent stimulants of human T-lymphocyte blastogenesis and belong to the newly designated family of superantigens. The V beta usage of human T cells stimulated with these toxins was investigated by using the polymerase chain reaction. We demonstrate that SPE A, B, and C as well as pep M5 stimulate the proliferation of T cells in a dose-dependent manner. pep M5 stimulates cells bearing V beta 2, 4, and 8 elements of the T-cell receptor (TCR), whereas SPE A stimulates TCR V beta 2-, 12-, 14-, and 15-bearing cells. SPE B stimulated only cells expressing TCR V beta 8 elements, while SPE C stimulated cells expressing V beta 1, 2, 5.1, and 10. These studies reveal that the preferential usage of particular V beta elements is distinct for these different superantigens, which may be important in the pathogenesis of various streptococcal diseases.

Antigens, Bacterial↗
PubMed1992

Immune cell lethality induced by streptococcal pyrogenic exotoxin A and endotoxin.

Streptococcal pyrogenic exotoxin (SPE) A has many effects on the immune system, including immunolethality, which is characterized by a significant decrease in circulating immune cells as well as depletion of the spleen and lymph nodes prior to death of experimental animals. In this report, characterization of the mechanism of immunolethality has been undertaken. Synergistic induction of immunolethality was observed in vitro when human lymphocytes were treated with both SPE A and lipopolysaccharide (LPS). The same effect was demonstrated in the absence of a mitogenic response with the murine T-cell receptor, as well as in the absence of antigen-presenting cells and their secreted cytokines. The addition of antigen-presenting cells did not significantly affect lethality. SPE A directly interacted with LPS through interaction with ketodeoxyoctonate as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and iodinated exotoxin overlays. This interaction was demonstrated to be important for immunolethality, since simultaneous addition of SPE A and LPS was required, whereas sequential addition of SPE A and LPS did not result in lethality. LPS appeared to be acting, in part, to enhance the cell-binding ability of SPE A, since SPE A could only be detected in A.E7 cell membrane preparations after simultaneous incubation with SPE A and LPS.

Animals↗
PubMed1998

Mutational analysis of superantigen activity responsible for the induction of skin erythema by streptococcal pyrogenic exotoxin C.

Streptococcal pyrogenic exotoxin C (SPEC), when injected intradermally, induces erythema in unsensitized rabbits. In the present study, we examined whether this erythema induction is due to the T-cell stimulatory activity of SPEC as a superantigen. Analysis by using single-residue mutant SPECs indicated that mutant SPECs Y15I, A16E, and Y17I, in which tyrosine 15, alanine 16, and tyrosine 17 were replaced with isoleucine, glutamic acid, and isoleucine, respectively, exhibited significantly reduced mitogenic activity for Vbeta2(+) human T cells in vitro, and Y15I showed as much as a 1, 000-fold reduction. Y15I mutant SPEC, however, retained the ability to bind to major histocompatibility complex class II antigen and to form a homodimer, implying that residue 15 is critically important for the interaction of SPEC with T-cell antigen receptor beta chains. When injected intradermally into normal rabbits, wild-type SPEC induced a characteristic erythema after 3 h in a dose-dependent fashion, which was associated with polymorphonuclear and mononuclear cell infiltration. This erythema formation was found to be severely suppressed by systemic pretreatment with cyclosporin A, suggesting the involvement of host T cells. Y15I mutant SPEC exhibited nearly 1, 000-fold less erythema induction in vivo than wild-type SPEC. Altogether, the present results strongly suggest that erythema induction in rabbits by SPEC is attributable mostly to its T-cell stimulatory activity as a superantigen.

Amino Acid Sequence↗
PubMed1999

Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells.

