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PubMed2004

The many faces of VIP in neuroimmunology: a cytokine rather a neuropeptide?

Neuroimmunomodulation has experienced an explosive growth not only in basic research, but expanding to the point that prospective clinical research could be now a reality. A crucial factor for the functioning of this intimate bidirectional network was the demonstration that the immune and neuroendocrine systems speak a mutual biochemical language. This implies 1) production of neuroendocrine hormones and neuropeptides by immune cells and of cytokines by neuroendocrine cells; 2) evidence for shared receptors on cells of the immune and neuroendocrine systems; 3) effect of neuroendocrine mediators on immune functions; and 4) effect of cytokines on the neuroendocrine system. This reduces traditional differences between neurotransmitters, hormones, and immune mediators and raises the following question: what can we now regard as immune or neuroendocrine? Vasoactive intestinal peptide (VIP) is one example of this paradigm. VIP has traditionally been classified as a neuropeptide/neurotransmitter based in its capacity to mediate and regulate neuronal functions. Recent work has demonstrated that VIP is produced by T cells, especially Th2 cells, and that through specific receptors it exerts immunological functions typically ascribed to Th2 cytokines in nervous and immune systems. Here, we postulate that instead of a neuropeptide, VIP could be fully considered a type 2 cytokine with a key role in neuroimmunology.

Allergy and Immunology↗
PubMed2005

Stress and the gastrointestinal tract.

Stress, defined as an acute threat to homeostasis, evokes an adaptive or allostatic response and can have both a short- and long-term influence on the function of the gastrointestinal tract. The enteric nervous system is connected bidirectionally to the brain by parasympathetic and sympathetic pathways forming the brain-gut axis. The neural network of the brain, which generates the stress response, is called the central stress circuitry and includes the paraventricular nucleus of the hypothalamus, amygdala and periaqueductal gray. It receives input from the somatic and visceral afferent pathways and also from the visceral motor cortex including the medial prefrontal, anterior cingulate and insular cortex. The output of this central stress circuit is called the emotional motor system and includes automatic efferents, the hypothalamus-pituitary-adrenal axis and pain modulatory systems. Severe or long-term stress can induce long-term alteration in the stress response (plasticity). Corticotropin releasing factor (CRF) is a key mediator of the central stress response. Two CRF receptor subtypes, R1 and R2, have been described. They mediate increased colonic motor activity and slowed gastric emptying, respectively, in response to stress. Specific CRF receptor antagonists injected into the 0 block these visceral manifestations of stress. Circulating glucocorticoids exert an inhibitory effect on the stress response by receptors located in the medial prefrontal cortex and hippocampus. Many other neurotransmitters and neuroimmunomodulators are being evaluated. Stress increases the intestinal permeability to large antigenic molecules. It can lead to mast cell activation, degranulation and colonic mucin depletion. A reversal of small bowel water and electrolyte absorption occurs in response to stress and is mediated cholinergically. Stress also leads to increased susceptibility to colonic inflammation, which can be adaptively transferred among rats by sensitized CD4(+) lymphocytes. The association between stress and various gastrointestinal diseases, including functional bowel disorders, inflammatory bowel disease, peptic ulcer disease and gastroesophageal reflux disease, is being actively investigated. Attention to the close relation between the brain and gut has opened many therapeutic avenues for the future.

Adaptation, Psychological↗
PubMed1987

Effect of hypothalamic lesions on experimental autoimmune diseases in rats.

The development of experimental autoimmune encephalomyelitis (EAE) was prevented in rats immunized with encephalitogenic antigen two weeks, but not twelve weeks, after stereotaxic electrolytic destruction of the anterior hypothalamus. Serum antibody level to the antigen myelin basic protein was decreased, and in vitro lymphocyte transformation response to a mitogen was increased. On the other hand, incidence and intensity of chronic experimental autoimmune myasthenia gravis (EAMG) induced by acetylcholine receptor immunization were higher in rats with anterior hypothalamic lesion. In addition, expression of EAE in rats was inhibited when dopamine and norepinephrine in brain were depleted due to intraventricular injection of 6-hydroxydopamine or subcutaneous injection of reserpine. The study indicates hypothalamic modulatory effects on autoimmune response as well as possible involvement of neurotransmitters in this kind of neuroimmunomodulation.

