RESUMEN
Many studies have demonstrated that ablation of the sympathetic nervous system (SNS) alters subsequent immune responses. Researchers have presumed that the altered immune responses are predominantly the result of the peripheral phenomenon of denervation. We, however, hypothesized that chemical sympathectomy will signal and activate the central nervous system (CNS). Activation of the CNS was determined by immunocytochemical visualization of Fos protein in brains from male C57BL/6 mice at 8, 24, and 48 h following denervation. A dramatic induction of Fos protein was found in the paraventricular nucleus (PVN) of the hypothalamus and other specific brain regions at 8 and 24 h compared to vehicle control mice. Dual-antigen labeling demonstrates that corticotrophin releasing factor (CRF)-containing neurons in the PVN are activated by chemical sympathectomy; however, neurons containing neurotransmitters which may modulate CRF neurons, such as vasopressin, tyrosine hydroxylase, and adrenocorticotropin, do not coexpress Fos. Our findings suggest an involvement of the CNS in sympathectomy-induced alterations of immunity.
Asunto(s)
Química Encefálica/inmunología , Sistema Hipotálamo-Hipofisario/inmunología , Neuroinmunomodulación/fisiología , Sistema Hipófiso-Suprarrenal/inmunología , Hormona Adrenocorticotrópica/análisis , Animales , Núcleo Arqueado del Hipotálamo/química , Núcleo Arqueado del Hipotálamo/inmunología , Arginina Vasopresina/análisis , Hormona Liberadora de Corticotropina/análisis , Masculino , Ratones , Ratones Endogámicos C57BL , Norepinefrina/inmunología , Bulbo Olfatorio/química , Bulbo Olfatorio/inmunología , Oxidopamina , Prosencéfalo/química , Prosencéfalo/inmunología , Proteínas Proto-Oncogénicas c-fos/análisis , Bazo/química , Bazo/inmunología , Simpatectomía , Sistema Nervioso Simpático/química , Sistema Nervioso Simpático/enzimología , Sistema Nervioso Simpático/inmunología , Simpaticolíticos , Tirosina 3-Monooxigenasa/análisisRESUMEN
Numerous studies have sought to delineate the impact of neuroendocrine function on overall immune responsiveness. Using various murine models, we and others have previously shown that both adrenal-dependent and adrenal-independent mechanisms associated with psychological stress modulate components of both the primary and memory cellular immune responses to herpes simplex virus type 1 (HSV-1) infection. We have extended these studies by determining the impact of 6-hydroxydopamine (6-OHDA)-mediated peripheral sympathetic denervation on both responses. C57BL/6 mice treated with 6-OHDA (200 mg/kg) exhibited reduced generation of both primary lymph node- and splenic-derived cytotoxic T lymphocytes (CTL) following a local (footpad) and systemic HSV infection, respectively. 6-OHDA also suppressed activation of HSV-specific memory CTL (CTLm). In both models, alterations in cytokine production and lymphocyte subset distribution were also observed. Administration of 6-OHDA also resulted in substantial but transient activation of the hypothalamic-pituitary-adrenal (HPA) axis as was indicated by a dramatic elevation of serum corticosterone and hypothalamic Fos expression. Moreover, the corticosterone levels were directly correlated with the extent of CTLm activation. Together, these findings suggest that peripheral sympathetic denervation alters immune function through activation of the HPA axis.
Asunto(s)
Herpes Simple/inmunología , Memoria Inmunológica/inmunología , Sistema Nervioso Simpático/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Células Cultivadas , Corticosterona/sangre , Ensayo de Inmunoadsorción Enzimática , Herpes Simple/sangre , Interferón gamma/análisis , Interferón gamma/biosíntesis , Interleucina-2/análisis , Interleucina-2/biosíntesis , Interleucina-4/análisis , Interleucina-4/biosíntesis , Interleucina-6/análisis , Interleucina-6/biosíntesis , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidopamina , Simpatectomía Química , Linfocitos T Citotóxicos/virologíaRESUMEN
Our previous work has documented that physical or psychological stress can alter interleukin (IL)-2, IL-4, and interferon (IFN)-gamma production by spleen or lymph node cells in vitro. To determine if adrenal hormones might be mediating these stress-induced changes in type 1 and type 2 cytokines and immune effector functions, we cultured spleen cells in vitro with either the synthetic glucocorticoid dexamethasone (DEX) or the putative restorative hormone dehydroepiandrosterone (DHEA). Spleen cells were obtained from either young (5-6 weeks old) or mature (7-8 months old) BALB/c mice that were either unimmunized or immunized with the T-cell-dependent antigen keyhole limpet hemocyanin (KLH). We determined that DEX suppressed production of all three cytokines examined. DHEA was not associated with any enhancement of cytokine production. These data challenge the hypothesis that glucocorticoids can differentially regulate Th1-like versus Th2-like cytokine production. Further, they suggest that in stress paradigms in which differential regulation of cytokine production and effector function has been observed, other neuroendocrine factors in addition to glucocorticoids must be relevant.
Asunto(s)
Citocinas/biosíntesis , Deshidroepiandrosterona/farmacología , Dexametasona/farmacología , Bazo/metabolismo , Animales , Complejo CD3/inmunología , Células Cultivadas , Femenino , Hemocianinas/inmunología , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
IL-1beta has been implicated in central nervous system effects, including activation of the hypothalamic-pituitary-adrenal axis. Less is known concerning the role of IL-6 in brain. To compare and contrast IL-1beta and IL-6 effects on brain, rats were administered intraperitoneal injections of IL-1beta, IL-6 or control vehicle (3-8 microg/rat), perfused 150-180 min post-injection, and brains and pituitaries were processed for Fos immunolabeling. IL-1beta induced Fos expression in corticotrophin-releasing factor (CRF) neurons of paraventricular nucleus (PVN) of the hypothalamus, and anterior pituitary gland. IL-6 also induced immunolabeled Fos in the anterior pituitary gland, however, it did not induce Fos expression in CRF neurons of PVN. Data suggest that IL-6 may directly activate the anterior pituitary gland, whereas IL-1beta may exert its effect on the pituitary directly and/or indirectly via activation of CRF neurons in the PVN.