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1.
Mol Psychiatry ; 18(9): 1006-17, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23089634

ABSTRACT

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1ß and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.


Subject(s)
Dimerization , Illness Behavior/drug effects , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Receptors, Glucocorticoid/metabolism , Animals , Body Temperature/drug effects , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Carbon Dioxide , Corticosterone/blood , Cytokines/blood , Gene Expression Regulation/drug effects , Male , Mice , Motor Activity/drug effects , Oxygen Consumption/drug effects , RNA, Messenger/metabolism , Telemetry , Time Factors
2.
Mucosal Immunol ; 3(5): 496-505, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20505661

ABSTRACT

Steroid hormones, such as progesterone, are able to modify immunity and influence disease outcome. Dendritic cells (DCs) drive potent immune responses, express receptors for steroid hormones, and may be a primary target of steroid hormone actions during infection of the genital tract, including uterine tissue. Here, we report that progesterone limited DC-associated activation marker expression and inhibited cytokine secretion by uterine DCs, which was associated with changes in signal transducer and activator of transcription 1 (STAT1) activity. We also found that DCs from mice at stages with higher progesterone concentrations (diestrus, metaestrus) were more sensitive to progesterone than those in stages with lower progesterone concentrations (proestrus, estrus), both in vitro and in vivo. This difference correlated with the levels of progesterone receptor expressed by DCs. These data suggest that progesterone regulates DC function and could contribute to the susceptibility of females to uterine and other genital tract infections at selected time periods throughout the life cycle.


Subject(s)
Cytokines/biosynthesis , Dendritic Cells/metabolism , Progesterone/metabolism , Receptors, Progesterone/biosynthesis , STAT1 Transcription Factor/metabolism , Administration, Intravaginal , Animals , Cell Differentiation/physiology , Cells, Cultured , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Lipopolysaccharides/immunology , Lipopolysaccharides/metabolism , Menstrual Cycle/blood , Mice , Mice, Inbred C57BL , Progesterone/blood , Progesterone/immunology , Receptors, Progesterone/genetics , Receptors, Progesterone/immunology , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , Signal Transduction/physiology , Transcriptional Activation/physiology , Uterus/cytology
3.
Horm Metab Res ; 39(6): 404-12, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17578756

ABSTRACT

Glucocorticoids have been reported to affect immunity at varying concentrations. While glucocorticoids have shown profound effects on innate immunity, their effects on rat dendritic cells have not been fully examined. In this study, we evaluated the effects of the synthetic glucocorticoid dexamethasone on cultured rat dendritic cells (DCs) from spleen and derived from bone marrow cells to determine whether responsiveness to dexamethasone varies between DCs from different organ sites. Cells were analyzed for expression of glucocorticoid receptor (GR), the primary receptor through which dexamethasone exerts its effects and was found to be primarily located in the cytoplasm of immature DCs. Bone marrow-derived DCs showed more sensitivity to dexamethasone treatment compared to splenic DCs. Dexamethasone treatment of LPS-matured DCs had profound dose-dependent effects on cytokine production. Dexamethasone treatment also led to a dose-dependent downregulation of expression of costimulatory molecules by mature DCs. Dexamethasone modified immature DC uptake of antigen (FITC-Dextran), with slightly higher numbers of splenic DCs taking up antigen compared to bone marrow-derived DCs. These data suggest that dexamethasone is able to similarly affect both bone marrow-derived and splenic DC function at the immature and mature DC states and could contribute to exacerbation of infection by hindering DC-mediated immune responses.


Subject(s)
Dendritic Cells/drug effects , Dexamethasone/pharmacology , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/physiology , Cytokines/biosynthesis , Dendritic Cells/physiology , Female , Lipopolysaccharides/pharmacology , Rats , Rats, Inbred F344 , Spleen/cytology
4.
J Neuroimmunol ; 121(1-2): 32-9, 2001 Dec 03.
Article in English | MEDLINE | ID: mdl-11730937

ABSTRACT

Lewis (LEW/N) and Fischer (F344/N) rats have different responses to inflammatory and behavioral stressors due to differences in hypothalamus-pituitary-adrenal (HPA) axis function. For example, LEW/N rats are more sensitive to restraint, inflammation and experimentally induced autoimmunity due to decreased HPA activity. The HPA axis response to peripheral inflammation is mediated, at least in part, by IL-1beta and its receptor, IL-1 type I (IL-1RI). Here, we studied the distribution of IL-1RI mRNA in the brains of LEW/N and F344/N rats, and demonstrated that IL-1RI mRNA expression has significantly increased in the basolateral nucleus (BLA) of the amygdala of LEW/N rats. These findings suggest that strain-specific HPA axis responses may be mediated by extrahypothalamic pathways.