Animals↗
PubMed1992

Mobilization of cutaneous immunity for systemic protection against infections.

This laboratory reported that a single subcutaneous (SC) injection of the natural steroid hormone dehydroepiandrosterone (DHEA) resulted in significant protection against a lethal herpes virus type 2 encephalitis or a systemic coxsackievirus B4 infection. Our previous results have shown that SC injection of DHEA resulted in upregulation of the specific host immune response resulting in protection against a lethal infection. This hormone did not have any direct antiviral effects in vitro. Furthermore, results indicate that, in vivo, DHEA is not the agent directly mediating the upregulation of the immune response. In the skin, DHEA is converted to androstenediol (AED) and it, in turn, is converted to androstenetriol; this is a metabolic process which appears unique to the skin. This report demonstrates that SC injection of AED results in markedly greater resistance against both viral and bacterial infection. Both DHEA and AED appear to function by facilitating and upregulating host immune responses via mobilization of cutaneous immunity to obtain systemic protection against infections. Because these steroids are native to the host and are regulated by the central nervous system, it is suggested that they may be an integral element of neuroimmunomodulation.

Androstenediols↗
PubMed1994

Stress, distress, and immunity.

Since psychoimmunology is now 10 to 20 years of age, it seems appropriate to expect a certain maturity in the field. It seems reasonably well established that there really is neuroimmunomodulation. The biological and medical importance of this is the possible influence of psychological factors on immune competence. Inasmuch as it is reasonably well established that psychological factors do have such an influence, the field must now endeavor to establish how important this influence is. It no longer suffices to show that some sort of stressor has some sort of action on some part of the immune cascade of responses. "Stressors" do not act indiscriminately; they are filtered and interpreted by the brain following psychological principles that again are reasonably well known. The distinction between "stress" and "distress" is important for the health consequences of how and with what success an individual is handling a stressful situation. Concepts such as coping, control, helplessness, and hopelessness are required to understand how immune responses are influenced by the brain and to establish the extent to which these mechanisms have clinical validity in man and animals.

Humans↗
PubMed2006

The role of the sympathetic nervous system in intestinal inflammation.

The nervous system in the intestine controls motility, secretion, sensory perception, and immune function. Peptidergic neurones with neurotransmitters such as substance P and nerve growth factors have been the main focus of neuroimmunomodulation research in the gut. This review summarises the present knowledge concerning the role of the sympathetic nervous system (SNS) in modulating intestinal inflammation. The role of the SNS for gut inflammation is compared with its role in rheumatoid arthritis which demonstrates notable similarities. Nerve fibres of the SNS not only enter the enteric plexuses but also innervate the mucosa and gut associated lymphoid tissue (GALT). The SNS has pro- and anti-inflammatory functions. Neurotransmitters such as norepinephrine, adenosine, and others can evoke remarkably different opposing effects depending on concentration (presence of sympathetic nerve fibres and extent of neurotransmitter release), receptor affinity at different receptor subtypes, expression of adrenoceptors, availability of cotransmitters, and timing of SNS activity in relation to the inflammatory course. This review attempts to integrate the different perspectives of the pro- and anti-inflammatory effects of the SNS on inflammatory disease of the gut.

Gastroenteritis↗
PubMed1996

Interleukin-6 (IL-6) is secreted from the brain after intracerebroventricular injection of IL-1 beta in rats.

