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PubMed2006

Novel role of TGF-beta in differential astrocyte-TIMP-1 regulation: implications for HIV-1-dementia and neuroinflammation.

Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)-1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV-1-associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP-1 in the brain. Astrocyte-TIMP-1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006), we investigate the mechanisms that may be involved in differential TIMP-1 regulation. One mechanism for TIMP-1 downregulation is the production of anti-inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)-signaling in astrocyte-MMP/TIMP-1-astrocyte regulation. TGF-beta1 and beta2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1beta and TGF-beta mimicked the TIMP-1 downregulation observed with IL-1beta chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-beta combined with IL-1beta increased MMP-2 and decreased proMMP-1 expression compared to IL-1beta alone. We propose that one of the mechanisms involved in TIMP-1 downregulation may be through TGF-signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte-TIMP-1 regulation.

AIDS Dementia Complex↗
PubMed1996

Identification and topography of neuronal cell populations expressing TNF alpha and IL-1 alpha in response to hippocampal lesion.

In previous studies, we have shown that a traumatic lesion to the hippocampus of adult mice induces the transitory expression of TNF alpha and IL-1 alpha by neurons of different brain areas and also by glial cells at the site of injury. The aim of the present study was to establish whether the expression of TNF alpha and IL-1 alpha is restricted to defined subpopulations, or else is common to most of the central neuronal populations. Using polyclonal anti-GAD 67, anti-TH and monoclonal anti-ChAT, and anti-5-HT antibodies in a double-labeling immunohistochemical procedure in combination with murine anti-TNF alpha and anti-IL-1 alpha polyclonal antibodies, we show that most GABAergic, catecholaminergic, and serotoninergic neurons, and a subgroup of the cholinergic neurons, express these cytokines. Although not immunohistochemically characterized, neurons in some glutamatergic structures such as the hippocampus and the prefrontal cortex also express these cytokines. Thus, we conclude that the capacity of central neurons to express cytokines like TNF alpha and IL-1 alpha in reaction to a brain injury is not restricted to peculiar neuronal subtypes, but could include most of the neuronal populations of the brain.

Acetylcholine↗
PubMed2006

Mycophenolate mofetil and tacrolimus: new therapeutic options in neuroimmunological diseases.

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.

Autoimmune Diseases of the Nervous System↗
PubMed1994

In vitro effects of CINC/gro, a member of the interleukin-8 family, on interleukin-6 secretion by rat posterior pituitary cells.

We investigated the effects of CINC/gro on IL-6 secretion by rat posterior pituitary cells. CINC/gro immunoreactivity was already detected in 1-h conditioned medium of normal posterior pituitary cells, and it increased significantly in a time-dependent manner during the first 24 h of culture. This immunoreactivity could be induced by TNF-alpha in a dose-dependent manner. On the other hand, CINC/gro stimulated IL-6 secretion by posterior pituitary monolayer cultures in a concentration dependent manner. Thus, CINC/gro significantly (P < 0.01) increased the secretion of IL-6 within 13 h of incubation, and this effect continued throughout 24 h of incubation. The stimulatory effect of 100 ng/ml CINC/gro on IL-6 secretion was completely blocked by 24-h incubation with 100 ng/ml IAP. These data demonstrate a new biological activity for CINC/gro in the posterior pituitary system.

Animals↗
PubMed1993

Exposure to conspecific alarm chemosignals alters immune responses in BALB/c mice.

Male BALB/cJ mice were exposed for 24 h to odors from donor mice that were either footshocked or undisturbed. Mice exposed to odors from footshocked donors had suppressed splenic IL-2 production following in vitro concanavalin A (Con A) stimulation compared to home cage or apparatus controls. Stress odor exposure also resulted in reduced natural killer (NK) cell cytotoxicity against YAC-1 tumor target cells compared to controls. Stress odor exposure 24 h after intraperitoneal injection of keyhole limpet hemocyanin (KLH) increased IgM and IgG antibody titers relative to the response of home cage or apparatus control animals. These results demonstrate that exposure to olfactory cues from stressed rodents alters both cellular and humoral immune responses. This paradigm may provide an ethnologically appropriate model of psychosocial stress in rodents.

Animals↗
PubMed1993

Prolonged isoproterenol treatment alters immunoregulatory cell traffic and function in the rat.

