摘要:

In neurodegenerative disease or after brain injury, parenchymal cells in the central nervous system are activated to produce inflammatory mediators, mainly consisting of cytokine-induced factors, in a manner similar to, but clearly different from a peripheral inflammatory response. The upregulated expression of several extracellular matrix proteins in astrocytes located surrounding a neuritic plaque in Alzheimer''s disease is a good example of such a response. A family of mediators which is cytokine-induced during an inflammatory response in the periphery are the matrix metalloproteinases. Matrix metalloproteinases are calcium-requiring, zinc-containing endopeptidases that constitute a major component of the enzyme cascade responsible for degradation of extracellular matrix proteins such as collagen, proteoglycan and laminin. Little is known about the cellular source or the function of matrix metalloproteinases in the central nervous system or how their expression is regulated in brain. Thus, it was of interest to determine which factors of the so-called ''brain inflammatory response'' regulate the expression of these proteases in the nervous system. To this end, we measured the expression of matrix metalloproteinases in cultured rat astrocytes and microglia after treatment with various cytokines. Interleukin-1β, tumor necrosis factor-αand lipo-polysaccharide were potent stimulators of matrix metalloproteinase-2 (gelati-nase A) and matrix metalloproteinase-9 (gelatinase B) in cultured rat astrocytes; the effect of each secretagogue was inhibited in the presence of glucocorticoid. Interleukin-1βand lipopolysaccharide also stimulated the production of matrix metalloproteinase-3 (stromelysin-1) in astrocytes. In addition, activated microglia release matrix metalloproteinase-9. The ''coactivator'' of monocytic phagocytes, interferon-γ, rather than augmenting the response to lipopolysaccharide, inhibited it. Thus, cytokines appear to be potent regulators of matrix metalloproteinase production in astrocytes and microglia. The presence of these enzymes in ''inflamed'' central nervous system may suggest their involvement in the pathogenesis or progression of neurodegenerative diseases which are associated with an inflammatory component. Much remains to be learned about the potential substrates for these enzymes and the mechanism of their activation in the central nervous sys

ISSN:1021-7401    

DOI:10.1159/000097229

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Alterations in the immune system are often accompanied by reproductive disorders. The bacterial endotoxin lipopolysaccharide (LPS) has central inflammatory effects, and activates the release of cytokines (immune system mediatory factors) in the hypothalamus, where the LHRH neurons are located. Therefore, these studies were designed to investigate a possible effect of the LPS on LHRH secretion and the possible interaction with excitatory and inhibitory amino acids. Animals were decapitated at 09.00 h, and the preoptic mediobasal hypothalamic area (PO/MBH) dissected and superfused. Superfusate fractions were collected at 15-min intervals. After a stabilization superfusion period of 60 min four fractions were collected; LPS (100 ng/ml) was then added to the superfusion medium for the duration of 1 h. This was followed by a washout period of 60 min. The PO/MBH fragments were then subjected to a 56 mMK+stimulus. Control PO/MBH fragments were continuously superfused with Earle''s balanced salt solution. LHRH release was significantly (p < 0.05) reduced during and following exposure to LPS. At this time GABA and taurine concentrations increased in the superfusion medium, while glutamate decreased significantly compared with the control group. These observations indicate that LPS inhibits LHRH and glutamate release, but stimulates taurine and GABA secretion. These effects may be explained by the stimulation of cytokines of neuronal and/or glial source which may interact with the excitatory and inhibitory amino acids.

ISSN:1021-7401    

DOI:10.1159/000097230

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Interleukin-1β(IL-1β) is a key regulatory component of host defense systems, and it is involved in physiological regulation including several central nervous system functions like fever and sleep. Nevertheless, little is known about how IL-1βis degraded. Based on their protease secreting capabilities, the ability of microglia, monocytes, and neutrophils to degrade IL-1βwas studied. Neutrophil cultures degraded IL-1β, whereas microglia and monocyte cultures did not. The degradation if IL-1βby neutrophils may constitute a downregulation mechanism for