Treatment of U937 human monocyte-like cells with Streptococcus pyogenes led to an induction of apoptosis in these cells. A comparison between the wild-type strain and its isogenic protease-negative mutant indicated that the production of streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, caused a greater extent of apoptosis in U937 cells. Further study using purified SPE B showed that this protease alone could induce U937 cells to undergo apoptosis, which was characterized by morphologic changes, DNA fragmentation laddering on the gel, and an increase in the percentages of hypodiploid cells. The protease activity of SPE B was required for apoptosis to proceed, since treatment with cysteine protease inhibitor E64 or heat inactivation abrogated this death-inducing effect. The SPE B-induced apoptosis pathway was interleukin-1beta converting enzyme (ICE) family protease dependent. Further experiments showed that the phagocytic activity of U937 cells was reduced by SPE B. Treatment with E64 and heat inactivation both abrogated this phagocytosis-inhibitory effect. Taken together, the present data show that SPE B not only possesses the ability to induce apoptosis in monocytic cells but also helps bacteria to resist phagocytosis by host cells.

Apoptosis↗
PubMed1999

Use of multiplex PCR to detect classical and newly described pyrogenic toxin genes in staphylococcal isolates.

Staphylococcus aureus may contain one or more genes that encode a variety of immunomodulatory pyrogenic toxins (PTs), including the staphylococcal enterotoxins and toxic shock syndrome toxin (TSST). The PTs interact with several cellular targets to produce disease, such as food poisoning and toxic shock syndrome. At present, nine serologically distinct enterotoxins and one immunoreactive form of TSST have been identified and characterized. As isolates of S. aureus are further assessed, it is anticipated that this number will increase. To facilitate screening, a multiplex PCR was designed to simultaneously determine which of these 10 currently known PT genes an individual S. aureus isolate possesses. We show here, using S. aureus isolates with characterized PT phenotypes, that this novel PCR technique reliably detects each of the known PTs in a single reaction.

Adult↗
PubMed1999

Invasive and noninvasive group A streptococcal isolates with different speA alleles in The Netherlands: genetic relatedness and production of pyrogenic exotoxins A and B.

Streptococcal pyrogenic exotoxin A (SPE-A) and SPE-B have been implicated in the pathogenesis of severe group A streptococcal (GAS) disease. We studied 31 invasive GAS strains including 18 isolates from patients with toxic shock syndrome and 22 noninvasive strains isolated in The Netherlands between 1994 and 1998. These strains were associated with the different allelic variants of the gene encoding SPE-A. We selected endemic strains with speA-positive M and T serotypes: speA2-associated M1T1 and M22-60T12 strains, speA3-associated M3T3 strains, and speA4-associated M6T6 strains. Since speA1-positive isolates were not frequently encountered, we included speA1 strains of different serotypes. The GAS strains were compared genotypically by pulsed-field gel electrophoresis and phenotypically by the in vitro production of SPE-A and SPE-B. All strains within one M and T type appeared to be of clonal origin. Most strains produced SPE-A and SPE-B, but only a minority of the speA4-positive isolates did so. Among our isolates, speA1- and speA3-positive strains produced significantly more SPE-A than speA2- and speA4-carrying strains, while SPE-B production was most pronounced among speA1- and speA2-containing strains. There was a marked degree of variability in the amounts of exotoxins produced in vitro by strains that shared the same genetic profile. We conclude that the differences in the in vitro production of SPE-A and SPE-B between our selected strains with identical M and T types were not related to either genetic heterogeneity or the clinical course of GAS disease in the patient from whom they were isolated.

Alleles↗
PubMed1982

Protein deficiency and endogenous pyrogen fever.

Blood monocytes have been shown to be a major source of endogenous pyrogen (EP), the protein mediator of fever. This study describes the effects of chronic dietary protein deficiency in rabbits on the in vitro production of EP by monocytes, the time course for the dietary effects on EP production, and the possible role for serum factors in the modification of EP production and (or) development of fever. EP harvested from rabbits on a protein-free diet for 4 weeks induced normal fevers when injected i.v. into recipient animals; EP produced from the protein-deprived rabbits after 6 and 8 weeks did not elicit fevers when bioassayed. Injection of EP supernatants derived from protein-deprived rabbits and containing standard protein serum resulted in less aberrant temperature responses than injection of EP supernatants containing sera from protein-deprived rabbits. These results suggest that: (i) the production of EP by rabbit blood monocytes is sensitive to dietary protein status, (ii) the effect of protein deficiency on EP production is a threshold phenomenon, and (iii) factors present in sera of protein-deprived rabbits may modify EP-induced fever.