The mechanisms by which the sympathetic nervous system modulates functional parameters of the immune system have not been fully defined. In vivo, acute and chronic beta 2-adrenergic stimulation have been shown to have dramatic but opposing effects on circulating lymphocyte number and subset distribution in humans. In vitro studies have suggested impairment of numerous lymphocyte effector functions in the presence of catecholamines. To better define the effects of short and long term beta-adrenergic stimulation on lymphocyte migration patterns between circulating and splenic pools, as well as function, we infused rats with either low or high doses of isoproterenol over various time intervals. Specifically, we determined the number and subset composition of peripheral blood and splenic lymphocytes in addition to assessing responsivity to the T cell mitogen concanavalin A and antibody production. As a measure of in vivo lymphocyte proliferation, we also monitored the effect of these infusions on the number of peripheral blood lymphocytes and splenocytes and the splenic weight. Isoproterenol led to dose-dependent, short-lived decrements in mitogen-induced lymphocyte proliferation with concomitant decreases in circulating and splenic lymphocyte number in a subset-specific manner. Analysis of the distribution of circulating and splenic subtypes with isoproterenol treatment suggests definite but limited influences on beta-adrenergic stimulation on immunoregulatory cell traffic. We conclude that beta-adrenergic stimulation in the rat model leads to a dose-dependent, transient effect on lymphocyte proliferation and migration patterns. The relative lack of functional beta-receptors on rat lymphocytes and the propensity for early sustained receptor desensitization on exposure to agonist may account for qualitative differences seen between rats and humans.

Animals↗
PubMed1993

Effect of neuropeptide Y on natural killer activity of normal human lymphocytes.

The in vitro effect of neuropeptide Y (NPY) on natural killer (NK) cell activities of normal lymphocytes was investigated. NPY at 10(-9) to 10(-12) M concentrations produced significant suppression of NK activity against K 562 target cells. NPY at 10(-9) to 10(-12) M concentrations also produced significant inhibitory effects on NK activities of NK-enriched large granular lymphocytes against LAV-infected 8E5/LAV target cells. The suppression was dose dependent against both targets. NPY-induced suppression of NK activity of lymphocytes against K 562 target cells was specifically reversed by rabbit anti-NPY antisera at 1:800 and 1:1600 dilutions, showing the specificity of reactions. Pretreatment of target cells with NPY concentrations capable of inhibiting NK activity did not affect the sensitivity of K 562 target cells for lysis by effector cells. Inhibition of cytotoxicity was not due to direct toxicity of effector cells, because lymphocytes treated with NPY showed normal levels of 51Cr release and their viability was comparable to that of untreated control cells. These studies demonstrated that NPY, a product of sympathetic nervous system activation, may have a significant immunoregulatory effect on NK cell activities of normal lymphocytes that may be of clinical significance.

Adult↗
PubMed1993

Immune responses in male mice with aggressive and submissive behavior patterns: strain differences.

Immune responses in two strains of male mice with aggressive and submissive behavior patterns was studied. In aggressive CBA males immunized on the 10th day of agonistic confrontations with submissive partners, greater numbers of plaque-forming cells (PFC) and rosette-forming cells (RFC) were noted compared to control mice. Unlike the CBA strain, both PFC and RFC levels in aggressive C57BL males did not increase, but both PFC and RFC numbers decreased in submissive animals.

Agonistic Behavior↗
PubMed1993

Sympathetic regulation of T-helper cell function.

The role of sympathetic neurotransmission in regulation of T-cell function was examined in mice. After in vivo priming with a model protein antigen, hen egg white lysozyme (HEL), the specific proliferative recall response of lymph node cells (LNCs) was examined. The release of endogenous catecholamines by amphetamine (5 mg/kg, 45 min prior to sacrifice) markedly inhibited the proliferative response of LNCs. Combined alpha- and beta-adrenergic blockade (phentolamine, 1.0 mg/kg+propranolol, 2.5 mg/kg) prevented this effect of amphetamine on proliferation. In vitro, the alpha-adrenergic agonist phenylephrine, but not the beta-agonist isoproterenol, inhibited proliferation in a dose-dependent manner, up to 80%. The effect of phenylephrine was blocked by the alpha-adrenoceptor antagonist phentolamine. The effects of catecholamines appear to be mediated at the level of antigen processing/presentation: Amphetamine given prior to sacrifice inhibited interleukin 2 production when irradiated spleen cells were used to present HEL and HEL-related peptides to HEL-specific T-cell hybridomas. In summary, the sympathetic nervous system seems to inhibit antigen processing/presentation and, indirectly, T-helper responses.

