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      Comparative Study of gp130 Cytokine Effects on Corticotroph AtT-20 Cells – Redundancy or Specificity of Neuroimmunoendocrine Modulators?

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          Abstract

          Objective: This comparative in vitro study examined the effects of all known gp130 cytokines on murine corticotroph AtT-20 cell function. Methods: Cytokines were tested at equimolar concentrations from 0.078 to 10 n M. Tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)3 and STAT1, the STAT-dependent suppressor of cytokine signaling (SOCS)-3 promoter activity, SOCS-3 gene expression, STAT-dependent POMC promoter activity and adrenocorticotropic hormone (ACTH) secretion were determined. Results: Leukemia inhibitory factor (LIF), human oncostatin M (OSM) and cardiotrophin (CT)-1 (LIFR/gp130 ligands), as well as ciliary neurotrophic factor (CNTF) and novel neurotrophin-1/B-cell stimulating factor-3 (CNTFRα/LIFR/gp130 ligands) are potent stimuli of corticotroph cells in vitro. In comparison, interleukin (IL)-6 (IL-6R/gp130 ligand) and IL-11 (IL-11R/gp130 ligand) exhibited only modest direct effects on corticotrophs, while murine OSM (OSMR/gp130 ligand) showed no effect. Conclusion: (i) CNTFR complex ligands are potent stimuli of corticotroph function, comparable to LIFR complex ligands; (ii) IL-6 and IL-11 are relatively weak direct stimuli of corticotroph function; (iii) differential effects of human and murine OSM suggest that LIFR/gp130 (OSMR type I) but not OSMR/gp130 (OSMR type II) are involved in corticotroph signaling. (iv) CT-1 has the hitherto unknown ability to stimulate corticotroph function, and (v) despite redundant immuno-neuroendocrine effects of different gp130 cytokines, corticotroph cells are preferably activated through the LIFR and CNTFR complexes.

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          Most cited references 18

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          Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation.

          Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic-pituitary-adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic-pituitary-adrenal axis during immunological challenge in the absence of hypothalamic input from CRH. IL-6 receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone levels after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly greater than in mice deficient in both CRH and IL-6. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstrated a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surprisingly, the relative contribution of IL-6 for modulation of the adrenal response to stress is greater in female than in male mice. This gender-specific difference in IL-6 action in mice suggests the utility of further analysis of IL-6 in determining the female predominance seen in many human inflammatory/autoimmune diseases.
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            Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure.

            Chronic heart failure is one of a number of disorders associated with the development of a wasting syndrome. The precise mechanisms of this remain unknown, but previous studies have suggested a role for immune and neurohormonal factors. We aimed to investigate in detail the differences in body composition (dual X-ray absorptiometry) and the relationship to candidate biochemical factors of the immune, neurohormonal and metabolic systems in 15 healthy controls, 36 stable non-cachectic and 18 cachectic patients with chronic heart failure. Non-cachectic patients showed reduced leg lean tissue (-9.1%, P<0.01) compared to controls. Cachectic patients had significantly reduced lean (-21.0% vs controls, -19.9% vs non-cachectics), fat (-33.0% vs controls, -37. 0% vs non-cachectics) and bone tissue (-17.5% vs controls, -15.9% vs non-cachectics) (all P<0.0001). Cachectic patients showed a significantly increased cortisol/dehydroepiandrosterone ratio (+203% vs controls, P<0.0001; +89% vs non-cachectics, P=0.0011) and increased cytokine levels (TNF-alpha, soluble TNF-receptor 1, interleukin-6). The levels of catabolic hormones and cytokines correlated significantly with reduced muscle and fat tissue content and reduced bone mass. Peripheral loss of muscle tissue is a general finding in chronic heart failure. The wasting in cardiac cachexia affects all tissue compartments and is significantly related to neurohormonal and immunological abnormalities. Copyright 1999 The European Society of Cardiology.
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              Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family.

              We have identified a cytokine of the IL-6 family and named it novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3). NNT-1/BSF-3 cDNA was cloned from activated Jurkat human T cell lymphoma cells. Its sequence predicts a 225-aa protein with a 27-aa signal peptide, a molecular mass of 22 kDa in mature form, and the highest homology to cardiotrophin-1 and ciliary neurotrophic factor. The gene for NNT-1/BSF-3 is on chromosome 11q13. A murine equivalent to NNT-1/BSF-3 also was identified, which shows 96% homology to human NNT-1/BSF-3. NNT-1/BSF-3 mRNA is found mainly in lymph nodes and spleen. NNT-1/BSF-3 induces tyrosine phosphorylation of glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and signal transducer and activator of transcription 3 in the SK-N-MC human neuroblastoma cells. NNT-1/BSF-3 shows activities typical of IL-6 family members. In vitro, it supports the survival of chicken embryo motor and sympathetic neurons. In mice, it induces serum amyloid A, potentiates the induction by IL-1 of corticosterone and IL-6, and causes body weight loss and B cell hyperplasia with serum IgG and IgM increase. NNT-1/BSF-3 is a gp130 activator with B-cell stimulating capability.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2004
                July 2004
                09 July 2004
                : 11
                : 4
                : 224-232
                Affiliations
                aMedizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, and bKlinik II und Poliklinik für Innere Medizin, Universität zu Köln, Köln, Germany; cAmgen Inc., Thousand Oaks, Calif., USA
                Article
                78440 Neuroimmunomodulation 2004;11:224–232
                10.1159/000078440
                15249728
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 43, Pages: 9
                Categories
                Original Paper

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