bluuebunny/crossref_metadata_2025 huggingface dataset:
Thymic Endocrinology
Authors: HADDEN JOHN W.
Published: February 2006

Abstract: The thymus involutes relatively early in life; cellular immune deficiencies of aging correspond to decline in function of the hypothalamic‐pituitary‐endocrine axis. Recent studies point to important roles for the pituitary, the pineal, and the autonomic nervous system as well as the thyroid, gonads and adrenals in the thymus integrity and function. Thymic function at the local level requires complex cellular interactions among thymic stromal cells and developing thymocytes involving paracrine and autocrine mediators including interleukins (ILs) 1, 2, 6, 7, 8, colony‐stimulating factors (CSFs), interferon‐γ, thymosin α1, and zinc‐thymulin. An important endocrine function of the thymus is to package zinc in zinc‐thymulin for delivery to the periphery. Thymic involution has been treated with interleukins, thymic hormones, growth hormone, prolactin, melatonin, zinc, and others. Our work to reverse thymic involution in hydrocortisone‐treated, aged mice with interleukins, thymosin α1, and zinc will be reviewed. Recent efforts to treat successfully immune deficiency in aged and cancer‐bearing humans will be presented.
Stress‐Induced Enhancement of Cell‐Mediated Immunitya
Authors: DHABHAR FIRDAUS S.
Published: February 2006

Abstract: We have demonstrated that acute stress induces a large‐magnitude, rapid, and reversible redistribution of leukocytes from the blood to other compartments within the body. These changes in leukocyte distribution are mediated by adrenal stress hormones. Because the skin is one of the target organs of a stress‐induced redistribution of leukocyes, we hypothesized that such a leukocyte redistribution could be one of the factors by which acute stress may enhance cutaneous immune function. This hypothesis was tested by examining the effects of acute stress on cutaneous delayed‐type hypersensitivity (DTH). DTH reactions are antigen‐specific, cell‐mediated immune responses that, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, and fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. DTH was induced by challenging the pinnae of previously sensitized rats with 2,4‐dinitro‐1‐fluorobenzene (DNFB). Experiments showed that acute stress administered immediately before the introduction of an antigenic challenge significantly enhances a cutaneous DTH response. In contrast, chronic stress suppresses cutaneous DTH. These results demonstrate a bidirectional relationship between stress and immune function, such that acute stress enhances, while chronic stress suppresses, an important class of immune responses in vivo. They also suggest that stress‐induced alterations in lymphocyte redeployment within the body may play an important role in mediating these bidirectional effects of stress on cell‐mediated immunity.
Mechanisms of Antiinflammatory Action of the Neuroimmunomodulatory Peptide α‐MSH
Authors: LIPTON JAMES M. , CATANIA ANNA
Published: February 2006

Abstract:The antiinflammatory effects of α‐melanocyte‐stimulating hormone (α‐MSH) molecules, specifically α‐MSH(1‐13) and its COOH‐terminal tripeptide α‐MSH(11‐13), are well established. The peptides have been effective in tests of all major models of inflammation, and more recent tests have been extended to include experimental inflammatory bowel disease, CNS ischemia/reperfusion injury, and bacterial endotoxin‐induced inflammation within the brain. The broad effectiveness of α‐MSH molecules in all major types of inflammation indicates that the peptides exert actions that are very basic to the inflammatory process. Three general mechanisms of antiinflammatory action of α‐MSH molecules have been identified: inhibition of production of inflammatory mediators by, or inhibition of inflammatory actions of, peripheral host cells; inhibition of peripheral inflammation induced by actions on melanocortin receptors within the brain; inhibition of CNS inflammation by local action of the peptides. It appears that α‐MSH molecules have multiple actions that modulate the primitive inflammatory response.
Signaling through Delta Opioid Receptors on Murine Splenic T Cells and Stably Transfected Jurkat Cells
Authors: SHARP BURT M. , McKEAN DAVID J. , McALLEN KATHY , SHAHABI NAHID A.
Published: February 2006

Abstract: β‐Endorphin (β‐EP) and delta opoid receptor (DOR) agonists affect immune functions such as lymphocyte chemotaxis, proliferation, and cytokine production. Recent studies indicate that both neuronal DOR and novel G‐protein‐coupled receptors with high affinity for β‐EP and DOR agonists are expressed by mononuclear cells. In addition, proenkephalin A mRNA and enkephalin‐related peptides are expressed by lymphocytes. These investigations were conducted to identify signal transduction pathways that mediate the effects of β‐EP and DOR agonists on T cells. Calcium mobilization was studied because it is central to T‐cell activation initiated by antigen presentation to the T‐cell receptor (TCR). Using the calcium‐sensitive dye Fluo‐3 and flow cytofluorometry to determine the concentration of free intracellular calcium, physiological concentrations of β‐EP were shown to enhance concanvalin. A (con A)‐stimulated calcium mobilization by murine splenic T cells (p < 0.01). The DOR antagonist, naltrindole, inhibited this, whereas CTAP, a selective mu OR antagonist, was ineffective. In addition, N‐Ac‐β‐EP and the μ OR agonist DAMGO, failed to mimic the effects of β‐EP. Although it was less potent than β‐EP, DADLE, a DOR agonist, also enhanced Con‐A‐induced calcium mobilization (p < 0.01). A DOR‐transfected human T‐cell line (DOR‐Jul.1) was developed to study signal transduction. Both DADLE and the selective DOR agonist, deltorphin, rapidly increased intracellular free calcium concentrations; ED50s were 10−9 M. Pertussis toxin prevented the response, and EGTA significantly reduced it. In addition, DADLE inhibited forskolin‐stimulated cAMP production (ED50: 10−11 M). These findings with normal splenic T cells and DOR‐transfected T‐cell line indicate that β‐EP and DOR agonists affect calcium mobilization. This is likely to modulate downstream pathways that regulate T‐cell activation and function.
KAT45 Human Pheochromocytoma Cell Line: A New Model for the In Vitro Study of Neuro‐Immuno‐Hormonal Interactionsa
Authors: VENIHAKI M. , GRAVANIS A. , MARGIORIS A. N.
Published: February 2006

