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The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R α) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 β mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 β mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 β mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated. © 1995 by The Endocrine Society.


Documento: Artículo
Título:Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression
Autor:Labeur, M.S.; Arzt, E.; Wiegers, G.J.; Holsboer, F.; Reul, J.M.H.M.
Filiación:Max Planck Institute of Psychiatry, Clinical Institute, Department of Neuroendocrinology, Munich, 80804, Germany
Instituto de Investigaciones Médicas and Dto. Biología, Facultad de Ciencias Exactas y Naturales, Uniuersidad de Buenos Aires and Consejo National de Znvestigaciones Científicas y Técnicas, Buenos Aires, Argentina
Palabras clave:concanavalin a; corticosterone; corticotropin; corticotropin releasing factor; cytokine; interleukin 1beta; interleukin 2; interleukin 2 receptor; lipopolysaccharide; messenger rna; proopiomelanocortin; animal cell; animal experiment; article; b lymphocyte; corticotropin blood level; gene expression; hypothalamus hypophysis adrenal system; immune system; intracerebroventricular drug administration; lateral brain ventricle; lymphocyte proliferation; nonhuman; priority journal; rat; spleen cell; t lymphocyte; weight gain; Animal; B-Lymphocytes; Corticotropin-Releasing Hormone; Cytokines; Human; Hypothalamo-Hypophyseal System; In Vitro; Injections, Intraventricular; Interleukin-1; Interleukin-2; Lymphocyte Activation; Male; Neuroimmunomodulation; Pituitary-Adrenal System; Rats; Rats, Wistar; Receptors, Interleukin-2; RNA, Messenger; Support, Non-U.S. Gov't; T-Lymphocytes
Página de inicio:2678
Página de fin:2688
Título revista:Endocrinology
Título revista abreviado:Endocrinology
CAS:concanavalin A, 11028-71-0; corticosterone, 50-22-6; corticotropin releasing factor, 9015-71-8; corticotropin, 11136-52-0, 9002-60-2, 9061-27-2; interleukin 2, 85898-30-2; proopiomelanocortin, 66796-54-1; Corticotropin-Releasing Hormone, 9015-71-8; Cytokines; Interleukin-1; Interleukin-2; Receptors, Interleukin-2; RNA, Messenger


  • Felten, S.Y., Felten, D.L., Innervation of lymphoid tissue (1991) Psychoneuroimmunology, pp. 27-69. , Ader R, Felten DS, Cohen N, ed 2. Academic Press, San Diego
  • Besedovsky, H.O., Del Rey, A., Immune-neuroendocrine circuits: Integrative role of cytokines (1992) Front Neuroendocrinol, 13, pp. 61-94
  • Bateman, A., Singh, A., Kral, T., Solomon, S., The immune-hypothalamic-pituitary-adrenal axis (1989) Endocr Rev, 10, pp. 92-112
  • Berkenbosch, F., Van Oers, J., Del Rey, A., Tilders, F., Besedovsky, H., Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1 (1987) Science, 238, pp. 524-526
  • Sapolsky, R.M., Rivier, C., Yamamoto, G., Plotsky, P., Vale, W., Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor (1987) Science, 238, pp. 522-524
  • Munck, A., Guyre, P.M., Holbrook, N.J., Physiological functions of glucocorticoids in stress and their relation to pharmacological actions (1984) Endocr Rev, 5, pp. 25-44
  • Sternberg, E.M., Hill, J.M., Chrousos, G.P., Kamilaris, T., Listwak, S.J., Gold, P.W., Wilder, R.L., Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats (1989) Proc Natl Acad Sri USA, 86, pp. 2374-2378
  • Wick, G., Hu, Y.H., Gruber, J., The role of the immunoendocrine interaction via the hypothalamo-pituitary-adrenal axis in autoimmune disease (1992) Trends Endocrinol Metab, 3, pp. 141-146
  • Holsboer, F., Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity (1989) Eur Arch Psychiatry Neurol Sri, 238, pp. 302-322