Animals↗
PubMed1993

The inhibitory effect of interferon-alpha on the serotonin-induced impairment of human NK cell activity in whole blood.

Serotonin (5-HT) at a concentration of 10(-4) to 10(-10) M impaired the cytotoxicity of human natural killer cells in whole blood. 5-HT added at the onset of the short-term cytotoxic assay had a pronounced inhibitory effect. It is very likely that the 5-HT2 receptor is involved in the inhibition of cytotoxicity because ketanserin, an inhibitor of the 5-HT2 receptor, partially prevented the effect of 5-HT. Treatment with 10(2)-10(4) IU/ml of interferon-alpha before or after the application of 5-HT decreased its inhibitory effect on the cytotoxicity. Radioligand binding studies revealed that the antagonistic effect of interferon was not due to the competition for the 5-HT2 receptors. Cycloheximide, an inhibitor of protein synthesis, did not block the suppression of natural killer activity by 5-HT, but it exerted a blocking effect on the acquisition of resistance to 5-HT induced by interferon.

Cells, Cultured↗
PubMed1993

Degradation of enkephalins by rat lymphocyte and purified rat natural killer cell surface aminopeptidases.

Enkephalins have been reported to induce an elevation in natural killer (NK) cell cytolytic function. In the central nervous system, the short-lasting biological activity of the enkephalins may be attributable to their rapid hydrolysis at the cell surface. In a similar manner, a potential mechanism for regulating the effects of enkephalins on NK cells is through their degradation at the cell surface. The purpose of this study was to determine if NK cells were capable of enzymatically degrading Met- and Leu-enkephalin and to determine the type(s) of enzymes responsible. We report that rat nylon wool enriched splenocytes, purified NK cells, and interleukin-2 activated NK (A-NK) cells were capable of hydrolyzing the N-terminal Tyr residue from Met- and Leu-enkephalin as determined by high-performance liquid chromatography. The rate of Tyr cleavage from Met-enkephalin was approximately twice that of Leu-enkephalin for both splenocytes, NK, and A-NK cells. On a cellular basis, enkephalin degradation was four to five times greater with A-NK cells than with splenocytes. Only a Tyr cleavage product was detected, which suggested the possibility of an aminopeptidase activity. This was confirmed by the ability of bestatin, a specific inhibitor of cell surface aminopeptidases, to almost completely inhibit enkephalin degradation by splenocytes (85%) and A-NK cells (96%). A-NK cells were more sensitive to bestatin inhibition as indicated by their IC50 values (0.01 mM for splenocytes and 0.001 mM for A-NK cells). In addition, the chelator 1,10-phenanthroline was also capable of effectively inhibiting enkephalin degradation, suggesting that the enzyme responsible has the characteristics of a metalloprotease. In contrast to the effects of bestatin or phenanthroline, typical inhibitors of serine and thiol proteases were without effect.

Amino Acid Sequence↗
PubMed1993

Differential effects of ethanol in mouse lines genetically selected for high and low antibody production.

There is considerable evidence of a relationship between the central nervous system and the immune system, and that several drugs with primary action at the central nervous system can affect different immune responses. In an attempt to obtain a better understanding of the interaction between ethanol's effects and immune functions, we used two mouse lines selected according to their high (HGP) or low (LGP) antibody production. These animals were injected with ethanol (20% w/v, 3.6 g/kg, ip); the latency for the loss of the righting reflex (LORR) and the time for the recovery of the righting reflex (RORR) were measured. Body temperature of both lines was also recorded before the injections and at RORR. Blood samples were taken at RORR to determine blood ethanol concentration. The results showed that the HGP mice presented shorter latency for sleep, longer sleeping time, and lower blood ethanol levels than the LGP mice. These data suggest that the HGP line is more sensitive to the effects of ethanol, and provide an additional approach for studying interactions between the immune and the central nervous systems.

Animals↗
PubMed1993

Immunocompetence in the long sleep and short sleep mouse lines: baseline versus primed responses.