Abstract: Normal rodent adrenal chromaffin cells and the PC12 rat pheochromocytoma cell line produce IL‐1 cytokines. The role, if any, of these cytokines is currently unknown. In PC12 cells, they induce the expression of the L‐AA decarboxylase mRNA, a major step in the biosynthesis of catecholamines. Very little if any of these cytokines are detectable in normal human adrenal medulla, being confined mainly in the 17α‐hydroxylase‐positive steroid cells of the zona reticularis. The aim of the present work was to find out if human pheochromocytomas produce IL‐1 cytokines, in vitro, and to examine what local role they may exert. As a model, we have used the new KAT45 cell line, which emerged spontaneously from a primary human pheochromocytoma cell culture. We have found that the KAT45 cells secrete IL‐1β at 47.8 ± 9 pg/mg total cellular protein (n= 7, at 24 hours). IL‐1β increased the concentration of norepinephrine in the KAT45 culture medium from 24.2 ± 3.5 μg/mg protein (n= 6 controls, at 24 hours), to 33.2 ± 3.5 (IL‐1β 10 mg/ml) or to 42.9 ± 8 (IL‐1β 30 mg/ml). This effect was blocked by IL‐1ra. The KAT45 cells also produce CRH and ACTH. IL‐1β stimulated the secretion of CRH from 19.2 ± 4 pg/mg protein (n= 5 at 36 hours) to 38.7 ± 4, an effect blocked by IL‐1ra in excess. IL‐1β had no effect on ACTH secretion.
Mechanisms of Hypothalamic‐Pituitary‐Adrenal Axis Stimulation by Immune Signals in the Adult Rata
Authors: TURNBULL ANDREW V. , LEE SOON , RIVIER CATHERINE
Published: February 2006

Abstract: Immune stimulation increases the activity of the HPA axis, a phenomenon directly or indirectly mediated through cytokines. We have used two models, the peripheral administration of endotoxin (LPS) or turpentine‐induced tissue injury to show that corticotropin‐releasing factor (CRF) and vasopressin (VP), hypothalamic peptides released by cytokines, play a dominant role in the increased ACTH measured in these two paradigms. In turn, CRF and VP synthesis and/or release is modulated by catecholamines, prostaglandins (PGs), and nitric oxide (NO). These secretagogues are produced in the periphery and/or the central nervous system (CNS) in response to increased cytokine levels and act on CRF/VP neurons and nerve terminals. Finally, endotoxemia and local tissue inflammation may upregulate brain levels of tumor necrosis factor α, interleukin‐1β, and/or interleukin‐6, providing yet another mechanism through which the occurrence of systemic inflammation is conveyed to the brain. The relative importance of brain or peripheral intermediates appears to depend on the site at which cytokine levels are increased. We have shown, for example, that peripheral, but not brain, PGs are important in mediating the neuroendocrine influence of blood‐borne cytokines, while PGs in the CNS play a role in situations characterized by elevated brain immune proteins. NO, on the other hand, restrains the response of the HPA axis to circulating, but not brain cytokines. These results illustrate the complexity of the mechanisms involved in the stimulation of the HPA axis and suggest that their specific involvement depends on the type, intensity, and duration of immune stimulation.
Growth Hormone Receptors and Immunocompetent Cellsa
Authors: DARDENNE M. , MELLO‐COELHO V. , GAGNERAULT M. C. , POSTEL‐VINAY M. C.
Published: February 2006

Abstract: Growth hormone plays a significant role in regulation of the humoral and cellular immune responses in physiological as well as pathological situations. This role is exerted via the existence of specific receptors on cells of the immune system. Using flow cytofluorometry and biotinylated bovine GH, we have recently analyzed the expression of GH receptors (GHRs) in murine lymphoid organs. GHRs are widely expressed in all murine hematopoietic tissues and in fetuses, newborns, and 3‐ and 7‐week‐old animals. In the bone marrow, all hematopoietic lineages express variable levels of GH receptors, whereas in the thymus, this expression is mainly seen in CD4−, CD8−, CD4+CD8+, and CD8+ subpopulations. At the periphery, 50% of splenocytes and peripheral blood lymphocytes and 20% of lymph node cells are GHR positive, with a wider receptor expression on B cells and macrophages (∼50%) than on T cells (∼20%), where the labeling is seen on both CD4+ and CD8+ cell subsets. Interestingly, the proportion of GHRs bearing CD4+ and CD8+ splenocytes is increased after T‐cell activation with Con A or anti‐CD3. Finally, all peripheral T cells expressing GHRs also express prolactin receptors. These data provide a molecular basis to study the factors controlling GHR expression and regulation of immune function.
Cytokine Expression and Molecular Mechanisms of Their Auto/Paracrine Regulation of Anterior Pituitary Function and Growth
Authors: ARZT E. , PEREDA M. PÁEZ , COSTAS M. , SAUER J. , RENNER U. , HOLSBOER F. , STALLA G. K.
Published: February 2006