  • Nowell, P.C., Inhibition of human leukocyte mitosis by prednisolone in vitro (1961) Cancer Res, 21, pp. 1518-1521
  • Munck, A., Guyre, P.M., Glucocorticoids and immune function (1991) Psychoneuroimmunology, pp. 447-474. , Ader R, Felten DS, Cohen N, ed 2. Academic Press, San Diego
  • Vale, W., Spiess, J., Rivier, C., Rivier, J., Characterization of 41 residue ovine hypothalamic peptide that stimulates the secretion of corticotropin and β-endorphin (1981) Science, 312, pp. 1394-1397
  • Holsboer, F., Spengler, D., Heuser, I., The role of corticotropin-releasing hormone in the pathogenesis of Cushing's disease, anorexia nervosa, alcoholism, affective disorders and dementia (1992) Prog Brain Res, 93, pp. 385-415
  • Rothuizen, J., Reul, J., Van Sluijs, F.J., Rijnberk, A., De Kloet, E.R., Differential neuroendocrine reactivity and brain corticosteroid receptor binding capacity in young and aged dogs (1993) Endocrinology, 132, pp. 161-168
  • Reul, J., Stec, I., Söder, M., Holsboer, F., Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system (1993) Endocrinology, 133, pp. 312-320
  • Arzt, E., Buric, R., Stelzer, G., Stalla, J., Renner, U., Stalla, G.K., Interleukin involvement in anterior pituitary cell growth regulation: Effects of IL-2 and IL-6 (1993) Endocrinology, 132, pp. 459-467
  • Tellides, G., Dallman, M.J., Kuprec-Weghiski, J.W., Functional blocking of the interleukin 2 receptor (IL-2R) may be important in the efficiency of IL-2R antibody therapy (1987) Transplant Proc, 19, pp. 4231-4233
  • Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by arid guanidinium thiocyanate-phenol-chloroform extraction (1987) Anal Biochem, 162, pp. 156-159
  • Saambrok, J., Fritsch, E.F., Maniatis, T., (1989) Molecular Cloning, a Laboratory Manual, , Cold Spring Harbor Laboratory Press, Cold Spring, New York
  • Reul, J., Stec, I., Wiegers, G.J., Linthorst, A., Labeur, M.S., Arzt, E., Holsboer, F., Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats (1994) J Clin Invest, 93, pp. 2600-2607
  • Roberts, J.L., Seeburg, P.H., Shine, J., Herbert, E., Baxter, J.D., Goodman, H.M., Corticotropin and ß-endorphin: Construction and analysis of recombinant DNA complementary to mRNA for the common precursor (1979) Proc Natl Acad Sri USA, 76, pp. 2153-2157
  • Page, T.H., Dallman, M.J., Molecular cloning of cDNAs for the rat interleukin 2 receptor alpha and beta chain genes: Differentially regulated gene activity in response to mitogenic stimulation (1991) Eur J Immunol, 21, pp. 2133-2138
  • Gillis, S., Ferm, M.M., Ou, W., Smith, K.A., T cell growth factor: Parameters of production and a quantitative microassay for activity (1978) J Immunol, 120, pp. 2027-2032
  • Hotta, M., Shibasaki, T., Yamauchi, N., Ohno, H., Benoit, R., Ling, N., Demura, H., The effects of chronic central administration of corticotropin-releasing factor on food intake, body weight, and hypothalamic-pituitary-adrenocortical hormones (1991) Life Sri, 48, pp. 1483-1491
  • Sutton, R.E., Koob, G.F., Moal, M.L., Rivier, J., Vale, W., Corticotropin-releasing factor produces behavioral activation in rats (1982) Nature, 297, pp. 331-333
  • Arase, K., York, D.A., Shimizu, H., Shargill, N., Bray, G.A., Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats (1988) Am J Physiol, 255, pp. E255-E259
  • Dallman, M.F., Akana, S.F., Cascio, C.S., Darlington, D.N., Jacobson, L., Levin, N., Regulation of ACTH secretion: Variations on a theme of B (1987) Recent Prog Horm Res, 43, pp. 113-173
  • Wiegers, G.J., Croiset, G., Reul, J., Holsboer, F., De Kloet, E.R., Differential effects of corticosteroids on rat peripheral blood T lymphocyte mitogenesis in vivo and in vitro (1993) Am J Physiol, 265, pp. E825-E830
