RESUMEN
OBJECTIVE: Peripheral afferents play an important role in fever. In the present study, we investigated the role of capsaicin-sensitive afferents in fever and cytokine responses during systemic (induced by intraperitoneal lipopolysaccharide, LPS) and local (induced by injection of Freund's incomplete adjuvant, FIA, into the paw) inflammation. METHODS: Fevers in rats (8-10 weeks of age) whose capsaicin-sensitive afferents were depleted by neonatal capsaicin (50 mg/kg) treatment were compared to those of rats treated as neonates with vehicle. To investigate a possible involvement of cytokines, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured during LPS- and FIA-induced fever in rats after capsaicin-induced desensitization. Body temperature was measured by biotelemetry. IL-6 and TNF bioactivities in plasma were determined using bioassays. RESULTS: The initial but not the late phase of LPS (50 microg/kg)-induced fever was markedly higher (approximately 1.0 degree C) in rats whose capsaicin-sensitive neurons were destroyed by neonatal capsaicin treatment. Capsaicin-induced desensitization also resulted in significantly higher plasma levels of IL-6 and TNF 1 but not 4 h after LPS challenge. In contrast, the day after injection with FIA (0.1 ml), rats treated with capsaicin had significantly lower body temperatures compared with vehicle-treated animals. No differences were found in plasma levels of IL-6 and TNF between capsaicin- and vehicle-treated animals in response to FIA. CONCLUSIONS: These data indicate that the role of capsaicin-sensitive afferents in fever depends on the type of inflammatory response. During systemic inflammation, capsaicin-sensitive afferents may be involved in modulating fever by regulating the levels of pyrogenic cytokines. During local inflammation, the late phase of fever is partially mediated via capsaicin-sensitive afferents.
Asunto(s)
Capsaicina/farmacología , Citocinas/metabolismo , Fiebre/etiología , Inflamación/fisiopatología , Neuronas Aferentes/fisiología , Nociceptores/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Animales Recién Nacidos , Atrofia , Capsaicina/toxicidad , Citocinas/sangre , Desnervación , Conducta Exploratoria/fisiología , Fiebre/fisiopatología , Pie , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/toxicidad , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/inmunología , Inyecciones Intraperitoneales , Interleucina-6/sangre , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/toxicidad , Pulmón/inervación , Pulmón/patología , Neuronas Aferentes/efectos de los fármacos , Peritonitis/inducido químicamente , Peritonitis/complicaciones , Peritonitis/inmunología , Peritonitis/fisiopatología , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/análisis , Vejiga Urinaria/inervación , Vejiga Urinaria/patologíaRESUMEN
We have previously reported that heat conditioning augments lipopolysaccharide (LPS)-induced fever in rats, which is accompanied by an accumulation of heat shock protein (HSP) in the liver and the reduction of the plasma level of tumor necrosis factor (TNF-alpha) (Kluger MJ, Rudolph K, Soszynski D, Conn CA, Leon LR, Kozak W, Wallen ES, and Moseley PL. Am J Physiol Regulatory Integrative Comp Physiol 273: R858-R863, 1997). In the present study we have tested whether inhibition of protein synthesis in the liver can reduce the effect of this heat conditioning on the LPS-induced febrile response in the rat. D-galactosamine (D-gal) was used to selectively inhibit liver protein synthesis. D-gal (500 mg/kg) or PBS as control was administered intraperitoneally 1 h before heat stress. LPS (50 microg/kg ip) was injected 24 h post-heat exposure. Treatment with D-gal blunted the febrile response to LPS. Moreover, heat-conditioned rats treated first with D-gal and subsequently with LPS demonstrated a profound fall in core temperature 10--18 h post-LPS. A significant increase of serum TNF-alpha accompanied this effect of D-gal on fever. Heat-conditioned animals receiving D-gal showed an inhibition in inducible HSP-70 in the liver. These data support the role of hepatic function in modulating the febrile response to LPS.