Abstract: The pituitary gland expresses cytokines and their receptors. IL‐2 receptor transcripts and protein products are co‐localized in ACTH‐, PRL‐, and GH‐producing cells (double immunofluorescence). IL‐2 and IL‐6 (1‐1000 IU/ml) are involved in the autocrine/paracrine regulation of normal and tumor (GH3 mammosomatotroph cell line and adenoma cell cultures) anterior pituitary hormone‐producing cell growth (cell number, DNA synthesis, c‐fos mRNA expression and autoradiography combined with hormone staining). IL‐1 regulates the growth of normal pituitary cells but does not act on GH3 cells. IL‐1ra, which blocks this action, is expressed in tumoral pituitary (mainly GH‐ and ACTH‐) cells. In ACTH‐ cells, IL‐1 enhances glucocorticoid feedback, stimulating glucocorticoid response element transcriptional activity. Cytokines, through specific functional receptors, act as inter/auto‐cellular factors that regulate not only the function but also the growth of anterior pituitary cells.
Selectivity of Effects of Vasoactive Intestinal Peptide on Macrophages and Lymphocytes in Compartmental Immune Responsesa
Authors: GOETZL EDWARD J. , PANKHANIYA RAVI R. , GAUFO GARY O. , MU YAJUN , XIA MENGHANG , SREEDHARAN SUNIL P.
Published: February 2006

Abstract: The major immunoregulatory effects of vasoactive intestinal peptide (VIP) are mediated by structurally distinct type I (VIPR1) and II (VIPR2) G protein‐associated receptors on many different types of immune cells. VIP is released in functionally relevant concentrations during many immunologic and inflammatory responses. Mast cells (VIPR1), macrophages (VIPR1 and VIPR2), B cells, and T cells (VIPR1, VIPR2, or VIPR1 and VIPR2) recognize and respond to VIP in patterns that are controlled by the relative levels of expression of VIPR1 and VIPR2. VIPR2 transduces human T‐cell chemotaxis, expression of matrix metalloproteinases (MMPs) 2 and 9 and consequently basement membrane and connective tissue transmigration, while signaling suppression of proliferation and cytokine production. In contrast, VIPR1 fails to transduce T‐cell chemotaxis but mediates suppression of chemotaxis and MMP expression elicited by some cytokines and chemokines. The relative representation of each type of VIPR, which is presumed to be under cytokine control, thus may determine T‐cell responses to VIP and other immune mediators in tissue compartments innervated by VIPergic nerves.
The Role of Cytokines in Infection‐Related Behaviora
Authors: DUNN ADRIAN J. , SWIERGIEL ARTUR H.
Published: February 2006

Abstract: Infections are associated with a specific behavioral pattern that includes hypomotility, hypophagia, increased sleep, decreased libido, and decreased exploration. This behavioral response is considered adaptive and important for the survival of the animal. A similar behavioral pattern was observed following treatment with endotoxin (lipopolysaccharide [LPS]) and cytokines, such as interleukin‐1 (IL‐1). Because the secretion of these cytokines is induced by LPS and infections, it is possible that they mediate the behavioral responses to infection. We have studied ingestive behavior and locomotor activity in mice following infection with influenza virus, or injection of LPS, IL‐1, or IL‐6. A lethal dose of influenza virus, LPS, IL‐1a and IL‐1b each decreased the intake of sweetened condensed milk and 24‐hour food pellet intake and decreased locomotor activity. Mouse IL‐6 was ineffective. A sublethal dose of influenza virus decreased food pellet intake and locomotor activity, but did not significantly alter milk intake. Indomethacin prevented the behavioral responses to IL‐1, and attenuated those to LPS, but had only a very small effect on those to influenza virus. Similar results were obtained with the IL‐1‐receptor antagonist (IL‐1ra); it completely prevented the responses to IL‐1, attenuated those to LPS, but, even after chronic high dose administration, attenuated the effects of influenza virus infection only slightly. Our results suggest that while IL‐1 may play an important role in the responses to infection, IL‐6 does not. Moreover, IL‐1 cannot be the only factor contributing to the altered behavior of LPS‐injected or influenza virus‐infected mice.
Cytokines and Sickness Behavior
Authors: DANTZER ROBERT , BLUTHÉ ROSE‐MARIE , LAYÉ SOPHIE , BRET‐DIBAT JEAN‐LUC , PARNET PATRICIA , KELLEY KEITH W.
Published: February 2006

Abstract: Peripheral and central injections of interleukin‐1 (IL‐1) and lipopolysaccharide (LPS) induce the expression of proinflammatory cytokines in the brain and have profound depressing effects on spontaneous and learned behaviors. These effects are mediated by vagal afferents, because they are abrogated by section of the vagus nerves at the subdiaphragmatic level in rats and mice. Vagotomy does not interfere with the synthesis and release of proinflammatory cytokines at the periphery, because plasma and tissue levels of interleukin‐1 of vagotomized animals are similar to those of sham‐operated animals. Furthermore, the consequences of vagotomy on the host behavioral response to peripheral cytokines are specific to the intraperitoneal route of administration of cytokines because vagotomized animals are still able to respond to IL‐1 injected intravenously, subcutaneously, and into the lateral ventricle of the brain. Finally, substance P and cholecystokinin do not appear to play a key role in the transmission of the immune message to the brain because pretreatment by capsaicin or by specific antagonists of CCKA and CCKB receptors does not alter the behavioral effects of LPS and IL‐1. All these findings point to the role of neural afferents for transmitting the immune message from the periphery to the brain.
Inflammatory Disease as Chronic Stress
Authors: SHANKS N. , HARBUZ M. S. , JESSOP D. S. , PERKS P. , MOORE P. M. , LIGHTMAN S. L.
Published: February 2006