Two lines of mice which were selectively bred for high (Long Sleep; LS) and low (Short Sleep; SS) reactivities to a sedative dose of ethanol, are also differentiated by agents that act at the GABAA-receptor complex. Since this supramolecular complex may also modulate immune function, measures of immunity have been examined in these lines. In the present study the immune responsiveness before and after an allogeneic priming stimulus was investigated. Lower mitogen-induced T-cell proliferation, mixed leukocyte reaction, and cytotoxic T lymphocyte activity were found in unprimed LS compared to unprimed SS mice. In contrast, the LS line exhibited a marked augmentation of these responses after priming, while the SS mice appeared unresponsive to this challenge. Addition of splenocytes or cell-free splenic cultures from primed mice to cultures from unprimed mice suggested that differences in priming-induced cell-to-cell interactions, rather than the release of a soluble helper factor(s) into the medium, are responsible for the marked augmentation of the secondary response in LS, compared to SS mice. Fewer T-helper and T-suppressor/cytotoxic cells were found in LS compared to SS mice, and this was unaffected by priming. These results extend previous findings demonstrating a higher natural killer cell activity and rate of tumor rejection in LS mice and suggest that these lines may be useful in studying the regulatory role of the GABAA complex in immune function.

Animals↗
PubMed1993

Alterations of immune status induced by the sympathetic nervous system: immunomodulatory effects of DMPP alone and in combination with morphine.

The aim of the present study was to explore the involvement of the sympathetic nervous system (SNS) in the immunomodulatory effects of morphine in Lewis rats and to assess the effects of alterations in SNS activity on immune status. In the first experiment, sympathetic tone was elevated by administering the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium (DMPP) in doses of 0, 0.01, 0.1, and 1.0 mg/kg, sc, 5 min before the sc administration of 15 mg/kg morphine or saline. Animals were sacrificed 1 h after the morphine injection and multiple in vitro immune assays were then conducted. Although DMPP did not significantly enhance morphine's suppressive effects in the spleen and blood mitogen stimulation assays or the splenic natural killer (NK) cell assay, DMPP alone produced effects on immune status in saline-treated animals. Therefore, a second experiment was conducted to examine the immunomodulatory effects of increasing peripheral sympathetic outflow in greater detail. Animals were administered a wider dose range of DMPP (0, 0.005, 0.05, 0.5, and 5.0 mg/kg, sc) 30 min prior to sacrifice and an expanded repertoire of immune assays was conducted. DMPP dose-dependently suppressed the mitogenic responsiveness of splenic T lymphocytes, splenic NK cell activity, and interleukin-2 (IL-2) and gamma-interferon production by stimulated splenocytes. DMPP did not alter the total number of splenic leukocytes or the proliferative response of splenic B lymphocytes. In the mesenteric lymph nodes, DMPP had no effect on mitogenic responsiveness, the production of IL-2 or the total number of leukocytes. In the blood, however, DMPP increased mitogenic responsiveness at intermediate doses and decreased proliferation at higher doses. DMPP also dose-dependently decreased the number of blood leukocytes/ml. Taken together, these results indicate that increasing peripheral sympathetic outflow results in profound effects on immune status that depend upon the degree to which SNS activity is altered, the compartment of the immune system, and the lymphocyte subtype.

Adjuvants, Immunologic↗
PubMed1994

An interleukin-1 beta-induced noradrenaline release in the spleen is mediated by brain corticotropin-releasing factor: an in vivo microdialysis study in conscious rats.

The purpose of this study was to investigate whether an intraperitoneal injection of interleukin-1 beta (IL-1 beta) affects noradrenaline release in the spleen through its action on the brain of conscious rats. An in vivo microdialysis technique consisting of high-performance liquid chromatography with electrochemical detection was used for chronic monitoring of the splenic noradrenaline. The perfusion of a high concentration of K+ Ringer solution through the microdialysis probe significantly increased the concentration of noradrenaline in the spleen, while a perfusion of either Ca(2+)-free or tetrodotoxin-containing Ringer solution decreased the noradrenaline level in the dialysate. These results indicate that the noradrenaline recovered in the splenic dialysate is mainly derived from the nerve terminals of the splenic sympathetic nerve. The intraperitoneal injection of IL-1 beta (100 ng/kg) produced an immediate and significant increase in the noradrenaline levels in the spleen. The increased level reached a maximum level 40 min after injection and then gradually returned to the basal level. An intracerebroventricular (ICV) injection of a corticotropin-releasing factor (CRF) antagonist (alpha-helical CRF9-41, 30 micrograms) significantly attenuated the IL-1 beta-induced increase in the noradrenaline release. An ICV injection of CRF (2 micrograms) also caused a significant increase in splenic noradrenaline, which showed two distinct peaks at 20 and 140 min, respectively. These results suggest that the intraperitoneal injection of IL-1 beta facilitates noradrenaline release in the spleen through activation of the sympathetic nerve, and the increased sympathetic activity is, at least in part, due to the excitation of neurons containing CRF in the brain.