To test the hypothesis that the brain is a source of the interleukin-6 (IL-6) that appears in the peripheral circulation of rats after intracerebroventricular (icv) injection of IL-1 beta, the concentration of bioactive IL-6 in superior sagittal sinus (SSS) blood plasma was compared with aortic plasma 4 h after icv injection of 100 ng of recombinant human IL-1 beta at a time at which cerebrospinal fluid (CSF) IL-6 concentration was found to be markedly elevated. In three separate experiments, CSF IL-6 concentration (pg/ml; values are means +/- SE) was significantly elevated after icv IL-1 beta compared with saline control injections (25,879 +/- 11,472 vs. 35.5 +/- 5; 32,323 +/- 4,945 vs. 128 +/- 29; 114,410 +/- 33,563 vs. 848 +/- 250, respectively). The concentration of plasma IL-6 (pg/ml) in the aortas of rats injected intracerebroventricularly with IL-1 was greater than in controls [252 +/- 93 vs. 36.7 +/- 8.3, P = 0.0037; 361 +/- 95 vs. 57 +/- 13, P = 0.02; 2,254 +/- 550 vs. 1,239 +/- 666, P = 0.26 (NS)]. In IL-1-injected animals, SSS venous plasma IL-6 (pg/ml) was greater than in the aorta in all three studies (1,617 +/- 357 vs. 252 +/- 93, P = 0.0011; 3,754 +/- 1,188 vs. 361 +/- 95, P = 0.024; 8,208 +/- 1,388 vs. 2,254 +/- 550, P = 0.0054). The concentration difference (pg/ml) between SSS and aorta was significantly greater after IL-1 beta injection than in diluent-injected animals (1,365 +/- 369 vs. 48.3 +/- 13, P = 0.0083; 3,393 +/- 1,203 vs. 126 +/- 59, P = 0.035; 5,954 +/- 1,260 vs. 494 +/- 774, P = 0.0042). Suppression of peripheral sympathetic activation by preganglionic cholinergic blockade (chlorisondamine, 250 micrograms sc) did not prevent the usual IL-1-induced elevation in aortic blood IL-6 (3,272 +/- 1,174 vs. 244 +/- 74 pg/ml, P = 0.0012) nor the increased SSS-aortic gradient (2,541 +/- 1,134 vs. 165 +/- 48, P = 0.0142 by Mann-Whitney comparison). Injection of rat/human corticotropin-releasing hormone (CRH; 10.0 micrograms) icv did not change IL-6 concentration in CSF or in peripheral blood. These studies demonstrated that the brain and/or its supporting structures are activated by icv IL-1 beta to release IL-6 into the blood and that the effect is not dependent on peripheral sympathetic activity or central mobilization of CRH. Direct secretion of IL-6 and possibly of other cytokines from the brain is postulated to be a pathway of neuroimmunomodulation.

Animals↗
PubMedDate not supplied

Melatonin modulates the effects of gastric injury in rats: role of prostaglandins and nitric oxide.

Experimental evidence has been presented connecting melatonin with the prevention or treatment of gastrointestinal disorders either by the scavenging properties of active oxygen or by receptor-mediated stimulation of gene expression of neutralizing enzymes. Prostaglandins and nitric oxide are important neuroimmunomodulators in digestive physiology and different studies have indicated that the protective properties of melatonin may be explained by prostaglandin and/or nitric oxide mechanisms. The aim of the present study was to examine the effect of intraperitoneal administration of melatonin on in vivo changes in PGE(2), generated in gastric mucosal lesions by ischemia-reperfusion. Cyclic GMP nucleotide was also studied as an index of the principal enzymatic activity involved in the metabolism of nitric oxide, the nitric oxide synthase. The different immunological tests showed that the intraperitoneal administration of melatonin prevents the postischemic decrease in prostaglandins. The concentration of this eicosanoid in the rat mucosa treated with 20 mg.kg(-1) of melatonin was significantly higher (p < 0.05) than that in the control rats. The amount of cyclic GMP in the stomach decreased because of ischemia-reperfusion. In treated animals however, a marked increase occurred in concentrations of GMP, but the difference was not statistically significant. The results suggest that the mechanism of protection afforded by melatonin against lesions induced by gastric ischemia-reperfusion may be due to stimulation of the synthesis of eicosanoid protectors during the ischemic process.

Animals↗
PubMed1997

Melatonin and the immune system.