Abstract: It is now established that communication between the CNS and the immune system is bidirectional, that endocrine factors can alter immune function and that immune responses can alter both endocrine and CNS responses. In many respects CNS and endocrine responses to acute inflammation are similar to the changes associated with acute stress exposure. In contrast, during chronic inflammation associated with adjuvant induced arthritis (AA), although circulating levels of corticosterone are increased, the peptidergic regulation of the hypothalamus is different from that seen during acute stress. As the disease progresses, a paradoxical reduction occurs in CRH mRNA in the paraventricular nucleus (PVN), whereas PVN AVP mRNA increases. These data suggest that there is increased expression of AVP mRNA within the CRH cells of the PVN with an increased emphasis on AVP regulation of HPA output. Additionally, HPA function is altered during chronic inflammation such that responses to psychological stress (i.e. restraint) are significantly dampened, while responses to further inflammatory challenges are maintained. These data suggest that alterations in PVN peptide colocalization may be important in regulating the progression of peripheral inflammatory responses and that the effects of inflammation on the hypothalamus alter stress‐responsive systems. In addition to the AA model, we have similarly observed alterations in PVN peptide mRNA expression with disease onset in the murine MRL lpr/lpr and MRL +/+ model of SLE. Disease onset in murine SLE is spontaneous and does not rely on exogenous application of adjuvant; however, decreased levels of CRH in the PVN were observed from early disease onset in this animal model. It is suggested that alterations in CRH regulation in response to either acute or chronic inflammation may contribute as etiological factors to both psychiatric (i.e. neuropsychiatric SLE) and stress‐related disease.
Interstitial Cystitis: A Neuroimmunoendocrine Disordera
Authors: THEOHARIDES THEOHARIDES C. , PANG XINZHU , LETOURNEAU RICHARD , SANT GRANNUM R.
Published: February 2006

Abstract: Interstitial cystitis (IC) is a sterile bladder condition occurring primarily in females. It is characterized by frequency, nocturia, and suprapubic pain. IC symptoms are exacerbated during ovulation and under stress, thus implicating neurohormonal processes. The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergic triggers, as well as chemicals, food preservatives, drugs, toxins, and adherent bacteria, all of which can activate bladder mast cells. Vasoactive, nociceptive, and proinflammatory molecules released can lead to immune cell infiltration and can sensitize neurons to secrete neurotransmitters or neuropeptides that can further activate mast cells. Mast cell‐derived proteases can directly cause tissue damage, and it is noteworthy that urine tryptase is elevated in IC. Bladder mast cells are located close to neuronal processes, which are increased in IC, and they can be activated in situ by acetylcholine (ACh) and substance P (SP). Such activation is augmented by estradiol, which acquires significance in view of the fact that human bladder mast cells express estrogen receptors, but few progesterone receptors, which may explain the worsening of IC symptoms during ovulation. Finally, acute psychological stress in rats leads to mast cell activation that can be reduced by depletion of SP or neutralization of peripheral immune corticotropin‐releasing hormone (CRH). These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.
Autonomic, Neuroendocrine, and Immune Responses to Psychological Stress: The Reactivity Hypothesisa
Authors: CACIOPPO JOHN T. , BERNTSON GARY G. , MALARKEY WILLIAM B. , KIECOLT‐GLASER JANICE K. , SHERIDAN JOHN F. , POEHLMANN KIRSTEN M. , BURLESON MARY H. , ERNST JOHN M. , HAWKLEY LOUISE C. , GLASER RONALD
Published: February 2006

Abstract: We examined the effects of brief psychological stressors on cardiovascular, neuroendocrine, and cellular immune response in 22 older women to investigate the common effects of stress across systems. Results revealed that psychological stressors heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected the cellular immune response (ps < 0.05). In a replication and extension, 27 women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls category matched for age and family income (low chronic stress) performed the 12‐min laboratory stressor. Measures were taken before (low acute stress) and immediately following (high acute stress) exposure to the laboratory stressors as well as 30 min after termination of the stressor (recovery period). Acute stress again heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected cellular immune responses (ps < 0.05), whereas chronic stress was associated with higher reports of negative affect, enhanced cardiac sympathetic activation, elevated blood pressure and plasma levels of ACTH, and diminished production of interleukin‐1β (ps < 0.05). Correlational analyses in both studies further suggested that individuals who showed the greatest stress‐related changes in HPA activation also exhibited the greatest diminution in cellular immune response.
Effects of Psychosocial Treatment in Prolonging Cancer Survival May Be Mediated by Neuroimmune Pathways
Authors: SPIEGEL DAVID , SEPHTON SANDRA E. , TERR ABBA I. , STITES DANIEL P.
Published: February 2006

