摘要:

The paper reviews data on bidirectional circuits between the hypothalamic-pituitary-thyroid (HPT) axis and the immune system. The effects of thyroliberin (TRH), thyrotropin (TSH) and of thyroid hormones (thyroxine and triiodothyronine) on the immune system, as well as the effects of mono- and lymphokines on the HPT axis are discussed.

ISSN:1021-7401    

DOI:10.1159/000097154

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Cytokine-induced release of corticotropin-releasing factor (CRF) from hypothalamic explants in vitro can be inhibited by femtomolar concentrations of α-melanocyte-stimulating hormone (α-MSH). Because the mechanism of the anticytokine action of α-MSH remains unknown, we examined if the peptide inhibits CRF release by interference with various steps in the activation of CRF release. Previous studies have shown that CRF release is induced by activation of phospholipase A2 (PLA2). Therefore, we examined the effect of α-MSH on the action of melittin (MEL), a PLA2 activator. After 60 min preincubation in Krebs-Ringer bicarbonate buffer, medial basal hypothalami were incubated for 30 min with Krebs-Ringer bicarbonate buffer or MEL with or without α-MSH (10–11 to 10–16M). CRF release into the incubation medium was measured by RIA. As reported previously none of the α-MSH concentrations used changed basal CRF release nor did any concentration of α-MSH significantly alter CRF release induced by MEL (10 μg/ml). Thus, α-MSH alters cytokine-induced CRF release at a step unrelated to the activation of PLA2. Because activation of PLA2 requires an increase in intracellular calcium ion (Ca2+) concentrations, we evaluated the effect of α-MSH on the release of CRF induced by a high concentration of potassium (56 mM). This concentration of potassium induced a 3.5-fold increase in CRF release that was not affected by α-MSH. Protein kinase C (PKC) stimulates CRF release. Consequently, we examined the effect of α-MSH on CRF release induced by phorbol myristate acetate (PMA), which in the presence of Ca2+ stimulates PKC. PMA (10–10M)stimulated CRF release. There was a bell-shaped dose-response curve with lesser stimulation at 10–11 and 10–9 M which was not significant statistically and a return to baseline levels of CRF release at concentrations of 10–8 and 10–7 M. α-MSH (10–16 to 10–13 M) completely blocked this effect, but α-MSH was ineffective at 10–12M. The results indicate that the action of α-MSH is not mediated by blocking the increase in intracellular Ca2+ or the activation of PLA2, which are required for CRF release, but instead is mediated by a blockade of the activation of PKC. We speculate that a-MSH acts on the adrenocorticotropic hormone receptor on the surface of the CRF neuron to activate it leading to blockade of the activation of PKC. We hypothesize that blockade of the action of PKC may be the basis for the anticytokine actions of α-MSH in the hypothalamus and also in the immune system.

ISSN:1021-7401    

DOI:10.1159/000097155

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The neuropeptide substance P (SP) is one of the principal mediators of neurogenic inflammation as well as a neurotransmitter in nociceptive affect neurons. The mechanisms by which binding of SP to its receptor stimulates diverse downstream biologic effects remain unknown. In order to elucidate this process we have established stably transfected cell lines expressing functional rat SP receptors (KNRK-SPR). When stimulated by SP, KNRK-SPR cells respond by simultaneously mobilizing intracellular Ca2+ and increasing cAMP levels. To determine if SP stimulation activates downstream transcriptional regulatory factors, we transfected KNRK-SPR cells with plasmids containing the activator protein 1 (AP-1) and cAMP-responsive (CRE) enhancer elements coupled to the chloramphenicol acetyltransferase (CAT) reporter gene. Stimulation with SP 1–1,000 nM caused a 1.5-to 2-fold increase in CAT activity in both AP-1-CAT- and CRE-CAT-transfected KNRK-SPR cells. Northern and Western blot analyses demonstrate that the mechanism by which SP stimulates AP-1 enhancer activity involves increases in both c-jun mRNA and protein. Moreover, gel retardation assays with oligomers containing the AP-1 and CRE binding sites showed that SP induces specific retardation bands consistent with increases in AP-1 and CRE complexes. These experiments suggest that SP-mediated stimulation of cells involves the participation of two signaling pathways resulting in several transcriptional regulatory mechanisms being activated.