In recent years, melatonin, i.e. the major endocrine product of the pineal gland, was investigated as to its possible regulatory role in the communication between the neuroendocrine and the immune systems. First indications that melatonin may be an endocrine immunomodulator came from early reports about antitumor effects in animals and humans. Since then evidence has accumulated suggesting that melatonin-as a well-preserved molecule during evolution-is indeed involved in the feedback between neuroendocrine and immune functions. At present we begin to discover molecular mechanisms, by which melatonin affects cellular functions in general, and from the variety of possible direct and indirect interactions it appears that melatonin may play a complex physiological role in neuroimmunomodulation. In this article we want to give a critical review of the numerous reports on melatonin influencing immune functions, and to discuss the possible different mechanisms of action, which were suggested recently.

Animals↗
PubMedDate not supplied

Can loss and grief activate latent neoplasia? A clinical case of possible interaction between genetic risk and stress in breast cancer.

BACKGROUND: Nineteenth-century physicians working with cancer patients frequently reported that severe emotional losses and grief occurred in some cases before cancer. Research on psychoneuroimmunology seems to reactivate this interest and could give a possible convincing background. METHOD: We recently observed the case of a 45-year-old woman who developed symptoms of breast cancer (ductal infiltrating carcinoma, T1, N1, M0) 3 years after the loss of her only child. The affection for the child compensated inadequacies of her marriage, which became increasingly unstable. The child died in a dramatic accident at home, while his mother was near him but unable to help. RESULTS: The patient had a moderate genetic-familial risk of mammary cancer. Animal studies strongly suggest that stress, through neuroimmunomodulatory mediatory mechanisms, can significantly affect appearance and progression of mammary cancer. The patient developed long-lasting intense grief, despair and hopelessness. DISCUSSION: We discuss the case from three main standpoints: genetic and risk factors for breast cancer; findings which demonstrated a relationship between stress, neuroimmunomodulation and cancer in animals; data from autopsy studies which found foci of latent breast cancer in 20% of healthy women in the same age range. Stress does not create cancer. However we hypothesize that in this case it could have contributed by the activation of a latent neoplasia and/or by impairing immunosurveillance during a critical life phase.

Adult↗
PubMed1988

Suppression of splenic natural killer cell activity in rats with brain tumors.

After inoculating 9L glioma cells into the brains or into subcutaneous regions of the back of rats, we investigated splenic natural killer (NK) cell activity for 3 weeks using a 4-hour 51Cr release assay. Only rats with brain tumors showed decreased splenic NK cell activity. The spleens of these rats were morphologically small and atrophic. Expansive brain tumors were compressing the basal ganglia, thalamus, and hypothalamus after 2 weeks, and the rats ultimately died of cerebral herniation, usually by 3 weeks after inoculation. The decreased splenic NK cell activity in rats with brain tumors might be the result of neuroimmunomodulation secondary to hypothalamic dysfunction due to increasing tumor compression.

Animals↗
PubMed1999

The influence of septal lesions on sodium and water retention induced by Walker 256 tumor.

In the course of studies on the effects of septal area lesions on neuroimmunomodulation and Walker 256 tumor development, it was observed that tumor-induced sodium and water retention was less marked in lesioned than in non-lesioned rats. In the present study possible mechanisms involved in this phenomenon were investigated. The experiments were performed in septal-lesioned (LW; N = 15) and sham-operated (SW; N = 7) 8-week-old male Wistar rats, which received multifocal simultaneous subcutaneous (sc) inoculations of Walker 256 tumor cells about 30 days after the stereotaxic surgery. Control groups (no tumor, sham-operated food-restricted (SFR), N = 7) and lesioned food-restricted (LFR, N = 10) were subjected to a feeding pattern similar to that observed in tumor-bearing animals. Multifocal inoculation of Walker 256 tumor rapidly induces anorexia, which is paradoxically accompanied by an increase in body weight, as a result of renal Na+ and fluid retention. These effects of the tumor were also seen in LW rats, although the rise in fractional sodium balance during the early clinical period was significantly smaller than in SW rats (day 4: SW = 47.6 +/- 6.4% and LW = 13.8 +/- 5.2%; day 5: SW = 57.5 +/- 3.5% and LW = 25.7 +/- 4.8%; day 6: SW = 54.4 +/- 3.8% and LW = 32.1 +/- 4.4%; P < 0.05), suggesting a temporary reduction in tumor-induced sodium retention. In contrast, urine output was significantly reduced in SW rats and increased in LW rats (LW up to -0.85 and SW up to 4.5 ml/100 g body weight), with no change in osmolar excretion. These temporary changes in the tumor's effects on LW rats may reflect a "reversal" of the secondary central antidiuretic response induced by the tumor (from antidiuretic to diuretic).