Abstract: Research has provided growing evidence of links between the social environment and cancer progression. Indeed, social support in the form of marriage, frequent daily contact with others, and the presence of a confidant may all have protective value against cancer progression. Furthermore, retrospective data suggest that major stressful life events are more prevalent in patients with relapse or malignancy, and thus may contribute to cancer morbidity. Initial studies of the effects of psychosocial intervention with cancer patients have provided some promising results. In three randomized prospective trials, protective effects of psychosocial interventions on cancer progression have been confirmed, while one matching and one randomized study showed no survivial effect after psychosocial treatment. Though more research is clearly needed in this area, this body of evidence suggests that psychosocial factors have potentially powerful modulating effects on the course of disease. Here we review evidence of one possible mechanism whereby psychosocial factors may influence disease‐resistance capabilities: the neuro‐immune connection. Suppressive effects of stress on immune function are well documented, and these effects have been shown to be modulated by social support. Thus, it is reasonable to hypothesize that supportive social relationships may buffer the effects of cancer‐related stress on immunity, and thereby facilitate the recovery of immune mechanisms that may be important for cancer resistance. Data addressing this hypothesis are reviewed.
Altered Reactivity of the Hypothalamus‐Pituitary‐Adrenal Axis in Patients with Atopic Dermatitis: Pathologic Factor or Symptom?a
Authors: BUSKE‐KIRSCHBAUM A. , JOBST S. , HELLHAMMER D. H.
Published: February 2006

Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease with the principal symptoms of dry skin, lichnification, eczematous inflammation, and an intense pruritus. Despite general acceptance that AD is a multifactorial skin disorder, dysregulation of immune functions (e.g., hypersecretion of immunoglobulin‐E, altered cytokine profiles) is considered to be mainly involved in AD pathogenesis. Considerable evidence points to an immunoregulatory function for the hypothalamus‐pituitary‐adrenal (HPA) axis, suggesting that appropriate reactivity of the HPA axis is necessary to prevent the immune system from reaching a level that may be damaging for the host. It is further hypothesized that dysfunctional reactivity of the HPA axis may increase the vulnerability of the organism to immune‐related disorders such as inflammatory diseases. In the present paper the role of the HPA axis for the development and chronification of allergic inflammation will be summarized and the potential pathological significance of a dysfunctional HPA axis in AD pathogenesis will be discussed.
Effects of Prolactin in Stimulating Disease Activity in Systemic Lupus Erythematosusa
Authors: WALKER SARA E. , MCMURRAY ROBERT W. , HOURI JOHN M. , ALLEN SUSAN H. , KEISLER DUANE , SHARP GORDON C. , SCHLECHTE JANET A.
Published: February 2006

Abstract: Systemic lupus erythematosus (SLE), a chronic autoimmune illness, is influenced by hormones. High prolactin concentrations were associated with early death from autoimmune renal disease in NZB/NZW mice, an animal model of severe SLE. NZB/NZW mice that delivered and nursed pups and those that underwent pseudopregnancy had changes in serum IgG and autoantibodies. NZB/NZW mice treated with the prolactin‐suppressing drug bromocriptine had prolonged lives. Elevated serum prolactin concentrations are reported in SLE patients of both sexes. We found four women with long‐standing hyperprolactinemia who developed SLE. A survey of premenopausal women whose sera were submitted for autoantibody testing showed that 20% with anti‐ds‐DNA antibodies also had high prolactin levels. Many hyperprolactinemic patients whose sera were referred to an endocrinology laboratory had positive FANA tests (women 33%, men 53%) but did not have SLE. Disease activity was suppressed in six of seven SLE patients treated with bromocriptine. All had elevated disease activity and five became unexpectedly hyperprolactinemic after treatment stopped. Manipulating serum prolactin affords a means of treating clinical SLE activity.
Host Resistance to Mycobacteria Is Compromised by Activation of the Hypothalamic‐Pituitary‐Adrenal Axisa
Authors: BROWN DAVID H. , LAFUSE WILLIAM P. , ZWILLING BRUCE S.
Published: February 2006

Abstract: Host resistance to the growth of Mycobacterium avium and Mycobacterium tuberculosis is controlled by a gene, termed Nramp1, that maps to chromosome 1 in mice. Activation of the HPA axis or treatment of macrophages from susceptible mice with corticosterone suppresses the expression of Nramp1 mRNA and results in an increased susceptibility to mycobacterial growth. In contrast, neither activation of the HPA axis nor treatment of macrophages from resistant mice with corticosterone results in an alteration in their resistance or suppression of Nramp1 expression. Investigation into the mechanism of the differential response of the macrophages to corticosterone indicated that differences were associated with the stability of the mRNA in macrophages from BCG‐resistant mice. Thus, corticosterone induced the accelerated degradation of Nramp1 mRNA as well as mRNA of several other macrophage activation genes in macrophages from BCG‐susceptible mice. Treatment of macrophages with corticosterone before the induction of Nramp1 resulted in the accelerated degradation of mRNA in macrophages from both resistant and susceptible mice. The Nramp1 gene product appears to protect the mRNA of macrophage activation genes from degradation induced by corticosterone by an iron‐dependent mechanism.
The Encephalopathy Associated with Murine Acquired Immunodeficiency Syndrome
Authors: SEI YOSHITATSU , KUSTOVA YELENA , LI YONG , MORSE HERBERT C. , SKOLNICK PHIL , BASILE ANTHONY S.
Published: February 2006