Asunto(s)
Fiebre/fisiopatología , Galactosamina/farmacología , Proteínas HSP70 de Choque Térmico/biosíntesis , Calor , Lipopolisacáridos/toxicidad , Hígado/metabolismo , Animales , Fiebre/sangre , Fiebre/inducido químicamente , Proteínas del Choque Térmico HSC70 , Interleucina-6/sangre , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/fisiopatología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Subclinical, repeated exposures of F344 rats to sarin resulted in brain alterations in densities of chlonergic receptor subtypes that may be associated with memory loss and cognitive dysfunction. The exposures also depressed the immune system. The rat appears to be a good model for studying the effects of subclinical exposure to a nerve gas.
Asunto(s)
Sustancias para la Guerra Química/efectos adversos , Trastornos del Conocimiento/etiología , Trastornos de la Memoria/etiología , Síndrome del Golfo Pérsico , Receptores Colinérgicos/análisis , Sarín/efectos adversos , Animales , Autorradiografía , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Sistema Inmunológico/efectos de los fármacos , Exposición por Inhalación , Ratas , Ratas Endogámicas F344 , Receptores Colinérgicos/efectos de los fármacosRESUMEN
In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 microg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 microg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11, 12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.
Asunto(s)
Sistema Enzimático del Citocromo P-450/fisiología , Fiebre/fisiopatología , Analgésicos no Narcóticos/farmacología , Animales , Sistema Enzimático del Citocromo P-450/farmacología , Eicosanoides/farmacología , Fiebre/inducido químicamente , Inyecciones Intraventriculares , Lipopolisacáridos , Masculino , Isoformas de Proteínas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Interleukin (IL)-11 is a member of the gp130 family of cytokines. In contrast to IL-6 (another gp130 cytokine), IL-11 does not induce fever in humans. In the present study, the effect of recombinant human IL-11 (hrIL-11) injected intracerebroventricularly on body temperature of afebrile and febrile rats was studied. Results showed that: (i) hrIL-11 in doses of 5, 50 and 500 ng injected into the cerebral ventricles does not alter body temperature in rats; (ii) febrile response induced by intraperitoneal injection of E. coli endotoxin (50 microg/kg) was initiated more rapidly in rats injected with 500 ng of hrIL-11 in the cerebral ventricles, and (iii) the enhancement of the initial phase of fever induced by hrIL-11 was not accompanied by changes in plasma concentrations of IL-6 and tumor necrosis factor (TNF). These results indicate that hrIL-11 is not pyrogenic when administered into the brain ventricles. The data obtained also demonstrate that central application of hrIL-11 alters body temperature in conditions of pyrogenic stimulation, but that this effect is not due to the alterations in plasma concentrations of IL-6 or TNF. These data suggest that during the development of the systemic inflammatory response, activation of gp130 subunit becomes effective in altering body temperature.
Asunto(s)
Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/inmunología , Fiebre/inmunología , Interleucina-11/farmacología , Animales , Fiebre/inducido químicamente , Células Híbridas , Hipotálamo/fisiología , Inyecciones Intraventriculares , Interleucina-6/sangre , Lipopolisacáridos , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Organismos Libres de Patógenos Específicos , Tercer Ventrículo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
This review summarizes recent studies on endogenous antipyretic mechanisms. Fever is the result of a balance between pyrogenic and cryogenic cytokines and hormones. Although there is considerable evidence that fever evolved as a host defense response, it is important that the rise in body temperature not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified during the last 25 years. These include alpha-MSH, arginine vasopressin, glucocorticoids, TNF (under certain circumstances), and IL-10. Most recently, evidence has accumulated that cytochrome P-450 (P-450), part of the alternative pathway for arachidonic acid metabolism, plays an important role in reduction of fever and inflammation. Supporting a role for P-450 in endogenous antipyresis and antiinflammation includes evidence that (1) inducers of P-450 reduce fever, (2) inhibitors of P-450 cause a larger fever, (3) and P-450 arachidonic acid metabolites reduce fever.