Animals↗
PubMed1983

Effect of protein deficiency on endogenous pyrogen-mediated acute phase protein responses.

Endogenous pyrogen (EP) is known to trigger a rise in the plasma concentrations of various acute phase reactant proteins. This study describes the effects of chronic protein deficiency in rabbits on EP-mediated changes in the plasma concentrations of fibrinogen, albumin, and alpha 2-macroglobulin. Injection (i.v.) of EP from healthy donors into protein-deprived rabbits produced a smaller rise in plasma fibrinogen and alpha 2-macroglobulin, and a smaller fall in plasma albumin than injection of EP into controls. Injection of EP, obtained from malnourished donors, into healthy rabbits also resulted in an attenuation of the acute phase protein response. These data are consistent with the hypothesis that EP activity is influenced by the nutritional status of both the donor and recipient of EP.

Animals↗
PubMed1991

Interleukin-6 is a centrally acting endogenous pyrogen in the rat.

Intracerebroventricular (i.c.v.) injection of human recombinant interleukin-6 (IL-6; 20-100 ng) caused significant increases in colonic temperature and resting oxygen consumption (VO2) in conscious rats. These effects were prevented by pretreatment with a cyclooxygenase inhibitor (flurbiprofen, 1 mg/kg, i.p.) or a corticotrophin-releasing factor antagonist (alpha-helical CRF9-41, 25 micrograms, i.c.v.). Higher doses of IL-6 (i.c.v.) caused only small changes in VO2 and temperature, and very high doses given intravenously (i.v.) (4 micrograms/kg) were required to stimulate these parameters. Central injection of anti-rat IL-6 antibody inhibited the effects of interleukin-1 beta (i.c.v.) or endotoxin injection (i.p.) on colonic temperature and VO2 in conscious rats. These data indicate that IL-6 is an important endogenous pyrogen that acts within the central nervous system.

Animals↗
PubMed2005

Central endothelin ET(B) receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat.

Blockade of central endothelin ET(B) receptors inhibits fever induced by LPS in conscious rats. The contribution of ET(B) receptor-mediated mechanisms to fever triggered by intracerebroventricular IL-6, PGE2, PGF(2alpha), corticotropin-releasing factor (CRF), and preformed pyrogenic factor derived from LPS-stimulated macrophages (PFPF) was examined. The influence of natural IL-1 receptor antagonist or soluble TNF receptor I on endothelin (ET)-1-induced fever was also assessed. The selective ET(B) receptor antagonist BQ-788 (3 pmol icv) abolished fever induced by intracerebroventricular ET-1 (1 pmol) or PFPF (200 ng) and reduced that caused by ICV CRF (1 nmol) but not by IL-6 (14.6 pmol), PGE2 (1.4 nmol), or PGF(2alpha) (2 nmol). CRF-induced fever was also attenuated by bosentan (dual ET(A)/ET(B) receptor antagonist; 10 mg/kg iv) but unaffected by BQ-123 (selective ET(A) receptor antagonist; 3 pmol icv). alpha-Helical CRF(9-41) (dual CRF1/CRF2 receptor antagonist; 6.5 nmol icv) attenuated fever induced by CRF but not by ET-1. Human IL-1 receptor antagonist (9.1 pmol) markedly reduced fever to IL-1beta (180 fmol) or ET-1 and attenuated that caused by PFPF or CRF. Murine soluble TNF receptor I (23.8 pmol) reduced fever to TNF-alpha (14.7 pmol) but not to ET-1. The results of the present study suggest that PFPF and CRF recruit the brain ET system to cause ET(B) receptor-mediated IL-1-dependent fever.