Abstract: Mice infected with the LP‐BM5 murine leukemia virus (MuLV) develop an immune deficiency syndrome together with an encephalopathy characterized by impairments in spatial learning and memory. These cognitive deficits are evident before the appearance of neuron loss and lymphoid cell invasion of the brain. Nonetheless, a prominent gliosis and a variety of neurochemical changes precede the development of cognitive deficits. The neurochemical abnormalities include significant decreases in striatal Met‐enkephalin and substance P (but not somatostatin), increases in concentrations of quinolinic acid and platelet‐activating factor, and alterations in brain fyn kinase. At this stage of the infection, some of these neurochemical changes can be reversed by glutamate receptor antagonists, cytokine inhibitors, and anti‐retroviral agents. In later stages of the infection, however, the infected mice develop irreversible neuronal loss, invasion of hematopoietic cells, and increased viral burden in the CNS. In addition, motor‐neuron dysfunction (hindlimb paralysis, weakness, and ataxia) and seizures are sometimes observed during the late stages of infection. Thus, the LP‐BM5 MuLV‐infected mouse is a useful model for studying the chronology of neurodegenerative changes, ranging from reversible neuron dysfunction to irreversible neuron loss, that are associated with retrovirus‐induced immunodeficiency.
Glucocorticoid Resistance and the Immune Function in the Immunodeficiency Syndrome
Authors: NORBIATO GUIDO , BEVILACQUA MAURIZIO , VAGO TARCISIO , CLERICI MARIO
Published: February 2006

Abstract: Glucocorticoids, the final product of HPA axis, and their receptors (GRs) on mononuclear cells are crucial mediators in the endocrine‐immune interaction. An alteration in GRs involving a lower receptor affinity (Kd) for glucocorticoids has been found in a group of advanced AIDS patients, who developed Addisonian symptoms (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis) in spite of hypercortisolism and normal or slightly elevated values of ACTH (AIDS‐GR). In these patients, data for the suppression test showed decreased cortisol and ACTH suppression in response to exogenous dexamethasone. The inhibitory effect of dexamethasone on radiolabeled‐thymidine incorporation in mononuclear cells from these patients was also reduced. Monocytes of AIDS‐GR patients had a receptor Kd of 10.5 ± 4.2 nmol/l that was higher than that of other AIDS patients (AIDS‐C) (2.9 ± 0.8 nmol/l) and normal subjects (2.0 ± 0.8 nmol/l: p < 0.01). Correlations were found between plasmatic IFN‐alpha and receptor Kd on monocytes of AIDS‐GR (r= 0.77). Poly (i)‐poly (c)‐induced IFN‐alpha production by monocytes was inhibited by glucocorticoids in the AIDS‐C group and controls (approx. 80% in both groups): The effect was reversed by the receptor antagonist RU‐486. By contrast, glucocorticoid did not inhibit IFN‐alpha production in AIDS‐GR group. In conclusion, levels of plasmatic IFN‐alpha, a cytokine with antiviral properties, may be increased several times, and dexamethasone fails to inhibit monocytes' IFN‐alpha production only in AIDS with cortisol resistance, a disturbance that confirms an important immunoregulatory role of glucocorticoids in HIV disease.
The Neuropeptide α‐MSH in HIV Infection and Other Disorders in Humansa
Authors: CATANIA ANNA , AIRAGHI LORENA , GAROFALO LETIZIA , CUTULI MARIAGRAZIA , LIPTON JAMES M.
Published: February 2006

Abstract: We measured plasma concentration of α‐melanoctye‐stimulating hormone (α‐MSH), a proopiomelanocortin derivative that modulates pyrogenic and proinflammatory effects of cytokines, in infectious and inflammatory disorders in humans to learn if changes in this peptide take place in naturally occurring disease. α‐MSH was elevated in HIV‐infected patients of the CDC groups III and IV. Although the peptide increased in the circulation of normal subjects injected with endotoxin, it was reduced in patients with septic syndrome. α‐MSH was found in the synovial fluid of arthritis patients, and its concentration was greater in the forms of arthritis marked by greater inflammation. We found that α‐MSH is increased in the circulation of patients with acute myocardial infarction receiving thrombolitic therapy. Plasma concentrations of α‐MSH is increased in the circulation of patients with acute myocardial infarction receiving thrombolitic therapy. Plasma concentrations of α‐MSH were lower in healthy elderly subjects than in young controls. Because an excess of proinflammatory cytokines can have detrimental effects, we investigated the influences of α‐MSH on the production of interleukin‐1 (IL‐1) and tumor necrosis factor (TNF) in HIV‐infected patients and in patients with septic syndrome. Production of these cytokines in whole‐blood samples stimulated with endotoxin was significantly reduced by treatment of blood with α‐MSH. α‐MSH has been injected into at least 106 human subjects to study its effects on pituitary function, menstrual bleeding, and tanning. The peptide was always well tolerated. α‐MSH administration could open new perspectives in treatment of inflammatory diseases in humans.
Regulation of the Sex Combs Reduced Gene in Drosophila
Authors: KENNISON JAMES A. , VÁZQUEZ MARTHA , BRIZUELA BRENDA J.
Published: February 2006

Abstract: The Sex combs reduced gene of the Antennapedia complex specifies the identities of the anterior thoracic and posterior head segments, including the primordium of the larval salivary gland. The Sex combs reduced transcription unit spans over 30 kb of genomic DNA, with another 40 kb of upstream cis‐regulatory sequences. The pattern of Sex combs reduced transcription is set in the early embryo by the segmentation genes and is then maintained by two competing sets of proteins, the Polycomb group and the trithorax group. One of the trithorax group genes required for activation, the brahma gene, encodes an evolutionarily conserved DNA‐stimulated ATPase that is part of a large protein complex. This complex facilitates the action of sequence‐specific, DNA‐binding proteins in regulating target genes, possibly by altering chromatin structure.
Integrins and Development: How Might These Receptors Regulate Differentiation of the Lens
Authors: MENKO SUE , PHILP NANCY , VENEZIALE BOB , WALKER JANICE
Published: February 2006