ISSN:1021-7401    

DOI:10.1159/000097156

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

On the basis of our previous investigations concerning the influence of some central nervous system structures on the immune reaction, we have shown the existence of a brain regulatory system for immune response (BRSIR). We have investigated this BRSIR using small electrolytic lesions placed in different brain areas of male rats, followed by two methods to evaluate the effect of the lesions on the immune response, the method of delayed skin hypersensitivity and the method of utilization of 3H-thymidine for synthesis of DNA after injection of muramyl dipeptide, a very potent immunostimulating compound. The experiments were performed on rats of the Wistar strain. Lesions were placed from the spinal cord through the brain stem to the cerebral cortex. The results suggest that the following structures constitute parts of the BRSIR: medial frontal cortex (areas Cg 1–3), subnucleus basomedialis and centralis of the amygdala, subnucleus medialis and dorsolateral of the nucleus parabra-chialis, lateral reticular formation (nucleus parvocellularis - mainly areas corresponding with aminergic groups A1–7), part of the raphe reticular formation (nucleus raphealis dorsalis and nucleus linearis – mainly areas corresponding with serotoninergic groups B6–8), and the spinal cord.

ISSN:1021-7401    

DOI:10.1159/000097157

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Indirect evidence suggests that dopamine within the brain may participate in the regulation of immune responses both in humans and in rodents. The aim of the present study was to investigate the possible modulatory role played by specific dopamine D1 receptor subtypes within discrete sites of the brain dopaminergic pathways. Mitogen responsiveness of splenocytes and natural killer (NK) cell activity were measured in rats following microinfusion of SKF 38393, a specific dopamine D1 receptor agonist, into the ventral tegmental area, the amygdala, the nucleus accumbens and the CA1 area of the hippocampus. We report here that microinfusion of SKF 38393 (100 nmol) within the central amygdala increased the proliferative response of splenocytes to concanavalin A (ConA) while it did not modify the proliferative response of splenocytes to lipopolysac-charide (LPS) or NK cell activity. On the contrary, microinfusion of SKF 38393 into the nucleus accumbens decreased the proliferative response of splenocytes to ConA and LPS, while NK cell activity remained unchanged. Similarly, microinfusion of SKF 38393 into the CA1 area of the hippocampus decreased the proliferative response of splenocytes to LPS, but not to ConA and did not affect NK cell activity. Finally, microinfusion of SKF 38393 into the ventral tegmental area did not significantly modify the proliferative response of splenocytes to either ConA or LPS and did not affect NK cell activity. All immunological changes evoked through the different areas of the brain following microinfusion of SKF 38393 were prevented by systemic administration of SCH 23390, a specific D1 receptor antagonist. In conclusion, the present results show for the first time that following specific activation of the dopamine Di receptors in selected areas of the limbic system, immunoenhancing or immunosuppressive effects may be elicited, and confirm the immunomodulatory role played by dopaminergic mechanisms in the brain.

ISSN:1021-7401    

DOI:10.1159/000097158

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Stem cell factor (SCF) promotes the growth of multilineage hematopoietic cells. SCF is a product of the steel (Sl) locus of the mouse, and it is a ligand for the c-kit proto-oncogene receptor. Previous studies have investigated the distribution of SCF mRNA in developing and adult tissues of the rat, including the brain. However, there have been conflicting reports on the distribution of SCF mRNA in adult rat brain. Specially noteworthy was one report of the absence of SCF mRNA in adult hippocampus, while another group reported the presence of that mRNA in the dentate gyrus of the hippocampus. We conducted this study to determine the precise localization of SCF mRNA in adult brain, and were especially interested in determining whether that mRNA is localized in adult hippocampus. We used in situ hybridization histochemistry to demonstrate that the gene encoding SCF is actively expressed in neuron-like cells in various regions of adult rat brain. Our data show that SCF mRNA is present in neuron-like cells in the thalamus, cerebral cortex, cerebellum, and hippocampus, particularly in the dentate gyrus, but also in CA1, CA2, and CA3. We did not localize SCF mRNA in glia-Iike cells. Dyskeratosis congenita is a severe human disorder, associated with dyskeratosis, anemia, and mental retardation. It has been postulated that dyskeratosis congenita is due to a deficiency in SCF function. It is unknown why patients with dyskeratosis congenita suffer from mental retardation. We suggest that it is possible that the mental retardation observed as part of the syndrome could be related to a deficiency of SCF in developing as well as in adult brain.