Animals↗
PubMed1989

Acute-phase response to endogenous pyrogen in rabbit: effects of age and route of administration.

Aspects of host defense, collectively called the acute phase response (APR), can be induced by central actions of cytokines. To determine whether aging alters this response, aged and young rabbits were given endogenous pyrogen (EP), a crude preparation containing interleukin 1 and other cytokines, via an intracerebroventricular cannula. Arterial blood was sampled before EP administration and 2, 4, and 24 h later. Measurements were made of changes in body temperature, white blood cells, neutrophils, concentration of antipyretic, anti-inflammatory peptide alpha-melanocyte stimulating hormone (alpha-MSH), corticosterone, and C-reactive protein (CRP) concentrations. EP caused greater fever and increases in corticosterone and CRP in young rabbits. EP-induced changes in circulating neutrophils did not show age-related differences. There was no significant change in alpha-MSH in either age group; thus only certain aspects of APR induced by central actions of EP were altered with aging. To determine whether changes in APR caused by peripherally administered cytokines are similar to those after central injection, young female rabbits were given EP by both routes. Although administration caused greater fever, increases in alpha-MSH and corticosterone concentrations and in neutrophil counts were greater after intravenous administration, perhaps the result of a combined influence on peripheral and central receptors. The EP-induced increase in circulating alpha-MSH is a new finding that indicates that this antipyretic and anti-inflammatory peptide is rapidly available to modulate host responses after challenge.

Acute-Phase Reaction↗
PubMed1990

Effects of pyrogen administration on temperature regulation in exercising rats.

To study the mechanism of rise in body temperature during exercise, endogenous pyrogen was administered to exercising rats. At rest and at a neutral ambient temperature (Ta) of 24 degrees C, intravenous injection of recombinant human interleukin 1 (IL-1, 40 micrograms/kg) produced a 0.5 degree C rise in rectal temperature (Tre) from 37.4 degrees C. At Ta of 34 degrees C, at which Tre was 38.6 degrees C, Tre rise in response to IL-1 was only 0.2 degree C greater than when saline was used. In the first series of exercise experiments, rats ran on a treadmill after IL-1 or saline injection at two different work intensities (estimated at 40 and 60% of maximal oxygen uptake) at 24 degrees C Ta. At either work intensity, the magnitude of Tre rise after IL-1 injection was approximately 0.5 degree C higher than after saline injection. Threshold Tre for tail vasodilation increased when IL-1 was injected. The difference in the threshold Tre between the IL-1 and saline conditions was 0.5 degree C at either work intensity. Evaporative heat loss was also suppressed and metabolic heat production facilitated when IL-1 was injected. In a second series of experiments, IL-1 was injected after Tre reached a steady state (38.5 degrees C) during exercise. After IL-1 injection Tre increased another 0.5 degrees C, but after saline injection Tre did not change. These results suggest that body temperature rise during exercise is not induced merely by an insufficient capability of dissipating heat and that the thermoregulatory set point is reset during exercise.

Animals↗
PubMed1999

Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice.

Fever is a phylogenetically ancient response that is associated with improved survival in acute infections. In endothermic animals, fever is induced by a set of pyrogenic cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, and IL-6] that are also essential for survival in acute infections. We studied the influence of core temperature on cytokine expression using an anesthetized mouse model in which core temperature was adjusted by immersion in water baths. We showed that raising core temperature from basal (36.5-37.5 degrees C) to febrile (39.5-40 degrees C) levels increased peak plasma TNF-alpha and IL-6 levels by 4.1- and 2. 7-fold, respectively, and changed the kinetics of IL-1beta expression in response to lipopolysaccharide challenge. TNF-alpha levels were increased predominantly in liver, IL-1beta levels were higher in lung, and IL-6 levels were widely increased in multiple organs in the warmer mice. This demonstrates that the thermal component of fever may directly contribute to shaping the host response by regulating the timing, magnitude, and tissue distribution of cytokine generation during the acute-phase response.

