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Horm Metab Res 2001; 33(10): 590-595
DOI: 10.1055/s-2001-17905
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Cyclosporin A Treatment is Able to Revert the Decrease in Circulating GH and IGF-I and the Increase in IGFBPs Induced by Adjuvant Arthritis

L. Soto 1 , A. I. Martín 3 , E. Vara 2 , A. López-Calderón 1
  • 1 Departamento de Fisiología Facultad de Medicina, Universidad Complutense, Madrid
  • 2 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid
  • 3 Departamento de CC Morfológicas y Fisiología, Universidad Europea, Madrid, Spain
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Publication Date:
18 October 2001 (online)

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The aim of this study was to find out whether cyclosporin A administration is able to revert the decrease in circulating growth hormone (GH) and insulin-like growth factor-I (IGF-I) and the increase in IGF-binding proteins (IGFBPs) levels caused by adjuvant-induced arthritis in rats. Male Sprague-Dawley rats were intradermically injected with Freund’s adjuvant or vehicle. Fourteen days later, rats were randomly divided into two groups - one injected with cyclosporin (15 mg/kg) and the other with vehicle from day 16 to 23 after adjuvant injection. Arthritis decreased body weight gain and serum concentrations of GH. Cyclosporin administration to arthritic rats prevented both effects, whereas cyclosporin had no effect in control rats. Arthritis decreased serum concentrations of IGF-I (p < 0.01), but increased IGFBPs. Cyclosporin administration increased circulating IGF-I, and there was a negative correlation between circulating IGF-I and arthritis index scores in arthritic rats injected with cyclosporin (p < 0.05). Cyclosporin treatment did not alter serum IGFBPs levels in control rats, whereas cyclosporin administration normalised IGFBPs in arthritic rats. These results indicate that the effects of cyclosporin administration on the GH-IGF-IGFBPs system may partly mediate its beneficial effect on body weight in arthritic rats.

Key words:

Immunosuppression - Cytokines - Freund’s Adjuvant - Chronic Inflammation - Somatotropic Axis - GH - IGF-I - IGFBPs