Subject(s)
Amygdala/immunology , Amygdala/physiopathology , Encephalitis/immunology , Encephalitis/physiopathology , Receptors, Interleukin-1/genetics , Animals , Female , Gene Expression/immunology , Hypothalamo-Hypophyseal System/immunology , In Situ Hybridization , RNA, Messenger/analysis , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Receptors, Interleukin-1 Type I , Species Specificity
5.
J Rheumatol ; 28(11): 2383-8, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11708406

ABSTRACT

OBJECTIVE: To study the occurrence and function of polymorphism in the human glucocorticoid receptor (hGR) gene in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used single stranded conformation polymorphism (SSCP) and direct sequencing to study the hGR gene in 30 patients with RA, 40 with SLE, and 24 controls. A newly identified polymorphism was transfected in COS-1 cells and the stability of the mRNA containing the polymorphism was tested using real-time PCR. RESULTS: A polymorphism in the hGR gene in exon9beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction of this polymorphism in the hGRb mRNA was found to significantly increase stability in vitro compared to the wild-type sequence. CONCLUSION: Our findings show an association between RA and a previously unreported polymorphism in the hGR gene. This polymorphism increased stability of hGRbeta mRNA, which could contribute to an altered glucocorticoid sensitivity since the hGRbeta is thought to function as an inhibitor of hGRalpha activity.


Subject(s)
Arthritis, Rheumatoid/genetics , RNA, Messenger/metabolism , Receptors, Glucocorticoid/genetics , Animals , COS Cells/drug effects , DNA/analysis , Dactinomycin/pharmacology , Female , Humans , Lupus Erythematosus, Systemic/genetics , Male , Polymorphism, Genetic , Polymorphism, Single-Stranded Conformational , Protein Isoforms , RNA Splice Sites/genetics , RNA Stability/genetics , RNA, Messenger/analysis , Receptors, Glucocorticoid/classification , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Transfection
6.
FEMS Immunol Med Microbiol ; 31(3): 219-25, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11720818

ABSTRACT

Cellular components of innate immunity (NK cells, monocytes and granulocytes) play an important role in early resistance to Listeria monocytogenes in the mouse model. Minimally invasive methods of measuring the bacteriocidal capacity of these cells may be useful as a biomarker of susceptibility in humans. A technique was developed whereby the uptake and survival of L. monocytogenes could be measured in human granulocytes and monocytes using small volumes of peripheral blood. This method used flow cytometry to detect the presence of PKH-2-labeled bacteria within these cells. Survival of bacteria was determined by sorting of infected cells based on a combination of fluorescence and light scattering properties. Considerable variation in bacterial recovery was seen between normal volunteers. There was consistently greater survival of a fully virulent strain of L. monocytogenes within monocytes and granulocytes compared with an isogenic strain lacking the hemolysin, listeriolysin O, when measured at baseline. There was no evidence of longer-term bacterial survival or growth at 2 or 24 h. This technique may be useful for assessment of both host resistance and pathogen virulence.


Subject(s)
Flow Cytometry , Granulocytes/immunology , Listeria monocytogenes/immunology , Monocytes/immunology , Phagocytosis , Adult , Cell Separation , Culture Media , Female , Fluorescent Dyes/metabolism , Granulocytes/microbiology , Hemolysin Proteins/genetics , Humans , Listeria monocytogenes/genetics , Listeria monocytogenes/isolation & purification , Listeria monocytogenes/pathogenicity , Listeriosis/microbiology , Male , Monocytes/microbiology , Organic Chemicals , Virulence
7.
J Endocrinol ; 169(3): 429-35, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11375112