Animals↗
PubMed2000

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.

Animals↗
PubMed1987

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

To investigate the direct effects of endogenous pyrogen (EP) and prostaglandin E2 (PGE2) on the activity of neurons in the preoptic and anterior hypothalamic (PO-AH) region, single-unit activity was recorded from brain tissue slices prepared from the PO-AH region of guinea pigs. When EP was applied into the perfusate 18% of warm-responsive neurons decreased their activity, and 23% of warm-responsive neurons increased their activity. Most of the thermally insensitive neurons did not respond to EP. PGE2 inhibited 29% of warm-responsive neurons and facilitated 15% of them. Moreover, when EP and PGE2 were applied to the same neurons at different times, the same directions of changes in neuronal activity were observed in 72% of total neurons examined. These results suggest that EP and PGE2 change the neuronal activity of the thermoresponsive neurons in the PO-AH region involved in fever induction. However, by these results, the direction of neuronal response induced by these substances could not be generally categorized based on the thermoresponsiveness of the individual neuron.

Animals↗
PubMed1989

Enhancement of the febrile responses of rats to endogenous pyrogen occurs within the OVLT region.

The febrile responses of male Sprague-Dawley rats to a semi-purified endogenous pyrogen (EP) derived from human monocytes are markedly enhanced 3 days after the animals are intravenously injected with a variety of immunoadjuvants. The present study was designed to investigate the site within the body at which these substances act to produce this febrile-enhancing phenomenon. Stainless steel microinjection cannula guide tubes were implanted within the region of the organum vasculosum lamina terminalis (OVLT) of the rats and control febrile dose-response curves to EP were established. Minute quantities of the immunoadjuvants zymosan, lipopolysaccharide endotoxin, and the synthetic adjuvant peptide, muramyl dipeptide, were microinjected into the OVLT region and 3 days later, the febrile responses of the animals were retested. In each case the febrile response elicited by a standard dose of EP was more than doubled, the slope of the fever dose-response curve was tripled, and the dose threshold was lowered by a factor of four to five. These responses are identical with those produced when much larger amounts of these immunoadjuvants are injected intravenously, and, thus, we conclude that the site of action of these substances in enhancing fever in response to EP resides in or near the OVLT region. It is proposed that EP stimulates a type of reticuloendothelial cell residing within the OVLT to release prostaglandin E, which in turn crosses the blood-brain barrier to effect the changes in the thermoregulatory neurons of the preoptic anterior hypothalamic area that result in fever.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits.

We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30-60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.

Alprostadil↗
PubMed1991

Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats.

We have demonstrated that the Ca2+ channel blocker verapamil, administered intravenously, exerts an antipyretic effect on the febrile responses of rats to intravenously injected endogenous pyrogen (EP). We have also shown that the same intravenous dose of verapamil is ineffective in blocking fevers induced by the microinjection of exogenous prostaglandin E (PGE) into the organum vasculosum laminae terminalis (OVLT) of rats. Experiments were conducted to determine whether the site of this verapamil antipyresis was in the OVLT itself. The febrile responses of six male Sprague-Dawley rats to EP were determined at thermoneutrality. Verapamil (10 micrograms/rat) was microinjected directly into the OVLT, and the febrile responses to the EP dose were redetermined 15-30 min later. In every case the EP fevers were attenuated after verapamil pretreatment. Intra-OVLT injections of verapamil alone were without effect on body temperature. When the same dose of verapamil was injected into the OVLT 15 min before the injection of PGE into the same site, it had no effect on the ensuing PGE-induced fever. In view of the fact that less than 1/250th of the effective systemic dose of verapamil, when injected into the OVLT, was equally effective in blocking the EP fevers, we conclude that verapamil acts within the OVLT to block fever rather than peripherally. Furthermore, because verapamil administered into the OVLT does not block PGE fevers, it is unlikely that PGE produces fever by acting as a Ca2+ ionophore on hypothalamic neurons.

Animals↗