Asunto(s)
Fiebre , Fiebre/inmunología , Homeostasis , Humanos , Inflamación , NeuroinmunomodulaciónRESUMEN
BACKGROUND: The mechanism and clinical relevance of increased core temperature (Tc) after surgery are poorly understood. Because fever is used as a diagnostic sign of infection, it is important to recognize what constitutes the normal postoperative thermoregulatory response. In the current study the authors tested the hypothesis that a regulated increase in Tc setpoint occurs after surgery. METHODS: The authors prospectively studied 271 patients in the first 24 h after a variety of vascular, abdominal, and thoracic surgical procedures. Tc measured in the urinary bladder, skin-surface temperatures, thermoregulatory responses (vasoconstriction and shivering), and total leukocyte counts were assessed. In a subset of 34 patients, plasma concentrations of tumor necrosis factor, interleukin (IL)-6, and IL-8 were measured before and after surgery. RESULTS: In the early postoperative period, the maximum increase in Tc above the preoperative baseline averaged 1.4 +/- 0.8 degrees C (2.5 +/- 1.4 degrees F), with the Tc peak occurring 11.1 /- 5.8 h after surgery. Fifty percent of patients had a maximum Tc greater than or equal to 38.0 degrees C (100.4 degrees F) and 25% had a maximum Tc greater than or equal to 38.5 degrees C (101.3 degrees F). The progressive postoperative increase in Tc was clearly associated with cutaneous vasoconstriction and shivering, indicating a regulated elevation in Tc setpoint. The elevated Tc was associated with an increased IL-6 response but not with leukocytosis. Maximum postoperative Tc was positively correlated with duration and extent of the surgical procedure. CONCLUSIONS: A regulated elevation in Tc setpoint (fever) occurs normally after surgery. The association between Tc elevation, extent and duration of surgery, and the cytokine response suggests that early postoperative fever is a manifestation of perioperative stress.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Fiebre/fisiopatología , Procedimientos Quirúrgicos Operativos , Anciano , Análisis de Varianza , Biomarcadores/sangre , Femenino , Fiebre/sangre , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Recuento de Leucocitos , Masculino , Tiritona/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , VasoconstricciónRESUMEN
Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or 'open field.' The beta-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these beta-antagonists discriminates between subtypes of beta-receptors. The purpose of this study was to determine the relative contribution of the different beta-receptor types to stress fever using beta1-, beta2-, and beta3-receptor subtype selective antagonists (atenolol [beta1], ICI-118551 [beta2], and SR 59230A [beta3]) and agonists (dobutamine [beta1], salbutamol [beta2], and BRL 37344 [beta3]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system beta-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the beta3-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective beta2-agonist, salbutamol, and the beta3-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by beta-blockers may be due to the sedative actions of these drugs.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Fiebre/fisiopatología , Receptores Adrenérgicos beta/fisiología , Estrés Psicológico/fisiopatología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Atenolol/farmacología , Regulación de la Temperatura Corporal/efectos de los fármacos , Fiebre/etiología , Inyecciones Intraventriculares , Masculino , Propanolaminas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos beta 1/efectos de los fármacos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Estrés Psicológico/complicacionesRESUMEN
Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 microgram/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 microgram/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-alpha, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fisher's exact test, P < 0.05). Fever in response to the injection of turpentine (100 microliter/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Fiebre/fisiopatología , Interleucina-10/farmacología , Lipopolisacáridos , Animales , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Interleucina-10/genética , Interleucina-6/sangre , Irritantes , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Proteínas Recombinantes , Factor de Necrosis Tumoral alfa/análisis , TrementinaRESUMEN
Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30 degreesC ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 micrograms/kg to 2.5 mg/kg. Phenidone (20-30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1-10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10-20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.