ISSN:1021-7401    

DOI:10.1159/000097231

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Utilizing immunohistochemistry for the c-fosprotein to detect neuronal activity, we examined the effects of continuous intravenous and intracerebroventricular infusion of interleukin (IL)-1βin the rat brain, and the involvement of prostaglandins (PGs) in IL-1β-induced c-fosexpression. Continuous intravenous infusion of IL-1β(10 ng/min) markedly augmented c-fosexpression in the paraventricular (PVN) and the supraoptic (SON) nuclei of the hypothalamus as well as in the central amygdaloid nucleus (CeA). The number of IL-1β-induced c-fos-positive cells in the PVN and SON was significantly lower in rats pretreated with indomethacin than in vehicle-treated rats. However, the number of IL1β-induced c-fos-positive cells in the CeA remained unchanged. c-fosprotein was induced after intracerebroventricular infusion of IL-1β(200 ng) in the PVN, SON and arcuate nuclei of the hypothalamus, and in the CeA. The induction of c-fosimmunoreactivity by central administration of IL-1βwas blocked by indomethacin (500µg/rat), except in the CeA. These findings suggest that PGs are involved in the complex transmission of signals from circulating or central IL-1βto hypothalamic

ISSN:1021-7401    

DOI:10.1159/000097232

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

We studied the inflammatory responses of LEW/N and F344/N inbred rat strains after peripheral injection of carrageenan. The inflammatory responses were assessed in terms of volume, relative and total white blood cell counts of the exudates. Moreover, in both strains, blood CD4, CD8, CD25, naive CD4 (CD4/CD45RC) cell and B (CD45R) cell counts and plasma corticosterone levels, constituents of systemic inflammatory responses to carrageenan were evaluated. In general, LEW/N rats are highly responsive to challenge with carrageenan, whereas F344 rats are not. The strong local inflammatory responses to carrageenan are primarily exhibited by female LEW/N rats. The intensity of local inflammatory responses of LEW/N rats changes with the rat age, the highest exhibited by LEW/N rats up to 3 months of age, thereafter the carrageenan-induced inflammatory responses decline. Our results indicate that peripheral injection of carrageenan induces strong systemic immune component. After carrageenan injection, increases in CD8 and naive CD4 blood lymphocytes are seen. Although the carrageenan challenge does not change CD4 blood lymphocytes in both LEW/N and F344/N rat strains, LEW/N rats exhibit higher levels of CD4 cells than F344/N rats. Additionally, LEW/N rats demonstrated lower levels of B cells and higher naive CD4 lymphocytes. Carrageenan challenges induce significant increases in plasma corticosterone response in F344/N rats, as well as increases in LEW/N rats 1 h after injection. Our data stress the importance of rat age and gender in experiments studying inflammatory responses.

ISSN:1021-7401    

DOI:10.1159/000097233

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The effect of pinealectomy, superior cervical ganglionectomy and melatonin replacement on diurnal variations in submaxillary lymph node ornithine decarboxylase activity, tyrosine hydroxylase activity and [3H]choline conversion to [3H]acetylcholine were examined in rats subjected to pinealectomy, bilateral superior cervical ganglionectomy or their respective sham-operations, and treated with Freund''s complete adjuvant or its vehicle. In both immunized and nonimmunized sham-operated rats, significant diurnal variations in ornithine decarboxylase activity were detectable, with a maximum at 13.00 h (vehicle) or at 17.00 h (Freund''s adjuvant). In rats subjected to pinealectomy, ornithine decarboxylase activity decreased by about half, still exhibiting significant diurnal variations with a maximum at 13.00 h. Abolition of circadian rhythmicity and depression of ornithine decarboxylase activity to about one third of controls were found in submaxillary lymph nodes of bilaterally superior cervical ganglionectomized rats. Administration of melatonin (30 µg/animal) in the late evening during 11 days counteracted the depressed levels and suppressed the amplitude of diurnal rhythmicity of ornithine decarboxylase in pinealectomized or bilaterally superior cervical ganglionectomized rats, as well as augmented enzyme activity in sham-operated controls. The amplitude and mean levels of 24-hour rhythms in submaxillary lymph node tyrosine hydroxylase activity and [3H]choline conversion to acetylcholine (that attained their maxima at 21.00–1.00 and 13.00–17.00 h, respectively) decreased significantly after pinealectomy, these effects being significantly counteracted by melatonin injection. Melatonin augmented tyrosine hydroxylase activity and acetylcholine synthesis in sham-pinealectomized rats. The results are compatible with the view that the pineal gland plays a role in circadian changes of immune responsiveness in lymphoid tissue via an immunopo-tentiating effect of melatonin on lymph node cell prolifera