ABSTRACT

Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; locally, at sites of inflammation. Estrogens also play an important role in immune modulation, and contribute to the approximately 2- to 10-fold higher incidence of autoimmune/inflammatory diseases seen in females of all mammalian species. During inflammation, cytokines from the periphery activate the central nervous system through multiple routes. This results in stimulation of the hypothalamic-pituitary-adrenal axis which, in turn through the immunosuppressive effects of the glucocorticoids, generally inhibits inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1- to a TH2-type pattern. Interruptions of this loop at any level and through multiple mechanisms, whether genetic, or through surgical or pharmacological interventions, can render an inflammatory resistant host susceptible to inflammatory disease. Over-activation of this axis, as occurs during stress, can also affect severity of infectious disease through the immunosuppressive effects of the glucocorticoids. These interactions have been clearly demonstrated in many animal models, across species, strains and diseases, and are also relevant to human inflammatory, autoimmune and allergic illnesses, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, allergic asthma and atopic skin disease. While many genes and environmental factors contribute to susceptibility and resistance to autoimmune/inflammatory diseases, a full understanding of the molecular effects on immune responses of combinations of neuropeptides, neurohormones and neurotransmitters at all levels has opened up new therapeutic approaches and are essential for the design of future therapies based on such principles.


Subject(s)
Autoimmune Diseases/physiopathology , Inflammation/physiopathology , Neurosecretory Systems/physiopathology , Glucocorticoids/physiology , Humans , Hypothalamo-Hypophyseal System/physiology , Immune System/physiopathology , Pituitary-Adrenal System/physiology
8.
Am J Reprod Immunol ; 44(4): 249-52, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11076098

ABSTRACT

PROBLEM: Although estrogen receptor (ER)-alpha has been well characterized, the recently identified novel ER-beta has not. In some tissues, there is overlap of the ERs, which allows for rescue in cases of deficiency; in other tissues, the ERs appear to have opposite effects. The objective of this study was to evaluate the expression of ER-beta during pregnancy. METHOD OF STUDY: Pregnant mouse uteri (embryonic days 6-14, 16, 18) were studied. ER-alpha and ER-beta oligonucleotide probes were end-labeled and in situ hybridization histochemistry was performed. RESULTS: ER-beta was strongly expressed in maternal ovaries; there was no other evidence of strong expression during gestation. ER-alpha was expressed in the uterus throughout gestation, with decreasing intensity as gestation progressed, and in maternal ovarian tissue. CONCLUSIONS: Differential expression of the two ERs was apparent during pregnancy, with ER-alpha playing a dominant role. This may have implications for selective drug treatment targeting estrogen receptors.


Subject(s)
Pregnancy, Animal/genetics , Receptors, Estrogen/genetics , Animals , Base Sequence , Estrogen Receptor beta , Female , Gene Expression , In Situ Hybridization , Mice , Oligonucleotide Probes/genetics , Pregnancy , Pregnancy, Animal/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tissue Distribution , Uterus/metabolism
9.
Mol Med ; 6(4): 319-31, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10949912

ABSTRACT

BACKGROUND: Inbred LEW/N and F344/N rats respectively, are susceptible and relatively resistant to a broad range of inflammatory/autoimmune diseases. We recently identified a quantitative trait locus (QTL) on chromosome 10 that protects the F344/N rat from carrageenan-induced exudation in a dominant fashion. Angiotensin I-converting enzyme (ACE) is one of the candidate genes located in this QTL region that plays an important role in inflammation. MATERIALS AND METHODS: RNA was extracted from both LEW/N and F344/N rat strains and used to produce full length cDNA by reverse transcription polymerase chain reaction (RT-PCR). Both strands of the PCR products were entirely sequenced to determine nucleotide differences between strains. ACE activity was measured using the synthetic substrate 3H-hippuryl-glycylglycine. ACE protein levels were determined by Western blot using a specific ACE antibody. ACE kinetic and inhibition studies were performed using specific substrates (Hip-His-Leu and Acetyl-Seryl-Aspartyl-Acetyl-Lysyl-Proline) and inhibitors (lisinopril, captopril and quinaprilat) for each C- and N-terminal active site. Finally, the dose-effects of lisinopril treatment on carrageenen-induced exudate volume and ACE activity was studied. RESULTS: In this study, we report for the first time a missense mutation in the coding region of ACE cDNA at 5' 1021 from C to T, resulting in a Leu-341 to Phe substitution, close to the N-domain active site in the F344/N rats. Full characterization of soluble and tissue ACE in both LEW/N and F344/N rat strains showed that soluble ACE levels in serum and exudate were 1.5 fold higher in the F344/N rats than those in LEW/N rats. In addition, the soluble ACE level was inversely correlated with the exudate volume. However, the specific ACE activity and its catalytic properties were identical in both strains. Furthermore, the chronic inhibition of serum and exudate ACE levels by lisinopril treatment did not affect the exudate volume in F344/N rats, indicating that several factors besides ACE were involved in the control of carrageenan-induced exudation. CONCLUSIONS: This report describes a complete molecular, biochemical, enzymatic and pharmacologic study of a missense mutation in the ACE cDNA in F344/N rats, that taken together, excludes ACE as a candidate gene involved with resistance to carrageenan-induced exudation in F344/N rats.