Animals↗
PubMed1994

Morphine-induced decreases in in vivo antibody responses.

Endogenous opioids have been shown to be released during acute stress and could play a role in immune modulation and activation of the hypothalamo-pituitary-adrenal axis. We investigated the ability of morphine sulfate to mimic stressor effects on decreases in in vivo antibody responses. Sprague-Dawley and Fischer 344 rats were given an intraperitoneal injection of an antigen, Keyhole limpet hemocyanin (KLH), followed by a single intravenous injection of either saline or varying doses of morphine sulfate. The corticosterone and anti-KLH IgG antibody responses to morphine were measured. A dose-dependent increase in corticosterone was observed. Significantly lower levels of anti-KLH IgG antibodies were observed in morphine-treated animals but these effects were strain and dose dependent. In Sprague-Dawley rats, 3 and 10 mg/kg doses of morphine decreased antibody levels while 1.5, 5, and 15 mg/kg did not change antibody responses. In Fischer 344 rats a dose of 5 mg/kg of morphine decreased antibody levels while 10 and 15 mg/kg did not change antibody responses. These results indicate that morphine can decrease antibody levels and that these decreases are not correlated with elevated levels of corticosterone. To determine if opioid binding is critical to these changes, animals received naltrexone prior to the administration of morphine. Naltrexone partially attenuated corticosterone levels, but completely blocked morphine-induced changes in immune function.

Animals↗
PubMed1994

Effect of one or more footshocks on spleen and blood lymphocyte proliferation in rats.

The effect of 1 (1.6 mA, 5 s), 3, 8, or 16 inescapable footshocks on the response of spleen and peripheral blood lymphocytes to nonspecific mitogenic stimulation and plasma corticosterone levels was studied in adult Lewis male rats. One footshock suppressed mitogenic activity in the spleen and this effect was comparable to 3, 8, and 16 footshocks. The maximum suppression to nonspecific mitogenic stimulation in the spleen was observed at 1 and 10 min after exposure to a single footshock and suppression of the mitogenic responses in the spleen persisted for at least 60 min. In contrast, immediately after a single footshock peripheral blood lymphocyte mitogenic function was not suppressed but instead was significantly enhanced. A significant suppression of mitogenic responsiveness of blood lymphocytes occurred 30 min after exposure to a single footshock and at 60 min the blood mitogenic activity did not differ from the home cage controls. Eight footshocks produced a significant suppression of mitogenic responses in the blood and 16 footshocks produced the greatest suppression of blood mitogenic function. These data suggest that 1 brief footshock caused activation of the HPA axis and sympathetic nervous system and resulted in significant alteration of the immune system. We suggest that noncomplex models of short-term stress may provide for a better understanding of the mechanisms underlying the development of stress reactions in the CNS and the periphery.

Animals↗
PubMed1994

Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations.

In this study, we examined hormonal regulation of the distribution profiles of leukocyte subpopulations in the peripheral blood of rats. Flow cytometric analysis revealed significant and selective changes in the numbers and the percentages of peripheral blood leukocyte subpopulations which were a function of diurnal variations in hormone secretion and hormonal changes induced by acute stress. Changes in numbers and percentages of leukocyte subpopulations, which varied with time of day, were similar to changes observed under stress conditions. At the beginning of the rat's active period, and after 1 h of restraint stress, there was a significant reduction in numbers of leukocytes and lymphocytes. This reduction was primarily accounted for by a decrease in numbers of B cells, natural killer cells, monocytes (diurnal study), and helper T cells (diurnal study). There was also a significant decrease in the percentage of lymphocytes which was mirrored by an increase in the percentage of neutrophils in the peripheral blood. Peripheral blood leukocyte numbers were inversely related to plasma corticosterone levels. These results suggest that the endocrine system plays a role in the regulation of immune cell turnover and/or redistribution between immune compartments under conditions of normal daily experiences, namely, the diurnal cycle, and mild acute stress. They also suggest that these effects are selective for certain subpopulations of leukocytes.

Acute Disease↗