Asunto(s)
Ácido Araquidónico/metabolismo , Regulación de la Temperatura Corporal/fisiología , Inhibidores de la Ciclooxigenasa/farmacología , Fiebre/fisiopatología , Inhibidores de la Lipooxigenasa/farmacología , Animales , Antioxidantes/farmacología , Temperatura Corporal , Regulación de la Temperatura Corporal/efectos de los fármacos , Clotrimazol/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Fiebre/inducido químicamente , Indometacina/farmacología , Lipopolisacáridos/toxicidad , Masculino , Masoprocol/farmacología , Ratones , Proadifeno/farmacología , Pirazoles/farmacología , Factores de Tiempo , Umbeliferonas/farmacologíaRESUMEN
Bacterial endotoxin induces fever by causing the release of interleukin (IL)-1beta into the circulation or the brain. IL-1beta is believed to mediate fever via triggering the production and/or release of IL-6 in the hypothalamus. The present study examined whether IL-1beta and IL-6 in the hypothalamus of the rat are also involved in fever during bacterial sepsis caused by cecal ligation and puncture (CLP). CLP induces fever for 2 days. Polyclonal rabbit antibody against rat IL-1beta (anti-IL-1beta, 2 microg/microl) or control rabbit IgG (2 microg/microl) was unilaterally microinjected into the hypothalamus of rats immediately after or 24 h after CLP or sham-CLP surgery. Anti-IL-1beta injected 24 h after CLP (when fever was already present) or sham-CLP surgery did not affect fever. Microinjection of anti-IL-1beta into the hypothalamus immediately after surgery caused a significant decrease in body temperature during the night after CLP surgery and a 48% reduction of fever on the following day. Although blood plasma levels of IL-6 were significantly elevated 1.5, 6, 24, and 48 h after CLP surgery, there were no differences in IL-6 concentrations in the extracellular fluid of the anterior hypothalamus (collected by push-pull perfusion). These data suggest that fever due to bacterial sepsis is initiated by IL-1beta within the hypothalamus, and this febrile response, unlike endotoxin-induced fever, is not accompanied by elevation in the hypothalamic concentration of IL-6.
Asunto(s)
Ciego/cirugía , Fiebre/fisiopatología , Hipotálamo/fisiopatología , Interleucina-1/fisiología , Sepsis/fisiopatología , Animales , Infecciones Bacterianas/etiología , Infecciones Bacterianas/fisiopatología , Ciego/microbiología , Fiebre/etiología , Hipotálamo/química , Hipotálamo/efectos de los fármacos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/análisis , Inyecciones Intraventriculares , Interleucina-1/administración & dosificación , Interleucina-1/antagonistas & inhibidores , Cinética , Ligadura , Masculino , Microinyecciones , Punciones , Conejos , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , Sepsis/etiología , Distribución TisularRESUMEN
Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-alpha signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Interleucina-6/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Sepsis/fisiopatología , Animales , Antígenos CD/metabolismo , Antígenos CD/fisiología , Regulación de la Temperatura Corporal/inmunología , Peso Corporal , Ciego , Cruzamientos Genéticos , Ingestión de Energía , Femenino , Hipotermia , Interleucina-6/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Sepsis/inmunología , Caracteres Sexuales , Análisis de Supervivencia , Factores de TiempoRESUMEN
Tobacco smoking may predispose humans to respiratory disease, and may be a compounding risk factor in HIV infection and progression to AIDS. We have demonstrated that chronic exposure of mice and rats to cigarette smoke or nicotine inhibits T cell responsiveness, which may account for the decreased antibody response to T-dependent antigens seen in these animals. This inhibition may result from aberrant antigen-mediated signaling and depletion of IP3-sensitive Ca2+ stores in nicotine-treated animals. Moreover, nicotine appears to moderate the inflammation associated with turpentine-induced sterile abscess and influenza infection. These anti-inflammatory properties of nicotine may account for longer survival of nicotine-treated than control mice lethally infected with influenza virus. However, because inflammation is required for clearance of many pathogens, nicotine-treated mice exhibit significantly higher titers of influenza virus following infection. These results offer an explanation for the higher susceptibility to some infectious diseases, but greater resistance to some inflammatory diseases among human smokers.