Subject(s)
Inflammation/enzymology , Inflammation/genetics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Amino Acid Sequence , Amino Acid Substitution/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Base Sequence , Binding Sites , Blotting, Western , Carrageenan/pharmacology , DNA Mutational Analysis , Exudates and Transudates/enzymology , Inflammation/chemically induced , Inflammation/metabolism , Inhibitory Concentration 50 , Kinetics , Lisinopril/pharmacology , Lung/enzymology , Molecular Sequence Data , Mutation, Missense/genetics , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/chemistry , Quantitative Trait, Heritable , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Solubility
13.
Ann N Y Acad Sci ; 917: 819-24, 2000.
Article in English | MEDLINE | ID: mdl-11268411

ABSTRACT

A variety of animal models have been used to study the role of neuroendocrine responses in various aspects of autoimmune/inflammatory disease. Complex models of autoimmune disease, such as inflammatory arthritis in rats and thyroiditis in chickens, indicate a role for blunted HPA axis and dysregulated sympathoneuronal responses in susceptibility to autoimmune disease. A variety of approaches including pharmacological, surgical (ablation, transplantation), genetic linkage and segregation studies have been used to identify factors contributing to the phenotypes of susceptibility or resistance to inflammatory/autoimmune disease. Innate inflammation, or the earliest nonspecific form of the inflammatory response, which is characterized by fluid exudation and migration of immune cells to inflammatory sites, is a subtrait of these forms of inflammatory disease. Genetic linkage and segregation studies in inflammatory susceptible and resistant rat strains indicate that this subtrait is multigenic and polygenic; that is, that multiple loci on multiple chromosomes, each with a weak effect, control this trait, and that there is a large environmental component to the variability of this trait. Such information derived from animal studies can be used to target candidate genes for further study and to inform the design of human studies.


Subject(s)
Inflammation , Neuroimmunomodulation , Neurosecretory Systems/immunology , Animals , Disease Models, Animal , Humans , Rats
14.
Med Sci Sports Exerc ; 31(12): 1799-806, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10613431

ABSTRACT

PURPOSE: Recent work indicates that among the normal population, persons can be classified as low (LR) or high (HR) stress responders based on hypothalamic-pituitary-adrenal (HPA) axis responses to high-intensity exercise. We studied whether differential activation of the HPA axis affected cytokine production and expression of selected lymphocyte subsets in HR and LR in response to high-intensity exercise after placebo and dexamethasone (DEX; 4 mg). METHODS: Healthy HR (N = 12) and LR (N = 10) underwent two exercise tests at 90% of VO2max, 8 h after placebo or DEX. Expression of lymphocyte surface markers (CD3+, CD4+, CD8+, CD56+), adhesion molecule markers (intercellular adhesion molecule-1/ICAM-1: CD54+ and L-selectin: CD62L+), and concentrations of plasma interleukin 6 (IL-6) were examined before and after exercise. RESULTS: Baseline percentages of CD8+ and CD56+ cells were significantly higher, and concentrations of IL-6 and percentages of CD4+ cells were significantly lower in HR as compared with LR. The percentage of CD54+ and CD62L+ cells was not significantly different in HR and LR. DEX significantly reduced the percentage of CD3+ and CD4+ and increased the percentage of CD8+ and CD56+ subsets; the percent of cells expressing CD54+ increased, whereas CD62L+ decreased. Exercise-induced changes in the percentage of lymphocyte subsets were similar to those induced by DEX. CONCLUSION: In summary, HR and LR have different baseline patterns of IL-6 and lymphocyte subsets, which may reflect differential sensitivity to endogenous glucocorticoids. However, exogenous glucocorticoids induced similar patterns of lymphocyte expression in HR and LR.