Abstract: Integrins transduce both internal signals and signals from the matrix. These interactions between integrins, their extracellular matrix ligands, and their cytoskeletal partners play an important role in the regulation of cellular differentiation. We have shown them to be important in lens cell differentiation. In the lens capsule there is a compartmentalization of matrix components with fibronectin, primarily localized to the anterior capsule, and tenascin in the posterior capsule. Integrins are developmentally regulated in the lens. α5β1 integrin, like fibronectin, is primarily associated with the lens epithelial cells, where together they are likely to be important in regulation of adhesion and proliferation. α6Aβ1, the integrin laminin receptor, is expressed at its highest levels in the equatorial epithelium and the peripheral fiber cells, both migratory populations. Because laminin is uniformly distributed in the lens capsule, such changes in α6A integrin expression are likely critical to the cell's ability to regulate its response to laminin in the matrix. The organization of cytoskeletal molecules associated with the integrin cytoplasmic face also changes with development. In the epithelial regions of the lens, where the initiation of lens cell differentiation occurs, expression of the cytoskeletal proteins involved in cell‐substrate interactions, talin, α‐actinin, and the signaling proteins, are high. In the fiber cell region of the lens, where the cells establish stable cell‐cell contacts, vinculin predominates and becomes highly associated with the cytoskeletal fraction. The role of integrins in lens development is not only regulated by changes in the expression of different integrin receptors but is also closely correlated with the expression and organization of the molecules with which they associate.
Integrins and Matrix Molecules in Salivary Gland Cell Adhesion, Signaling, and Gene Expression
Authors: LAFRENIE ROBERT M. , YAMADA KENNETH M.
Published: February 2006

Abstract: Integrins play crucial roles in embryonic and adult cell adhesion, migration, morphogenesis, growth, and differentiation in many cell systems, including human salivary gland cells. Integrins function by binding through their extracellular domain to a specific peptide recognition site in a ligand, and then transmitting information to the cytoplasm by way of their cytoplasmic tails. By this transmembrane signaling process, integrins can mediate assembly of adhesion sites and organization of the actin‐containing cytoskeleton by forming supermolecular complexes of cytoskeletal and signaling molecules. The specific steps in the assembly of these complexes as well as novel mechanisms for synergy between integrin and growth factor signaling pathways are still being determined. Integrin‐mediated interactions also have major effects on gene expression. For example, integrin‐mediated adhesion to fibronectin by the HSG salivary gland cell line significantly alters the pattern of proteins synthesized and genes expressed. In fact, at least five transcription factors are activated, and over 30 genes (many of them novel) are found to be induced by such integrin‐mediated interactions by salivary gland cells. The roles of integrins, in collaborative interactions with growth factors and signaling pathways, and in the induction of novel genes during salivary gland development, should provide fruitful areas of research for many years.
Expression of Rhizobium Chitin Oligosaccharide Fucosyltransferase in Zebrafish Embryos Disrupts Normal Developmenta,
Authors: SEMINO CARLOS E. , ALLENDE MIGUEL L. , BAKKERS JEROEN , SPAINK HERMAN P. , ROBBINS PHILLIPS P.
Published: February 2006

Abstract: In this report we present data about the effect of the Rhizobium NodZ enzyme on zebrafish development. We injected zebrafish embryos with a plasmid expressing NodZ protein, and we confirmed that the enzyme is active and has chitin oligosaccharide fucosyltransferase (NodZ) activity in vitro. In addition, the embryos injected with the NodZ‐expressing plasmid, but not with a control plasmid, showed malformations or bends in the tail, and in some cases shunted tail structures and fused somites. These results clearly indicate that the likely substrates for this enzyme, chitin oligosaccharides and free N‐glycans, have essential functions during early vertebrate embryogenesis.
Regulation and Formation of the Drosophila Salivary Glandsa,
Authors: ANDREW DEBORAH J.
Published: February 2006

Abstract: The homeotic gene, Sex combs reduced (Scr), is a master regulator of Drosophila salivary gland formation. Embryos in which Scr function is missing do not form salivary glands, and embryos in which SCR protein is expressed everywhere form extra salivary glands. However, other known proteins, including the homeotic protein Abdominal‐B, the unusual zinc finger protein Teashirt, and the secreted signaling molecule Decapentaplegic (a TGF‐β family member), limit the recruitment of SCR‐expressing cells to salivary glands. To learn the molecular details of how salivary gland gene expression is controlled and as a first step toward understanding how the SCR transcription factor controls salivary gland morphogenesis, we screened for genes expressed in the developing salivary gland. Among our best candidates for potential direct downstream targets of SCR in the salivary gland are the genes trachealess (trh), dCREB‐A, jalapeño, and Semaphorin II (SemaII). Our genetic studies suggest distinct and important roles for each of these genes in salivary gland morphogenesis. Current work includes studying the molecular interactions between SCR and these downstream target genes and asking how target genes coordinate their activities to effect the cell biological changes required to build functional salivary glands.
Salivary Gland Nucleotide Receptors: Changes in Expression and Activity Related to Development and Tissue Damagea,
Authors: TURNER JOHN T. , PARK MINJUNG , CAMDEN JEAN M. , WEISMAN GARY A.
Published: February 2006

Abstract: Experiments were performed to document the presence of G protein‐coupled P2Y nucleotide receptors in rat salivary glands and to examine changes in receptor expression during development and under conditions in which gland architecture is altered. The results indicate that, as opposed to mature rat submandibular gland (SMG), immature glands express functional P2Y1 receptors. P2Y1 receptor activity was highest at birth and declined over the next four weeks to undetectable levels. P2Y1 receptor mRNA levels remained constant over this time course, suggesting that receptor activity is regulated at some point other than transcription.