Asunto(s)
Inmunosupresores/farmacología , Nicotina/farmacología , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Absceso/inducido químicamente , Absceso/inmunología , Animales , Calcio/metabolismo , Fiebre/etiología , Virus de la Influenza A/efectos de los fármacos , Inositol 1,4,5-Trifosfato/metabolismo , Ratones , Infecciones por Orthomyxoviridae/inmunología , Neumonía Viral/inmunología , Ratas , Ratas Endogámicas Lew , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/fisiología , TrementinaRESUMEN
Nicotine (NT) treatment impairs T-cell receptor (TCR)-mediated signaling, leading to the arrest of T cells in the G1 phase of the cell cycle and inhibition of the antibody plaque-forming cell (AFC) response to sheep red blood cells (SRBC). This paper summarizes some of the previous findings related to cigarette smoke/NT and the immune response, and presents preliminary evidence suggesting that mice chronically treated with NT (0.5 mg/day/kg body weight) have a depressed inflammatory response in the turpentine-induced abscess model of inflammation. This ability of nicotine to attenuate an inflammatory response may also be the cause of reduced mortality of chronically nicotine-treated mice from acute influenza A pneumonitis. Moreover, in LEW rats, decreased anti-SRBC AFC responses were also observed after intracerebroventricular (i.c.v.) administration of relatively small concentrations of NT (28 micrograms/day/kg body weight) which, when given peripherally, did not affect the AFC response. In vitro the addition of NT to T cells increased protein tyrosine kinase (PTK) activity and intracellular Ca2+ concentration [Ca2+]i. These results support the hypothesis that NT alters immune responses by directly interacting with T cells, as well as indirectly through brain-immune interactions.
Asunto(s)
Sistema Inmunológico/efectos de los fármacos , Inmunidad/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Absceso/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacología , Temperatura Corporal/efectos de los fármacos , Calcio/metabolismo , Técnica de Placa Hemolítica , Virus de la Influenza A , Inyecciones Intraventriculares , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/fisiopatología , Proteínas Tirosina Quinasas/metabolismo , Ratas , Ratas Endogámicas Lew , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Exposure to an open field has been shown to cause a rise in the body temperature of rats. In many respects, this rise in body temperature is similar to fevers caused by endotoxin and other inflammatory stimuli. Rats repeatedly injected with endotoxin develop tolerance to the fever-inducing action of endotoxin. We hypothesized that repeated pretreatment with endotoxin would modify the fever caused by exposure to psychological stress. To test this hypothesis, we compared open field-induced fevers in rats made endotoxin tolerant to those rats not endotoxin tolerant. We found that endotoxin tolerance had no effect on open field fevers.
Asunto(s)
Endotoxinas/toxicidad , Ambiente , Fiebre/fisiopatología , Lipopolisacáridos/toxicidad , Estrés Psicológico/fisiopatología , Animales , Temperatura Corporal/fisiología , Tolerancia a Medicamentos , Fiebre/etiología , Manejo Psicológico , Inyecciones Intraperitoneales , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/complicacionesRESUMEN
1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques. 2. Interleukin (IL)-1beta appears to be critically involved in fever caused by some routes of infection/inflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL-1beta-induced fevers in knockout mice appear to be via the induction of IL-6, similar to LPS-induced fevers in rats. Interleukin-6 also appears to be critically involved in turpentine-induced fever. 3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture. 4. The roles of these cytokines in fevers induced by injection of LPS, IL-1beta, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatory/infectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.
Asunto(s)
Citocinas/genética , Citocinas/fisiología , Fiebre/genética , Fiebre/fisiopatología , Ratones Noqueados/genética , Ratones Noqueados/fisiología , Animales , Ratones , RatasRESUMEN
Exposure to heat stress leads to both short-term and long-term effects on morbidity. Male rats were exposed to a high ambient temperature of 40 degrees C, which resulted in biotelemetered core body temperature rising to approximately 42 degrees C. This treatment led to a marked enhancement in lipopolysaccharide (LPS)-induced fever at 24 h after exposure to heat stress. The increase in fever was accompanied by a significant suppression in the circulating concentration of tumor necrosis factor. Heat-shock protein-70 measured in liver was elevated by the heat exposure (but not further elevated by the injection of LPS). An enhanced fever to LPS and other inflammatory stimuli found in heat-stressed human subjects could explain the apparent increase in susceptibility to disease.