Animals↗
PubMed2004

Tachykinins and tachykinin receptors: structure and activity relationships.

In addition to the classical neurotransmitters, acetylcholine and noradrenaline, a wide number of peptides with neurotransmitter activity have been identified in the past few years. Among them, the tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) appear to act as mediators of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission. Tachykinins interact with specific membrane proteins, belonging to the family of G protein-coupling cell membrane receptors. Until now, three tachykinin receptors termed NK1 (NK1R), NK2 (NK2R) and NK3 (NK3R) have been cloned in different species. A large amount of reports suggests that these peptides are involved in nociception and neuroimmunomodulation, and in the development of different diseases such as bronchial asthma, inflammatory bowel syndrome and psychiatric disorders. Tachykinin receptor antagonists are therefore promising, therapeutically relevant agents. However, and in spite of extensive research, the obtention of selective antagonists of tachykinin receptors have revealed very difficult. An understanding of how ligands interact with their receptors is essential to permit a rational design of compounds acting selectively at the tachykinin receptor level. The major aim of the present article is to review the structure-activity data that exist for tachykinins and their receptors, with the purpose of getting insight into basic structural requirements that determine ligand/receptor interaction.

Amino Acid Sequence↗
PubMed2005

Characterization of membrane-associated substrates of Ca2+-dependent kinases in astrocytes.

Membrane-associated kinase substrates are likely transducers of extracellular signals elicited by neuroimmunomodulators and other signaling molecules. Whereas specific signal transduction pathways in astrocytes are being defined, the global view is lacking. We, therefore, characterized membrane-associated substrates of Ca2+-dependent kinases in primary astrocytes using 2-dimensional gel electrophoresis. Ten proteins were phosphorylated in vitro and characterized with respect to their relative molecular mass (in the range 10 kDa - 100 kDa), isoelectric point (range 4.2 - 9.0) and four conditions of phosphorylation. They varied broadly in their requirements for phosphorylation displaying distinct kinase preferences. Eight phosphoproteins were substrates of protease kinase C. Judging by abundance and intensity of phosphorylation, the principal PKC substrates were three acidic proteins associated with the plasma membrane. These results suggest that a relatively small number of membrane-associated proteins serve as transducers of signals mediated by Ca2+-dependent kinases and most of them are PKC substrates in astrocytes.

Animals↗
PubMed1988

Neural mechanisms in the pyrogenic and acute-phase responses to interleukin-1.

It has become increasingly apparent over the past several decades that the hypothalamus, among other brain regions, plays an important part in the modulation of the immune system (reviewed in Korneva et al., 1985; Roszman & Brooks, 1985; Jankovic & Spector, 1986; Cotman et al., 1987). Since the hypothalamus also mediates the fever and various other acute-phase responses characteristic of the early stages of infection (reviewed in Hellon & Townsend, 1983; Blatteis, 1984, 1985; Cooper, 1987), it is possible that the localization within a common brain region of the controllers of several, different host defense reactions is not a happenstance, but represents a highly organized neuronal network serving to coordinate them. Indeed, pyrogenic, inflammatory, and immune responses do interact in the defense of the host against infection (reviewed in Dinarello, 1984). It is not yet known how immune responses are integrated centrally, but some data are available on the neural mechanisms controlling fever and certain components of the acute-phase reaction. The purpose of this paper is to review these briefly in the hope that a background can be provided against which features that may be common to neuroimmunomodulation and to the control of acute-phase reactions might be revealed.