Subject(s)
Dexamethasone/pharmacology , Exercise/physiology , Hypothalamo-Hypophyseal System/physiology , Lymphocyte Subsets/physiology , Pituitary-Adrenal System/physiology , Cell Adhesion Molecules/analysis , Female , Humans , Male
15.
Environ Health Perspect ; 107 Suppl 5: 701-7, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10502534

ABSTRACT

The etiology of autoimmune diseases is multifactorial, resulting from a combination of genetically predetermined host characteristics and environmental exposures. As the term autoimmune implies, immune dysfunction and dysregulated self-tolerance are key elements in the pathophysiology of all these diseases. The neuroendocrine and sympathetic nervous systems are increasingly recognized as modulators of the immune response at the levels of both early inflammation and specific immunity. As such, alterations in their response represent a potential mechanism by which pathologic autoimmunity may develop. Animal models of autoimmune diseases show pre-existing changes in neuroendocrine responses to a variety of stimuli, and both animal and human studies have shown altered stress responses in the setting of active immune activation. The potential role of the neuroendocrine system in linking environmental exposures and autoimmune diseases is 2-fold. First, it may represent a direct target for toxic compounds. Second, its inadequate function may result in the inappropriate response of the immune system to an environmental agent with immunogenic properties. This article reviews the relationship between autoimmune diseases and the neuroendocrine system and discusses the difficulties and pitfalls of investigating a physiologic response that is sensitive to such a multiplicity of environmental exposures.


Subject(s)
Inflammation/etiology , Neurosecretory Systems/immunology , Animals , Arthritis, Rheumatoid/etiology , Autoimmune Diseases/etiology , Chickens , Disease Models, Animal , Environmental Exposure , Humans , Lupus Erythematosus, Systemic/etiology , Mice , Rats , Sjogren's Syndrome/etiology , Stress, Physiological/complications
16.
Mamm Genome ; 10(4): 362-5, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10087293

ABSTRACT

Inbred LEW/N rats are relatively susceptible, while histocompatible inbred F344/N rats are relatively resistant to development of a wide variety of inflammatory diseases in response to a range of pro-inflammatory stimuli. In a LEW/N vs. F344/N F2 intercross, we identified a quantitative trait locus (QTL) on Chr 10 that protects in a dominant fashion against the exudate volume component of innate inflammation in the F344/N rat, as well as a suggestive QTL on Chr 2 near the Fibrinogen cluster region. The exudate volume linkage region on Chr 10 may be similar to one of the multiple regions found to link to inflammatory arthritis phenotypes in other crosses. The suggestive linkage on Chr 2 has not been previously reported and does not seem to contribute to this phenotype in the same manner as the QTL on Chr 10. These findings are consistent with the hypothesis that the innate exudate volume trait is a sub-phenotype of more complex inflammatory phenotypes, such as arthritis, and genes within the Chr 10 linkage region could account for differences in this non-specific acute phase component of the inflammatory response. Since the rat Chr 10 exudate volume linkage region we have identified is syntenic with a region of human Chr 17 that has been shown to link to a variety of autoimmune/inflammatory diseases, including insulin-dependent diabetes mellitus, multiple sclerosis, and psoriasis, identification of genes within this linkage region will shed light on genes relevant to the earliest inflammatory component and to susceptibility and resistance to such human autoimmune/inflammatory diseases.


Subject(s)
Genetic Linkage , Genetic Predisposition to Disease , Genome , Inflammation/genetics , Rats, Inbred F344/genetics , Animals , Chromosome Mapping , Humans , Rats
17.
J Neuroimmunol ; 100(1-2): 13-20, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10695711

ABSTRACT

Animal models have been used successfully to study various aspects of neural-immune interactions. Although different approaches carry certain advantages and disadvantages, current high sensitivity screening and manipulation methods coupled with molecular and genetic approaches can be successfully used to tease out the neural pathways that regulate inflammatory disease and the effects of immune molecules, such as interleukins, on neuronal function and pathology. Newer methodologies that measure gene expression of thousands of genes will in the future add to the ability to evaluate complex systems interactions in whole animal models. This review addresses the advantages and disadvantages of some of these approaches in the context of application to neural-immune interactions.