Conversely, short‐term culture of cells from the three major salivary glands resulted in upregulation of functional P2Y2 receptors. Responses to the P2Y2‐selective agonist, UTP, were obtained after 3 h in culture and were maximal by 72 hours. This increase was paralleled by increased steady‐state P2Y2 receptor mRNA levels. Upregulation of P2Y2 receptors also occurred in vivo following ligation of the main excretory duct of the SMG. These studies suggest that nucleotide receptors are dynamically regulated during development and as a result of perturbations to gland architecture.
The Role of the Insulin‐like Growth Factor I Receptor in Transformation and Apoptosis
Authors: RESNICOFF MARIANA , BASERGA RENATO
Published: February 2006

Abstract: The insulin‐like growth factor I receptor (IGF‐IR) regulates cell proliferation by at least three different mechanisms: (1) it is mitogenic; (2) it is required for the establishment and maintenance of the transformed phenotype; and (3) it protects cells from apoptosis both in vitro and in vivo.
Apoptosis: A Modulator of Cellular Homeostasis and Disease States
Authors: DELONG MARY J.
Published: February 2006

Abstract: In normal epithelial tissue, a homeostatic balance is maintained between cell replication and apoptosis. Disruption of this balance has serious pathological consequences in disease states, such as Sjögren's syndrome, salivary gland degeneration, and cancers. Apoptosis may be modulated by cytokine endogenous factors and exogenous factors. A vast array of environmental compounds, such as differentiating agents and microconstituents found in the diet, initiate apoptosis through a redox signal mechanism. In addition to increasing apoptosis, these redox signals and transient or permanent changes in cellular redox status elevate detoxification enzymes known to protect against many disease states. Clearly a further understanding of the regulation of apoptosis and protective enzyme elevation by exogenous redox signals will lead to the development of future therapeutic strategies against disease.
Clinical Implications of the Dry Mouth: Oral Mucosal Diseases
Authors: JENSENA J. L. , BARKVOLL P.
Published: February 2006

Abstract: Salivary hypofunction caused by salivary gland disease, medication, or radiation may predispose for secondary oral mucosal diseases. In these patients the protective coating of saliva is reduced or absent, leaving the oral mucosa more vulnerable. Candidiasis, burning mouth syndrome, and white lesions of the oral mucosa are increased in frequency. The aim of management is to prevent oral pathological changes. The management procedure may include proper oral hygiene, saliva‐stimulating agents, or saliva substitutes, depending on the severity of the salivary dysfunction. Treatment includes antifungal therapy if candidiasis is diagnosed. In severely distressed patients, local or systemic corticosteroids may be indicated. Precautions, like refraining from smoking and avoiding toothpastes containing sodium lauryl sulfate, should also be taken. In the future, agents combining antibacterial and antiinflammatory actions, like triclosan, may show promising effects in patients with oral mucosal diseases secondary to salivary hypofunction.
Combination Gene Therapy for Salivary Gland Cancer
Authors: O'MALLEY BERT W. , LI DAQING
Published: February 2006

Abstract: An established combination gene therapy strategy involving adenovirus vector delivery of the herpes thymidine kinase (tk) and murine interleukin‐2 genes was adapted to treat salivary gland cancer in a murine model. Salivary tumors were generated by transcutaneous injection of 5 × 105 murine squamous carcinoma cells into the submandibular gland of syngeneic C3H/HeJ mice. After one week, established submandibular gland tumors were injected with a recombinant adenovirus containing therapeutic and control genes. Animals were subsequently administered ganciclovir twice daily (25 mg/kg) for six days. All animals receiving tk and ganciclovir demonstrated tumor regression, however a significantly greater response was seen in mice that were treated with both tk + mIL‐2. Residual tumors from all treatment and control groups were harvested for microscopic evaluation and immunohistochemistry staining. Specific immunostaining revealed a predominance of CD8+ lymphocytes in the tumor beds of the animals treated with IL‐2, suggesting a preferential immune response resulting from the local IL‐2 expression. Although still in its infancy, the concept of using adenoviral gene therapy strategies to provide less invasive means of treating salivary tumors is promising.
In vitro and In vivo Models for the Reconstruction of Intercellular Signalinga,
Authors: BOUHADIR KAMAL H. , MOONEY DAVID J.
Published: February 2006

Abstract: A critical need in both tissue‐engineering applications and basic cell culture studies is the development of synthetic extracellular matrices (ECMs) and experimental systems that reconstitute three‐dimensional cell‐cell interactions and control tissue formation in vitro and in vivo. We have fabricated synthetic ECMs in the form of fiber‐based fabrics, highly porous sponges, and hydrogels from biodegradable polymers (e.g., polyglycolic acid) and tested their ability to regulate tissue formation. Both cell seeding onto these synthetic ECMs and subsequent culture conditions can be varied to control initial cell‐cell interactions and subsequent cell growth and tissue development. Three‐dimensional tissues composed of cells of interest, matrix produced by these cells, and the synthetic ECM (until it degrades) can be created with these systems. For example, smooth muscle cells can be grown on polyglycolic acid fiber‐based synthetic ECMs to produce tissues with cell densities in excess of 108 cells/mL. These tissues contain extensive elastin and collagen, and the smooth muscle cells within the tissue express the contractile phenotype (e.g., α‐actin staining). Similar approaches can be used to grow a number of other tissues (e.g., dental pulp) that resemble the native tissue. These engineered tissues may provide novel experimental systems to study the role of three‐dimensional intercellular signaling in tissue development and may also find clinical application as replacements to lost or damaged tissues.