Acute-Phase Reaction↗
PubMed1991

The pineal gland in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology. Clinical, neurochemical, and neuroradiological data implicate the pineal gland in the pathophysiology of MS. To investigate the relationship of MS to the pineal gland further, we surveyed the prevalence of pineal calcification (PC) on CT scan in a cohort of 29 MS patients (7 men, 22 women, mean age: 40.1 years, SD = 8.9) who were admitted consecutively to a neurological service for acute exacerbation of symptoms. For the purpose of comparison, we also surveyed the prevalence of choroid plexus calcification (CPC) in the sample. Twenty-one age and sex-matched neurological patients served as controls (5 men, 16 women, mean age: 37.0, SD = 9.2). PC was seen in 100% of MS patients, while 72.4% patients (N = 21) had CPC. In the control sample, PC was found in 42.8% (N = 9) and CPC in 28.5% (N = 6). Thus, the strikingly high prevalence of PC in MS provides indirect support for an association between MS and abnormalities of the pineal gland. Moreover, since pineal melatonin is involved in neuroimmunomodulation, we propose, for the first time, that abnormalities of pineal melatonin functions are implicated in the pathophysiology of the disease.

Adult↗
PubMed1996

Involvement of delta-opioid receptors in immunosuppression.

The present experiments demonstrate that: (1) activation of delta-opioid receptors by a highly selective agonist DSLET leads to immunosuppression, whereas the blockade of these receptors by enkephalin analog ICI 174864 produces immunostimulation; (2) the immunomodulating effect of delta-opioid receptors is mediated by central mechanisms involving the hypothalamus-hypophysis complex; (3) the postsynaptic 5-HT (serotonin) receptors of 5-HT-2 type are involved in the immunoinhibitory action of DSLET. On the other hand, the immunostimulating effect of ICI 174864 is realized with the participation of D-2 postsynaptic DA (dopamine) receptors. It has also been shown that thymus is implicated in the immunostimulating influence of ICI 174864. The data obtained are explained as a result of the interaction of the neuromediator and opioid peptidergic systems in neuroimmunomodulation.

Analgesics↗
PubMed1997

Transactivation of proenkephalin gene by HTLV-1 tax1 protein in glial cells: involvement of Fos/Jun complex at an AP-1 element in the proenkephalin gene promoter.

The human T-cell lymphotropic virus type 1 (HTLV-1), an etiologic agent for adult T-cell leukemia, is strongly associated with tropical spastic paraparesis, a chronic neurological disease. The HTLV-1 genome encodes a protein, tax1, an autoregulator of enhanced viral RNA transcription, that also transactivates/represses certain cellular gene promoters. Enkephalins are opioid peptides that function as neurotransmitters and neuroimmunomodulators. We earlier reported that the proenkephalin gene is transactivated by tax1 protein in glial cells. The nucleotide sequence upstream of -190 base pairs in the proenkephalin gene promoter is necessary for maximal transactivation by tax1 while the sequence downstream of -190 bp confers modest activation by tax1. We investigated the cellular transcription factors in tax1 expressing glial cells that associate with the proenkephalin promoter and herein demonstrate the enhanced interaction and involvement of c-Fos/c-Jun proteins in the complexes formed at the AP-1 site. The HTLV-1 tax1 expressing stable glial cell lines produced functional tax1 protein that increased the expression of endogenous proenkephalin gene. The comparative electrophoretic mobility shift and 'supershift' analysis using specific antibodies indicated the enhanced presence of c-Fos and c-Jun proteins in the DNA: protein complex formed at the AP-1 site. The c-Fos protein expression significantly increased in the tax1 expressing glial cells. The tax1 induced c-Fos protein levels and the concurrently increased association of c-Fos/c-Jun transcription factors at the AP-1 site imply a strong functional significance in the activation of proenkephalin gene expression in tax1 expressing glial cells.

Animals↗