ISSN:1021-7401    

DOI:10.1159/000097159

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is known to suppress cytokine-mediated inflammation. In addition, we previously found that α-MSH suppressed the production of the proinflammatory cytokine interferon (IFN)-γ by antigen-stimulated primed lymph node T cells. This immunosuppressive activity of α-MSH on lymph node T cell cultures is similar to that of interleukin (IL)-4. To further examine the potential ‘IL-4 like’ activities of α-MSH, antigen-stimulated lymph node T cell cultures were treated with α-MSH in the presence of neutralizing anti-IL-4 antibodies. The enhanced production of IFN-γ caused by the presence of anti-IL-4 alone in the T cell cultures was squelched by α-MSH. This demonstrated that in these cultures, α-MSH regulation of IFN-γ production operates in a fashion similar to that of endogenous IL-4. Addition of exogenous IL-4 to antigen-stimulated lymph node T cell cultures did not intensify α-MSH down-regulation of IFN-γ production, and the addition of α-MSH to IL-4-treated cultures did not further depress IFN-γ production. These and the previous results suggest that the mechanism of α-MSH suppression of IFN-γ production in the antigen-stimulated T cell cultures is similar to, but independent of, IL-4. When antigen-presenting cells (APCs) were the only cells in the antigen-stimulated T cell cultures treated with a-MSH, there was a significant reduction (60-70%) of APC elicitation of IFN-y production by untreated primed T cells. Moreover, α-MSH prevented IFN-γ production by 80-100% when primed T cells were the only cells treated with a-MSH. The mechanism of a-MSH prevention of antigen-stimulated IFN-γ production in T cell cultures involves both APC and primed T cells. Since α-MSH is constitutively present in the skin, serum, brain and eye, this neuropeptide may play an important immunomodulatory role linking the nervous system and the rest of the body. In particular, α-MSH may be critical to the phenomenon of immune privilege in the eye and brain.

ISSN:1021-7401    

DOI:10.1159/000097167

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Previous experiments in this and other laboratories have revealed that nitric oxids (NO) plays a role in controlling the release of corticotropin-releasing hormone (CRH) and luteinizing-hormone-releasing hormone (LHRH). Therefore, we have investigated its role in control of growth hormone (GH) release in conscious rats by microinjecting NG-monomethyl-L-arginine (NMMA), an inhibitor of NO synthase (NOS), into the third ventricle (3V) of conscious, freely moving castrate male rats. An initial blood sample (0.3 ml) was drawn from an indwelling intra-atrial catheter just prior to injection of NMMA [1 mg in 5 μl of 0.9% NaCl (saline)] into the 3V. To maintain the inhibitory action on NOS, a second injection of NMMA was administered into the 3V 60 min after the first. Additional blood samples (0.3 ml) were removed at 10 min intervals for 120 min. Other animals received injections of the diluent at the same times and volumes as NMMA. Interleukin (IL)-1α (0.06 pmol in 2 μl saline) was injected into the 3V immediately after the first injection of NMMA, whereas other animals received the NMMA diluent followed by IL-1α. The effects of IL-1α were almost identical to those of NMMA in that there was a dramatic lowering of plasma GH achieved primarily by a reduction in height of the GH pulses without a significant reduction in their number. When IL-1α as well as NMMA were administered, results were similar to those with NMMA or IL-1α alone except for a significant decrease (p < 0.025) in number of pulses and a small but significant increase in pulse height. The area under the plasma GH curve was highly significantly and similarly decreased in all treatment groups. Since NMMA decreased pulse height without altering frequency, this indicates that pulse height is controlled by NO, probably by stimulating release of GH-releasing hormone (GRH). Other experiments have shown that NO stimulates somatostatin release. Consequently, the elevation in pulse height in animals injected with IL-1α plus NMMA above the level in the animals injected only with IL-1α, may be due to suppression of somatostatin release in the IL-1α-plus-NMMA-injected animals. Since the response to NMMA and IL-1α was almost identical, we hypothesize that IL-1α blocks the response of the GRH neuron to NO.

ISSN:1021-7401    

DOI:10.1159/000097160

出版商:S. Karger AG    

年代:1994

数据来源: Karger