RESUMEN
Glucocorticoids can dampen inflammatory responses by inhibiting neutrophil recruitment to tissue sites. The detailed mechanism by which glucocorticoids exert this affect on neutrophils is unknown. L-selectin is a leukocyte cell surface receptor that is implicated in several steps of neutrophil recruitment. Recently, several studies have shown that systemic treatment of animals and humans with glucocorticoids induces decreased L-selectin expression on neutrophils, suggesting one mechanism by which inflammation may be negatively regulated. However, when neutrophils are treated in vitro with glucocorticoids, no effect on L-selectin expression is observed. Thus, the existence of an additional mediator is plausible. In this study, we investigate whether annexin 1 (ANX1), a recognized second messenger of glucocorticoids, could be such a mediator. We show that ANX1 induces a dose- and time-dependent decrease in L-selectin expression on both peripheral blood neutrophils and monocytes but has no effect on lymphocytes. The loss of L-selectin from neutrophils is due to shedding that is mediated by a cell surface metalloprotease ("sheddase"). Using cell shape and a beta(2) integrin activation epitope, we show that the ANX1-induced shedding of L-selectin appears to occur without overt cell activation. These data may provide the basis for further understanding of mechanisms involved in the down-regulation of inflammatory responses.
Asunto(s)
Anexinas/fisiología , Dexametasona/farmacología , Selectina L/metabolismo , Células Mieloides/metabolismo , Animales , Anexinas/aislamiento & purificación , Anexinas/metabolismo , Bovinos , Tamaño de la Célula/efectos de los fármacos , Relación Dosis-Respuesta Inmunológica , Regulación hacia Abajo , Citometría de Flujo , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/enzimología , Leucocitos/metabolismo , Metaloendopeptidasas/fisiología , Células Mieloides/efectos de los fármacos , Células Mieloides/enzimología , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Activación Neutrófila/efectos de los fármacos , Receptores de Formil Péptido , Receptores Inmunológicos/metabolismo , Receptores de Péptidos/metabolismo , Acetato de Tetradecanoilforbol/farmacologíaAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/economía , Carbamatos/economía , Carbamatos/uso terapéutico , Inhibidores de la Colinesterasa/economía , Inhibidores de la Colinesterasa/uso terapéutico , Fármacos Neuroprotectores/economía , Fármacos Neuroprotectores/uso terapéutico , Fenilcarbamatos , Anciano , Ahorro de Costo , Humanos , RivastigminaRESUMEN
Clinical findings suggest that inflammatory disease symptoms are aggravated by ongoing, repeated stress, but not by acute stress. We hypothesized that, compared with single acute stressors, chronic repeated stress may engage different physiological mechanisms that exert qualitatively different effects on the inflammatory response. Because inhibition of plasma extravasation, a critical component of the inflammatory response, has been associated with increased disease severity in experimental arthritis, we tested for a potential repeated stress-induced inhibition of plasma extravasation. Repeated, but not single, exposures to restraint stress produced a profound inhibition of bradykinin-induced synovial plasma extravasation in the rat. Experiments examining the mechanism of inhibition showed that the effect of repeated stress was blocked by adrenalectomy, but not by adrenal medullae denervation, suggesting that the adrenal cortex mediates this effect. Consistent with known effects of stress and with mediation by the adrenal cortex, restraint stress evoked repeated transient elevations of plasma corticosterone levels. This elevated corticosterone was necessary and sufficient to produce inhibition of plasma extravasation because the stress-induced inhibition was blocked by preventing corticosterone synthesis and, conversely, induction of repeated transient elevations in plasma corticosterone levels mimicked the effects of repeated stress. These data suggest that repetition of a mild stressor can induce changes in the physiological state of the animal that enable a previously innocuous stressor to inhibit the inflammatory response. These findings provide a potential explanation for the clinical association between repeated stress and aggravation of inflammatory disease symptoms and provide a model for study of the biological mechanisms underlying the stress-induced aggravation of chronic inflammatory diseases.