Subject(s)
Autoimmune Diseases/immunology , Disease Models, Animal , Inflammation/immunology , Animals , Autoimmune Diseases/genetics , Brain/immunology , Central Nervous System/immunology , Central Nervous System/pathology , Cytokines/metabolism , Genetic Linkage , Humans , Inflammation/genetics , Mice , Mice, Transgenic , Rats
18.
Ann N Y Acad Sci ; 840: 1-8, 1998 May 01.
Article in English | MEDLINE | ID: mdl-9629231

ABSTRACT

The field of neuroimmune interactions is a prime example of interdisciplinary research spanning immunology, neurobiology, neuroendocrinology, and behavioral sciences. It also exemplifies research from the molecular to the clinical domain. The greatest challenge of the field, which this conference seeks to stimulate, is research that is at the same time precise, focused, and integrative. Several levels of interdisciplinary overlap will be highlighted. At the molecular level, neuro- and immune mediator molecules or their receptors may be members of the same superfamily or may regulate each other's expression or function. Most extensively studied are cytokine-neuropeptide/neurotransmitter interactions, including expression of cytokines within the central nervous system and production of neuropeptides by immune cells or at inflammatory sites. Advances relating cytokine-neurohormone interactions to mechanisms of apoptosis will ultimately shed light on the role of neuroimmune interactions in neuronal cell death and survival and immune cell selection, processes important in neuronal plasticity and immune specificity. At a systems level, advances have been made in cross-disciplinary application of modes of thinking. Incorporation of neurobiology's appreciation of anatomical organization, endocrinology's temporal dimension of neurohormonal secretion, and immunology's understanding of stimulus specificity all contribute to a more precise definition of how these complex systems interact at multiple levels. More precise understanding of effects of disruptions of these communications on disease susceptibility and expression will clarify how perturbations of one system, such as stimulation of the neuroendocrine stress response, might affect expression of disease in the other, such as autoimmune/inflammatory or infectious diseases.


Subject(s)
Allergy and Immunology , Immune System/physiology , Nervous System Physiological Phenomena , Neurology , Societies, Medical , Humans
20.
Exp Neurol ; 146(2): 305-14, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9270039

ABSTRACT

To more directly define the role of central nervous system factors in susceptibility to peripheral inflammatory disease, we examined the effect of intracerebroventricular transplantation of neuronal tissue from inflammatory resistant into inflammatory susceptible rats on subcutaneous carrageenan-induced inflammation (a measure of innate immunity), and on the relative percentage of naive and memory T helper cells in peripheral blood (a measure of the anamnestic immune response). Female inflammatory disease susceptible Lewis (LEW/N) rats transplanted with hypothalamic tissue from inflammatory resistant Fischer (F344/N) rats exhibited > 85% decrease in carrageenan inflammation compared to naive LEW/N rats, LEW/N rats transplanted with F344/N spinal cord, or sham-operated animals. LEW/N rats transplanted with LEW/N hypothalamic tissue exhibited > 50% decrease in carrageenan inflammation. In contrast, intracerebroventricular transplantation of neuronal tissue did not affect the characteristically twofold higher percentage of naive versus memory T helper cells in LEW/N rats, suggesting that the central nervous system (CNS) and hypothalamus play a greater role in the innate inflammatory response than in the acquired immune processes. Grafted tissue survived well and did not show extensive gliosis or inflammation. Compared to naive LEW/N rats, LEW/N rats transplanted with F344/N or LEW/N hypothalamic tissue expressed significantly greater hypothalamic corticotropin releasing hormone mRNA. LEW/N rats transplanted with F344/N hypothalamic tissue also showed significant increases in plasma corticosterone responses to lipopolysaccharide. These data indicate that intracerebroventricular transplantation of fetal hypothalamic tissue from inflammatory resistant into inflammatory susceptible rats suppresses peripheral inflammation partially through hypothalamic factors. These findings have implications for understanding the contribution of specific neuronal tissue in regulation of components of the immune/inflammatory response and in susceptibility to inflammatory disease. Furthermore, this model could be used in the development of potential new treatments for inflammatory/autoimmune diseases aimed specifically at sites within the CNS.


Subject(s)
Cerebral Ventricles/physiology , Fetal Tissue Transplantation , Inflammation/genetics , Inflammation/prevention & control , Nerve Tissue/embryology , Animals , Carrageenan , Female , Genetic Predisposition to Disease , Immunohistochemistry , In Situ Hybridization , Inflammation/chemically induced , Lipopolysaccharides/pharmacology , Lymphocyte Count , Rats , Rats, Inbred F344 , Rats, Inbred Lew , T-Lymphocytes/pathology
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