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      Bidirectional Effects of Corticosterone on Splenic T-Cell Activation: Critical Role of Cell Density and Culture Time

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          Abstract

          Glucocorticoids inhibit stimulus-induced T-cell proliferation, an early and essential parameter of cellular immunity. It was recently found however that physiological concentrations of glucocorticoids can also accelerate, not only inhibit, rat T-cell mitogenesis. We investigated mechanism(s) underlying mitogenic actions of glucocorticoids on anti-T-cell receptor (TCR)- and concanavalin A (Con A)-induced T-cell proliferation. Surprisingly, the ability of the glucocorticoid corticosterone (CORT) to either enhance or inhibit T-cell proliferation was found to depend primarily on the cell density and the timing of the cultures. At cell densities up to 1 × 10<sup>5</sup> cells/well (i.e. ‘low’ density), CORT inhibited T-cell proliferation irrespective of the culture time. In contrast, at cell densities of 2 × 10<sup>5</sup> cells/well and higher (‘high’ density), CORT potently stimulated T-cell mitogenesis during the first 2–3 culture days, but subsequently inhibited the proliferative response after 5–7 days. The glucocorticoid receptor antagonist RU486 completely abolished the effects of CORT. However, production of the main T cell growth factor interleukin (IL)-2 was inhibited by CORT at both ‘low’ and ‘high’ cell densities. In addition, irrespective of cell density, T-cell mitogenesis under either control conditions or in presence of CORT was completely blocked by an anti-IL-2-receptor-α-chain (IL-2Rα) antibody, indicating that T-cell proliferation was dependent on the IL-2 pathway. Immunofluorescence staining of IL-2Rα on CD4+ cells after 2–3 days in culture was increased by CORT, but only on cells cultured at ‘high’ density. Thus, glucocorticoids increase T-cell responsiveness to IL-2 under conditions of ‘high’ cell density only. We conclude that glucocorticoids may contribute to a more efficient early stage of cellular immune responses under conditions of intimate cell-to-cell contact (i.e. ‘high’ cell density), a situation likely to be present in vivo, for instance in lymph nodes. Thus, these findings are relevant to our understanding of the glucocorticoid control of immune function.

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          A monoclonal antibody to a constant determinant of the rat T cell antigen receptor that induces T cell activation. Differential reactivity with subsets of immature and mature T lymphocytes

          mAb R73 detects a T cell-specific surface molecule consisting of two disulfide-linked subunits of 40 and 46 kD, respectively, on 97% of peripheral rat T cells, as defined by the OX-52 marker. Of the few OX- 52+ R73- cells, none are CD4+ but many express the CD8 antigen known to be present on rat NK cells. mAb R73 is mitogenic for unseparated spleen cells and for purified T cells. In the absence of non-T "accessory cells", stimulation by R73 requires artificial crosslinking of the mAb and is largely dependent on exogenous IL-2. Overnight incubation of purified T cells with crosslinked R73 mAb induces blastoid transformation, IL-2-R expression, and modulation of the R73 antigen. In the rat thymus, mature medullary cells express the R73 determinant at the same level as peripheral T cells, whereas 94% of CD4-CD8- thymocytes are R73-. The major CD4+8+ thymocyte population contains 25% R73- and 70% R73low cells. Thymocytes of the CD4-CD8+OX-44- subpopulation that are the direct precursors of CD4+CD8+ cells display a continuum of R73 antigen density from undetectable to very low levels. We conclude that R73 is most likely directed at a constant determinant of the rat alpha/beta heterodimeric TCR and suggest that CD8+ immature thymocytes are the first cells in the T cell differentiation pathway to express this molecule at their surface.
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            A human keratinocyte cell line produces two autocrine growth inhibitors, transforming growth factor-beta and insulin-like growth factor binding protein-6, in a calcium- and cell density-dependent manner.

            Two growth inhibitors were identified in culture medium conditioned by a human keratinocyte cell line, HaCat. TGF-beta was detected in media conditioned by growing or confluent HaCat cells, as well as in media conditioned at physiological (1 mM) or low (0.03 mM) Ca2+ concentrations. However, a considerable part of transforming growth factor beta (TGF-beta) in media conditioned at a physiological Ca2+ concentration was in active form, whereas most TGF-beta in media conditioned at a low Ca2+ concentration was latent. The other growth-inhibitory activity, which was detected only in media conditioned by confluent cells at a physiological Ca2+ concentration, was purified to homogeneity by a four-step procedure. The N-terminal amino acid sequence of the 33-kDa protein was identical with that of insulin-like growth factor binding protein-6 (IGFBP-6). Purified IGFBP-6 inhibited the growth of HaCat and Balb/MK keratinocyte cell lines, as well as Mv1Lu cells. The growth activity was also demonstrated by human recombinant IGFBP-6. In summary, HaCat cells secrete at least two possible autocrine growth inhibitors: TGF-beta which is secreted constitutively, but activated in a Ca(2+)-dependent manner, and IGFBP-6 which is secreted in a cell density- and Ca(2+)-dependent manner.
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              Author and article information

              Journal
              NEN
              Neuroendocrinology
              10.1159/issn.0028-3835
              Neuroendocrinology
              S. Karger AG
              0028-3835
              1423-0194
              2001
              February 2001
              23 February 2001
              : 73
              : 2
              : 139-148
              Affiliations
              aMax Planck Institute of Psychiatry, Section of Neuropsychopharmacology, Munich, Germany, and the bDepartment of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
              Article
              54630 Neuroendocrinology 2001;73:139–148
              10.1159/000054630
              11244301
              © 2001 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: 6, Tables: 3, References: 52, Pages: 10
              Categories
              Neuroimmune Interactions

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