Asunto(s)
Permeabilidad Capilar , Inflamación/etiología , Estrés Fisiológico/complicaciones , Hormona Adrenocorticotrópica/farmacología , Animales , Bradiquinina/farmacología , Corticosterona/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Metirapona/farmacología , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Ratas Sprague-Dawley , Restricción Física , Estrés Fisiológico/metabolismoRESUMEN
Although the inflammatory response is essential for protecting tissues from injury and infection, unrestrained inflammation can cause chronic inflammatory diseases such as arthritis, colitis and asthma. Physiological mechanisms that downregulate inflammation are poorly understood. Potent control might be achieved by regulating early stages in the inflammatory response, such as accumulation of neutrophils at the site of injury, where these cells release chemical mediators that promote inflammatory processes including plasma extravasation, bacteriocide and proteolysis. To access an inflammatory site, neutrophils must first adhere to the vascular endothelium in a process mediated in part by the leukocyte adhesion molecule L-selectin. This adhesion is prevented when L-selectin is shed from the neutrophil membrane. Although shedding of L-selectin is recognized as a potentially important mechanism for regulating neutrophils, its physiological function has not been demonstrated. Shedding of L-selectin may mediate endogenous downregulation of inflammation by limiting neutrophil accumulation at inflammatory sites. Here we show that activation of nociceptive neurons induces shedding of L-selectin from circulating neutrophils in vivo and that this shedding suppresses an ongoing inflammatory response by inhibiting neutrophil accumulation. These findings indicate a previously unknown mechanism for endogenous feedback control of inflammation. Failure of this mechanism could contribute to the etiology of chronic inflammatory disease.
Asunto(s)
Artritis/fisiopatología , Ácidos Hidroxámicos , Selectina L/metabolismo , Neutrófilos/metabolismo , Dolor/fisiopatología , Animales , Artritis/sangre , Artritis/patología , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Células Cultivadas , Regulación hacia Abajo , Estimulación Eléctrica , Retroalimentación , Citometría de Flujo , Miembro Posterior , Masculino , Neuronas Aferentes/fisiología , Neutrófilos/fisiología , Nociceptores/fisiología , Dolor/sangre , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor alpha immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Dihidrotestosterona/farmacología , Estradiol/farmacología , Inflamación/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Testosterona/farmacología , Animales , Femenino , Sistema Hipotálamo-Hipofisario/fisiología , Inmunohistoquímica , Masculino , Ovario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/análisis , Testículo/fisiologíaRESUMEN
Annexin I is a local mediator in neural-endocrine feedback control of inflammation. J. Neurophysiol. 80: 3120-3126, 1998. Activation of primary afferent nociceptors induces a neural endocrine-mediated inhibition of the inflammatory response via a circuit that includes ascending spinal pathways and activation of the hypothalamic-pituitary adrenal (HPA) axis. This circuit inhibits sympathetic neuron-dependent plasma extravasation (PE) in the rat knee joint produced by bradykinin (BK), but not sympathetic neuron-independent PE produced by platelet activating factor (PAF). Noxious (25 mA) but not non-noxious (2.5 mA) electrical stimulation significantly increased plasma corticosterone concentrations, and intravenous infusion of corticosterone (5 micrograms/min) mimicked inhibition of BK-induced PE produced by noxious stimulation. However, perfusion of corticosterone locally through the knee joint, at doses that do not have a systemic action (i.e., =1 microM), did not inhibit BK-induced PE. Annexin I (lipocortin-1), a 37-kDa member of a family of phospholipid and calcium binding proteins, can mediate local anti-inflammatory effects of glucocorticoids via a mechanism that is partially dependent on inhibition of phospholipase A2 activity and adhesion and transmigration of polymorphonuclear leukocytes. Because BK-induced PE is dependent on both polymorphonuclear leukocytes and phospholipase A2 activity, we tested the hypothesis that the action of corticosterone to inhibit BK-induced PE is mediated by stimulating the production and release of annexin I. Perfusion of BK (150 nM) through the rat knee joint induces a rapid and sustained increase in PE. Co-perfusion of BK with annexin I (100 ng/ml) through the knee joint mimics the inhibition of BK-induced PE produced by noxious electrical stimulation or by intravenous corticosterone. Co-perfusion of BK with annexin I antibody (LCPS1, 1:60 dilution) prevented the inhibition of BK-induced PE produced by noxious electrical stimulation or intravenous corticosterone adminstration. PAF-induced PE, which is not dependent on polymorphonuclear leukocytes, was not inhibited by local perfusion of annexin I. These data suggest that the inhibitory effect of C-fiber activity on BK-induced PE, acting via an HPA circuit, is mediated by annexin I in the knee joint.