  • Cupps, T.R., Gerrard, T.L., Falkoff, J.M., Whalen, G., Fauci, A.S., Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation (1985) J Clin Invest, 75, pp. 754-761
  • Irwin, M.R., Hauger, R., Brown, M., Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: Increased responsivity of the aged rat (1992) Endocrinology, 131, pp. 1047-1053
  • Irwin, M.R., Vale, W., Britton, K.T., Central corticotropin-releasing factor suppresses natural killer cytotoxicity (1987) Brain Behav Immun, 1, pp. 81-87
  • Irwin, M.R., Hauger, R.L., Brown, M., Britton, K.T., CRF activates autonomic nervous system and reduces natural killer cytotoxicity (1988) Am J Physiol, 255, pp. R744-R747
  • Irwin, M.R., Hauger, R.L., Jones, L., Provencio, M., Britton, K.T., Sympathetic nervous system mediates central corticotropin-releasing factor-induced suppression of natural killer cytotoxicity (1990) J Pharmacol Exp Ther, 255, pp. 101-107
  • Hauger, R., Irwin, M.R., Lorang, M., Aguilera, G., Brown, M.R., High intracerebral levels of CRH result in CRH receptor downregulation in the amygdala and neuroimmune desensitization (1993) Brain Res, 616, pp. 283-292
  • Smith, E.M., Hughes, T.K., Hashemi, F., Stefano, G.B., Immunosuppressive effects of corticotropin and melanotropin and their possible significance in human immunodeficiency virus infection (1992) Proc Natl Acad Sri USA, 89, pp. 782-786
  • Smith, E.M., Corticotropin and immunoregulation (1994) Neuropeptides and Immunoregulation, pp. 28-45. , Scharrer B, Smith EM, Stefano GB, Springer-Verlag, Berlin
  • Smith, K.A., Interleukin-2: Inception, impact, and implications (1988) Science, 240, pp. 1169-1176
  • Toribio, M.L., Gutierrez-Ramoz, J.C., Pezzi, L., Marcos, M., Martinez, A.C., Interleukin 2-dependent autocrine proliferation in T-cell development (1989) Nature, 342, pp. 82-85
  • Reed, J.C., Abidi, A.H., Alpers, J.D., Hoover, R.G., Robb, R.J., Nowell, P.C., Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression (1986) J Immunol, 137, pp. 150-154
  • Grabstein, K., Dower, S., Gillis, S., Urdal, D., Larsen, A., Expression of interleukin 2, interferon-?, and the IL 2 receptor by human peripheral blood lymphocytes (1986) J Immunol, 136, pp. 4503-4508
  • Gillis, S., Crabtree, G.R., Smith, K.A., Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation (1979) J Immunol, 123, pp. 1624-1631
  • Vacca, A., Martinotti, S., Screpanti, I., Maroder, M., Felli, M.P., Farina, A.R., Gismondi, A., Gulino, A.T., Transcriptional regulation of the interleukin 2 gene by glucocorticoid hormones. Role of steroid receptor and antigen-responsive 5'-flanking sequences (1990) J Biol Chem, 265, pp. 8075-8080
  • Vacca, A., Felli, M.P., Farina, A.R., Martinotti, S., Maroder, M., Screpanti, I., Meco, D., Gulino, A., Glucocorticoid receptor-mediated suppression of the interleukin 2 gene expression through impairment of the cooperativity between nuclear factor of activated T cells and AP-1 enhancer elements (1992) J Exp Med, 175, pp. 637-646
  • Pang, S.-Y., Legido, A., Levine, L.S., Temeck, J.W., New, M.I., Adrenal androgen response to metyrapone, adrenocorticotropin, and corticotropin-releasing hormone stimulation in children with hypopituitarism (1987) J Clin Endocrinol Metab, 65, pp. 282-289
  • Daynes, R.A., Dudley, D.J., Araneo, B.A., Regulation of murine lymphokine production in vivo. II. Dehydroepiandrostenedione is a natural enhancer of interleukin 2 synthesis by helper T cells (1990) Eur J Immunol, 20, pp. 793-802
  • Trotter, J.L., Clifford, D.B., Erson, C.B., Van Der Veen, R.C., Hicks, B.C., Banks, G., Elevated serum interleukin-2 levels in chronic progressive multiple sclerosis (1988) N Engl J Med, 318, p. 1206