Asunto(s)
Regulación de la Temperatura Corporal , Fiebre/fisiopatología , Lipopolisacáridos/toxicidad , Estrés Fisiológico/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Temperatura Corporal , Peso Corporal , Corticosterona/sangre , Escherichia coli , Fiebre/sangre , Fiebre/inducido químicamente , Proteínas HSP70 de Choque Térmico/biosíntesis , Calor , Humanos , Hierro/sangre , Hígado/metabolismo , Masculino , Modelos Biológicos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The purpose of this study was to assess the effects of inhibitors of protein kinase C (PKC) on lipopolysaccharide (LPS)-induced fever and changes in circulating interleukin-6 (IL-6) levels in freely moving biotelemetered rats. We used PKC inhibitors with different inhibition constants (Ki): H-7 (Ki = 6 microM) and chelerythrine (Chel; Ki = 0.66 microM; a more potent PKC inhibitor). Rats were injected subcutaneously with either 3 or 15 microM/kg of these inhibitors and then 1 h later were injected intraperitoneally with LPS (50 micrograms/kg). Blood samples for IL-6 bioassay were collected 4 h after LPS injection. H-7 at lower doses did not significantly affect fever and LPS-induced elevation of circulating IL-6, whereas at a higher dose (15 microM/kg) H-7 reduced both fever and the increase of IL-6 (analysis of variance, Scheffé's test, P < 0.05). Chel (3 and 15 microM/kg) significantly reduced fever and almost completely inhibited the LPS-induced elevation of plasma IL-6. In separate experiments, we studied the effect of H-7 on antipyresis due to dexamethasone (Dex). Dex at a dose of 0.6 microM/kg given subcutaneously 1 h before LPS partially prevented fever (approximately 55% inhibition) and attenuated the increase of IL-6 (P < 0.05). Simultaneous pretreatment of the rats with Dex and H-7 (3 microM/kg; a dose that did not affect fever and IL-6 elevation) led to a potentiation of the antipyretic effect of Dex, resulting in no fever. H-7 did not potentiate, however, the inhibitory effect of Dex on LPS-induced elevation of circulating IL-6. We conclude that PKC is involved in the regulation of LPS fever and constitutes a rate-limiting factor in modulation of the fever by glucocorticoids.
Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Regulación de la Temperatura Corporal/fisiología , Inhibidores Enzimáticos/farmacología , Fiebre/fisiopatología , Fenantridinas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Alcaloides , Analgésicos no Narcóticos/farmacología , Análisis de Varianza , Animales , Benzofenantridinas , Regulación de la Temperatura Corporal/efectos de los fármacos , Dexametasona/farmacología , Escherichia coli , Fiebre/inducido químicamente , Interleucina-6/sangre , Lipopolisacáridos , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
We tested the hypothesis that increased dietary fish oil levels (via modulation of the production of inflammatory mediators) modulate sickness symptoms (i.e., anorexia, cachexia, fever, lethargy) of systemic and local inflammation. Swiss Webster mice were implanted with biotelemeters to measure body temperature and motor activity and were fed a diet high in n-3 fatty acids (17% wt/wt menhaden oil) or a reference diet (17% wt/wt hydrogenated coconut oil or normal rodent chow) for 6 wk. Local inflammation was induced by subcutaneous injection of turpentine (100 microl/mouse). Systemic inflammation was elicited by intraperitoneal injection of lipopolysaccharide (LPS; 2.5 mg/kg). Fever, lethargy, anorexia, and weight decrease during turpentine abscess were all inhibited (P < 0.05) in mice fed the fish oil diet. Indomethacin, similar to the fish oil diet, attenuated the turpentine-induced symptoms in mice fed a normal diet. Dietary n-3 fatty acids prevented fever and attenuated the decrease in body weight caused by LPS but did not affect the LPS-induced lethargy and anorexia. Within 90 min of LPS injection, the bioactivity of plasma tumor necrosis factor-alpha (TNF-alpha) increased to 98.2 +/- 5.1 ng/ml in mice fed fish oil compared with 32.6 +/- 3.6 ng/ml in those fed the reference diet (P < 0.05). Plasma prostaglandin E2 (PGE2) levels after LPS injection of mice fed the control diet increased within 90 min to 16.4 +/- 5.1 pg/ml. Mice fed the fish oil diet did not show any elevation in plasma PGE2 levels at that time (P < 0.05). We speculate that dietary n-3 fatty acids suppressed PGE2-related responses, including a PGE2-dependent negative feedback on TNF-alpha production, which resulted in differential modulation of sickness behavior depending on the locus of inflammation.