ISSN:1021-7401    

DOI:10.1159/000097234

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The brain is an immune-privileged site. To understand the mechanism of immune privilege in the brain, human cerebrospinal fluid (CSF) was examined for characteristics associated with fluids derived from other immune-privileged tissues. We first assayed for CSF suppression of effector T cell inflammatory activities. Primed T cells were activated with antigen and antigen-presenting cells in the presence of normal human or rabbit CSF, and T cell proliferation and interferon-γproduction were assayed. Human and rabbit CSF enhanced antigen-stimulated lymph node T cell proliferation and human CSF suppressed IFN-γproduction. T cell proliferation was suppressed by a low molecular weight (<5 kDA) fraction of CSF and by transiently acidified unfractionated CSF. Normal CSF, similar to fluids from other immune-privileged sites, has the capacity to suppress production of proinflammatory lym-phokines by antigen-stimulated effector T cells. Normal CSF also contains factors that have the potential to suppress effector T cell proliferation. Human CSF was assayed for factors known to mediate immunosuppression in other immune-privileged sites. Human CSF contained the immunosuppressive cytokine-transforming growth factor-β(1.7±0.6 ng/ml), and the immunosuppressive neuropeptides α-melanocyte stimulating hormone (60±11 pg/ ml), and vasoactive intestinal peptide (42±3 ng/ml). Much as fluids from other immune-privileged sites, CSF contains immunosuppressive cytokines that prevent activation of inflammatory-mediating (delayed-type hypersensitivity) T cells. This suggests that, similar to other immune-privileged sites, cytokines and neuropeptides mediate immunosuppression in the

ISSN:1021-7401    

DOI:10.1159/000097235

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Previously, we have shown that novel mononuclear-cell-derived factor(s) [molecular weight (MW) <3,000] stimulate the release of epinephrine (EPI) from adrenal medullary chromaffin cells to levels comparable to that of maximal cholinergic stimulation. The present study provides evidence that the observed bioactivity is due to the action of a single peptide of 627 Da apparent MW. The peptide nature of the bioactive component was suggested by a decreased bioactivity after acid hydrolysis as well as altered bioactivity subsequent to peptidase (carboxypeptidase Y, leucine aminopeptidase) treatment. The bioactive conditioned-medium (CM) peptide(s) were isolated and further characterized using SDS-PAGE analysis. SDS-PAGE separation of G-25 Sephadex purified CM shows that bioactivity resides in a single peptide band. Additional studies revealed that CM also mediates norepinephrine release from sympathetic ganglia cells. Regulation of peptide production was shown to involve negative feedback in that incubation with mononuclear cells with EPI prevented further bioactive peptide release. This feedback inhibition was partially blocked by theβ-adrenergic receptor antagonist propranolol. These findings suggest a novel and potentially important mechanism by which the immune system can alter neuroendocrine function

ISSN:1021-7401    

DOI:10.1159/000097236

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Parkinson''s disease (PD) is characterized by a markedly decreased number of nigrostriatal dopaminergic neurons. The pathogenesis of PD is still unknown; among other etiological factors, immunological abnormalities have been suggested. Recently, interleukin-2 (IL-2) has been hypothesized to be an endogenous cytokine that regulates striatal dopaminergic function. We examined the plasma concentrations of IL-1, IL-2, IL-6 and blood levels of ACTH, Cortisol and prolactin of 21 patients with PD without any previous treatment. Age-and sex-matched subjects without any neurological or immune disorders were used as controls. Significantly higher serum concentrations of IL-2 in patients with PD were found. Treatment with antiparkinsonian drugs reduced IL-2 levels in these patients. Our results suggest a functional relationship between central dopaminergic and immune systems and a possible involvement of the latter in the pathogenesis of PD.

ISSN:1021-7401    

DOI:10.1159/000097237

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

To investigate the role of tumor necrosis factor-α(TNF-α) in the brain in nociception, we injected recombinant human TNF-α(rhTNF-α; 1 pg–10 ng/rat) into the lateral cerebroventricle (LCV) in rats and observed the changes in paw withdrawal latency to radiant heat by using the plantar test for 90 min after injection. LCV injections of TNF-αat doses of 10 pg, 100 pg and 1 ng reduced paw withdrawal latency, showing a maximal response at a dose of 10 pg which peaked 60 min after injection. TNF-αat doses of 1 pg and 10 ng had no effect on nociception during the test period. The TNF-α(10 pg)-induced reduction in paw withdrawal latency was blocked by simultaneous injection of diclofenac (1 ng), a cyclooxygenase inhibitor, or interleukin-1 receptor antagonist (IL-1ra, 10 ng). LCV injection of neither diclofenac (1 ng) nor IL-1ra (10 ng) had any effect on nociception by itself. The results suggest that TNF-αin the brain induces thermal hyperalgesia and that the brain TNF-α-induced hyperalgesia is mediated by the central action of interleukin-1 and activation of the cyclooxygenase pathway of the ar

ISSN:1021-7401    

DOI:10.1159/000097238

出版商:S. Karger AG    

年代:1996

数据来源: Karger