  • Heath, W.R., Allison, J., Hoffman, M.W., Schoenrich, G., Haemmerling, G., Arnold, B., Miller, J.F., Autoimmune diabetes as a consequence of locally produced interleukin-2 (1992) Nature, 359, pp. 547-549
  • Wick, G., Hu, Y., Schwarz, S., Kroemer, G., Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases (1993) Endocr Rev, 14, pp. 539-563
  • Mizel, S.B., Interleukin 1 and T cell activation (1982) Immunol Rev, 63, pp. 51-72
  • Dinarello, C.A., Wolff, S.M., The role of interleukin-1 in disease (1993) N Engl J Med, 328, pp. 106-113
  • Beutler, B., Krochin, N., Milsark, I.W., Luedke, C., Cerami, A., Control of cachectin (Tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance (1986) Science, 232, pp. 977-979
  • Lee, S.W., Tsou, A.P., Chan, H., Thomas, J., Petrie, K., Eugui, E.M., Allison, A.C., Glucocorticoids selectively inhibit the transcription of the interleukin 10 gene and decrease the stability of interleukin 10 mRNA (1988) Proc Natl Acad Sri USA, 85, pp. 1204-1208
  • Kern, J.A., Lamb, R.J., Reed, J.C., Daniele, R.P., Nowell, P.C., Dexa-methasone inhibition of interleukin 10 production by human monocytes: Posttranscriptional mechanisms (1988) J Clin Invest, 81, pp. 237-244
  • Lew, W., Oppenheim, J.J., Matsushima, K., Analysis of the suppression of IL-la and IL-10 production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone (1988) J Immunol, 140, pp. 1895-1902
  • Daynes, R.A., Araneo, B.A., Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4 (1989) Eur J Immunol, 19, pp. 2319-2325
  • Wong, H.L., Costa, G.L., Lotze, M.T., Wahl, S.M., Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo (1993) J Exp Med, 177, pp. 775-781
  • Neta, R., Oppenheim, J.J., Douches, S.D., Interdependence of the radioprotective effects of human recombinant interleukin la, tumor necrosis factor a, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor (1988) J Immunol, 140, pp. 108-111
  • Van Der Meer, J., Barza, B., Wolff, S.M., Dinarello, C.A., A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal gram-negative infection (1988) Proc Natl Acad Sri USA, 85, pp. 1620-1623
  • Kaplan, E., Dinarello, C.A., Wakabayashi, G., Burke, J.F., Connolly, R.S., Gelfand, J.A., Interleukin-1 pretreatment protects against endotoxin-induced hypotension in rabbits: Association with decreased tumor necrosis factor levels (1993) J Infect Dis, 167, pp. 244-247
  • Dinarello, C.A., Lnterleukin-1 and interleukin-1 antagonism (1991) Blood, 77, pp. 1627-1652
  • Robb, R.J., Interleukin 2: The molecule and its function (1984) Immunol Today, 5, pp. 203-209
  • Pontzer, C.H., Griggs, N.D., Johnson, H.M., Interleukin 2 (1992) Advances in Neuroimmunology, 2, pp. 17-31
  • Karanth, S., McCann, S.M., Anterior pituitary hormone control by interleukin 2 (1991) Proc Natl Acad Sei USA, 88, pp. 2961-2965


---------- APA ----------
Labeur, M.S., Arzt, E., Wiegers, G.J., Holsboer, F. & Reul, J.M.H.M. (1995) . Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression. Endocrinology, 136(6), 2678-2688.
---------- CHICAGO ----------
Labeur, M.S., Arzt, E., Wiegers, G.J., Holsboer, F., Reul, J.M.H.M. "Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression" . Endocrinology 136, no. 6 (1995) : 2678-2688.
---------- MLA ----------
Labeur, M.S., Arzt, E., Wiegers, G.J., Holsboer, F., Reul, J.M.H.M. "Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression" . Endocrinology, vol. 136, no. 6, 1995, pp. 2678-2688.
---------- VANCOUVER ----------
Labeur, M.S., Arzt, E., Wiegers, G.J., Holsboer, F., Reul, J.M.H.M. Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression. Endocrinology. 1995;136(6):2678-2688.