摘要:

In in vivo studies, a conditioned increase in NK cell activity can be obtained by pairing odor of camphor (conditioned stimulus, CS) with poly I:C (unconditioned stimulus, US) in a single-association paradigm. We identified interferon (IFN) as the signal that reaches the central nervous system (CNS) to make an association with the camphor CS. We have also established that the CS/US association is an IFN-dependent step, and the expression stage is an opioid-dependent pathway which can be blocked with naltrexone and dexa-methasone. Here we have focused on the signals responsible for the expression of conditioned augmentation of natural killer (NK) cell activity. The possible efferent signal molecules that were considered were IFN, β-endorphin (β-END), and adrenocorticotropic hormone (ACTH). Plasma levels of β-END and ACTH of conditioned and control mice were quantitated by radioimmunoassay, and the changes in IFN message in the spleen cells were determined by Northern hybridization analysis. Results indicate that the ACTH levels and IFN-α gene expression were higher in the conditioned animals than in the controls. These studies support the view that ACTH released from the pituitary gland is involved in the up-regulation of IFN-α, which in turn stimulates the NK cells in the spleen.

ISSN:1021-7401    

DOI:10.1159/000097093

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Cyclosporin A (CSA), a potent immunosuppressive drug, has recently been shown to bind with high affinity to the immunophilin, cyclophilin. Calcineurin, the calcium-dependent protein phosphatase, binds the cyclophilin/CSA complex, rendering it inactive and blocking dephosphorylation of phospho-proteins. Very high concentrations of cyclophilin have been reported in the brain with a localization identical to that of caicineurin. We have reported that interleukin-2 (IL-2) releases corticotropin-releasing hormone (CRH) by generation of nitric oxide (NO). Nitric oxide synthase (NOS), the enzyme in nitric oxidergic neurons that converts arginine into citrulline plus NO, is inactive in the phosphorylated state. We hypothesized that cyclosporin might therefore inhibit IL-2-induced acute CRH release by blocking the dephosphorylation of NOS by calcineurin. Consequently, we examined the effect of CSA on the release of CRH from mediobasal hypothalami (MBH) in vitro in 'basal' conditions and in the presence of IL-2, which we had previously shown to stimulate CRH release acutely in this preparation. Incubation of MBH for 30 min with IL-2 (10–13M),the concentration that was most effective in previous experiments, evoked a significant release of CRH. CSA at 10–6or 10–8Mdid not alter basal release of CRH; however, addition of either concentration completely blocked the IL-2-induced release of CRH. This acute action of CSA within the brain is probably mediated by blockade of the dephosphorylation of NOS by calcineurin.

ISSN:1021-7401    

DOI:10.1159/000097094

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Nitric oxide (NO) synthase (NOS), the enzyme that converts arginine into citrulline plus NO, the latter a highly active free radical, occurs in a large number of neurons in the brain, including certain neurons in the hypothalamus. Our previous experiments have shown that norepinephrine (NE)-induced prostaglandin E2(PGE2) release from medial basal hypothalamic explants (MBH) is mediated by NO. Because release of luteinizing hormone (LH)-releasing hormone (LHRH) is also driven by NE and PGE2, we hypothesized that NO controls pulsatile release of LHRH in vivo, which in turn induces pulsatile LH release. Indeed, in vivo and in vitro experiments using an inhibitor of NOS (NG-monomethyl-L-arginine; NMMA) demonstrated that pulsatile LH release is mediated by NO; LHRH release in vitro is also mediated by this free radical. Cytokines that are released from cells of the immune system during infection also inhibit LHRH release. We compared the action of one such cytokine, interleukin-1α(IL-1α), on LHRH release with that of substances which inhibit or induce NO release. Microinjection of IL-1α(0.06 pmol in 2μl) into the third cerebral ventricle (3V) of conscious, castrated male rats had an action similar to that of 3V microinjection of NMMA (1 mg in 5μl): it blocked pulsatile LH, but not follicle-stimulating hormone (FSH) release. The only difference between the responses to NMMA and IL-1αwas that the latency to onset was greater with IL-1α. When both NMMA and IL-1αwere microinjected together, there was an additive suppressive effect on LH release during the first hour after injection. As in the case of NMMA, there was no effect on pulsatile FSH release of IL-la injected alone or together with NMMA. The latter results suggest that hypothalamic control of FSH release is distinct from that of LH and does not involve NO. Previous in vitro experiments showed that IL-1αalso has an action identical to that of NMMA; inhibition of NE-induced PGE2and LHRH release from MBH explants. Therefore, IL-1αappears to act on its receptors on the NOergic neurons to prevent the release of NO, or on the LHRH terminals to inhibit the response to NO. To test the hypothesis that IL-1αdirectly inhibits the response of LHRH terminals to NO, we incubated MBH explants with sodium nitroprusside (NP; 500μM)twhich spontaneously releases NO. NP-induced LHRH release was inhibited by IL-1α(10 pM).We conclude that IL-1αdirectly suppresses the response of the LHRH terminals to NO.

ISSN:1021-7401    

DOI:10.1159/000097095

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Recent research indicates that the proopiomelanocortin derivative α-melano-cyte stimulating hormone (α-MSH) is a significant modulator of host reactions including fever and inflammation. Although the precise mechanism of action is still unknown, cytokine antagonism is believed to be responsible for at least a part of its anti-inflammatory/antipyretic influence:α-MSH antagonizes pyrogenic and proinflammatory effects of cytokines such as interleukin-1(IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and interferonγ(IFNγ).Although it is clear that the peptide can act within the brain to inhibit fever and peripheral inflammation, an anti-inflammatory effect on a peripheral target was evidenced in animals with transection of the spinal cord. Recent data show thatα-MSH is significant also in human disorders such as AIDS, rheumatoid arthritis, and myocardial infarction. This molecule is believed to be a key factor in neuroirnmunomodulation and it may be useful as a therapeutic agent in control of inflammatory reactions.

ISSN:1021-7401    

DOI:10.1159/000097096

出版商:S. Karger AG    

年代:1994

数据来源: Karger