References

  • 1 Rofe A M, Whithehouse M W, Bourgeois C S, Haynes D R, Vernon-Roberts B. Prevention of adjuvant-induced cachexia in rats by cyclosporin A.  Immunol Cell Biol. 1990;  68 63-69
    PubMedGoogle Scholar
  • 2 Roubenoff R, Roubenoff R A, Cannon J G, Kehayias J J, Zhuang H, Dawson-Hughes B Dinarello C A, Rosenberg I H. Rheumatoid cachexia: cytokine-driven hypermetabolism and loss of lean body mass in chronic inflammation.  J Clin Invest. 1994;  93 2379-2386
    CrossrefPubMedGoogle Scholar
  • 3 Roubenoff R, Freeman L M, Smith D E, Abad L W, Dinarello C A, Kehayias J J. Adjuvant arthritis as a model of inflammatory cachexia.  Arthritis Rheum. 1997;  40 534-539
    PubMedGoogle Scholar
  • 4 Van den Berghe G. Novel insights into the neuroendocrinology of critical illness.  Eur J Endocrinol. 2000;  143 1-13
    CrossrefPubMedGoogle Scholar
  • 5 Aitman T J, Palmer R G, Loftus J, Ansell B M, Royston J P, Teale J D, Clayton R N. Serum IGF-I levels and growth failure in juvenile chronic arthritis.  Clin Exp Rheumatol. 1989;  7 557-561
    PubMedGoogle Scholar
  • 6 Davies U M, Rooney M, Preece M A, Ansell B M, Woo P. Treatment of growth retardation in juvenile chronic arthritis with recombinant human growth hormone.  J Rheumatol. 1994;  21 153-158
    PubMedGoogle Scholar
  • 7 Templ E, Koeller M, Riedl M, Wagner O, Graninger W, Luger A. Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis.  British J Rheumatol. 1996;  35 350-356
    PubMedGoogle Scholar
  • 8 López-Calderón A, Soto L, Martín A I. Chronic inflammation inhibits GH secretion and alters the serum insulin-like growth factor system in rats.  Life Sci. 1999;  65 2049-2060
    CrossrefPubMedGoogle Scholar
  • 9 Ibáñez de Cáceres I, Villanúa M A, Soto L, Martín A I, López-Calderón A. IGF-I and IGF-binding proteins in rats with adjuvant-induced arthritis given recombinant human growth hormone.  J Endocrinol. 2000;  165 537-544
    CrossrefPubMedGoogle Scholar
  • 10 Peisen J N, McDonnell K J, Mulroney S E, Lumpkin M D. Endotoxin-induced suppression of the somatotropic axis is mediated by interleukin-1β and corticotropin-releasing factor in the juvenile rats.  Endocrinology. 1995;  136 3378-3390
    CrossrefPubMedGoogle Scholar
  • 11 Thissen J P, Verniers J. Inhibition by interleukin-1 and tumor necrosis factor-α of the insulin-like growth factor I messenger ribonucleic acid response to growth hormone in rat hepatocyte culture.  Endocrinology. 1997;  138 1078-1084
    CrossrefPubMedGoogle Scholar
  • 12 Selgas L, Arce A, Esquifino A I, Cardinali D P. Twenty-four-hour rhythms of serum ACTH, prolactin, growth hormone, and thyroid-stimulating hormone, and of median-eminence norepinephrine, dopamine, and serotonin, in rats injected with Freund’s adjuvant.  Chronobiol Int. 1997;  14 253-265
    PubMedGoogle Scholar
  • 13 Ferraccioli G, Guerra P, Rizzi V, Bartoli E. Cyclosporin A increases somatomedin C insulin-like growth factor I levels in chronic rheumatic diseases.  J Rheumatol. 1995;  22 1060-1064
    PubMedGoogle Scholar
  • 14 López-Calderón A, Soto L, Villanúa M A, Vidarte L, Martín A I. The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats.  Life Sci. 1999;  65 2049-2066
    CrossrefPubMedGoogle Scholar
  • 15 Tanaka H, Ueta Y, Yamashita U, Kannan H, Yamashita H. Biphasic changes in behavioral, endocrine, and sympathetic systems in adjuvant arthritis in Lewis rats.  Brain Res Bull. 1996;  39 33-37
    CrossrefPubMedGoogle Scholar
  • 16 Vara E, Tamarit-Rodriguez J. Islet secretion of immunoreactive thyrotropin-releasing hormone and the “paracrine-like” effects of its exogenous administration.  Acta Endocrinol. 1988;  118 429-436
    PubMedGoogle Scholar
  • 17 Cattel V, Cook T, Moncada S. Glomeruli synthesize nitrite in experimental nephrotoxic nephritis.  Kidney Int. 1990;  38 1056-1060
    PubMedGoogle Scholar
  • 18 Borel J F, Weisinger D, Gubler H U. Effect of the anti-lymphocyte agent cyclosporin A in chronic inflammation.  Eur J Rheumatol Inflamm. 1978;  1 237-241
    PubMedGoogle Scholar
  • 19 del Pozo E, Graeber M, Elford P, Payne T. Regression of bone and cartilage loss in adjuvant arthritis rats after treatment with cyclosporin A.  Arthritis Rheum. 1990;  33 247-252
    PubMedGoogle Scholar
  • 20 del Pozo E, Zapf J. Skeletal growth and bone density as sensitive parameters in experimental arthritis: effect of cyclosporin A.  Bone. 1994;  15 625-628
    CrossrefPubMedGoogle Scholar
  • 21 Jiang H, Yang X, Soriano R N, Fujimura T, Krishnan K, Kobayashi M. Distinct patterns of cytokine gene suppression by the equivalent effective doses of cyclosporine and tacrolimus in rat heart allografts.  Immunobiol. 2000;  202 280-292
    PubMedGoogle Scholar
  • 22 Ohye H, Sato M, Murao K, Matsubara S, Tokuda M, Takahara J. Cellular signalling mechanism for stimulation of growth hormone secretion and growth hormone primary transcripts by immunosuppressant agents, FK506 and cyclosporin A, in cultured rat pituitary cells.  Neuroimmunomodulat. 1998;  5 309-317
    PubMedGoogle Scholar
  • 23 Antoni F A, Shipston M J, Smith S M. Inhibitory role for calcineurin in stimulus-secretion coupling revealed by FK506 and cyclosporin A in pituitary corticotrope tumor cells.  Biochem Baffies Res Co. 1993;  194 226-233
    PubMedGoogle Scholar
  • 24 Anton F A, Barnard R AO, Skipton M L, Smith S M, Simpson J, Paterson J M. Calcineurin feedback inhibition of agonist-evoked CAMP formation.  J Biol Chem. 1995;  270 28 055-28 061
    PubMedGoogle Scholar
  • 25 Menegazo L A, Ursich M L, Fukui R T, Rocha D M, Silva M E, Ianhez L E, Sabbaga E, Wajchenberg B L. Mechanism of the diabetogenic action of cyclosporin A.  Horm Metab Res. 1998;  30 663-667
    PubMedGoogle Scholar
  • 26 Stephanou A, Sarlis N J, Knight R A, Lightman S L, Chowdrey S. Effects of cyclosporine A on the hypothalamic-pituitary-adrenal axis and anterior pituitary interleukin-6 mRNA expression during chronic inflammatory stress in the rat.  J Neuroendocrinol. 1992;  41 215-222
    PubMedGoogle Scholar
  • 27 Thakore J H, Dinan T G. Growth hormone secretion: the role of glucocorticoids.  Life Sci. 1994;  55 1083-1099
    CrossrefPubMedGoogle Scholar
  • 28 Fernihough J K, Billingham M E, Cwyfan-Hughes S, Holly J M. Local disruption of the insulin-like growth factor system in the arthritic joint.  Arthritis Rheum. 1996;  39 1556-1565
    PubMedGoogle Scholar
  • 29 Matsumoto T, Gargosky S E, Iwasaki K, Rosenfeld R G. Identification and characterization of insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases in human synovial fluid.  J Endocrinol Metab. 1996;  81 150-155
    PubMedGoogle Scholar
  • 30 Wu A, Kurarasch R, Katz J, Fox P, Baum B, Atkinson J. Effect of TNFα and INFγ on the growth of HSG cell line.  J Cell Physiol. 1994;  161 217-226
    CrossrefPubMedGoogle Scholar
  • 31 Katz J, Nasatzky E, Werner H, Le Roith D, Shemer J. Tumor necrosis factor α and interferon γ-induced cell growth arrest is mediated via insulin-like growth factor binding protein-3.  Growth Horm IGF Res. 1999;  9 174-178
    PubMedGoogle Scholar
  • 32 Sunic D, Mc Neil J D, Rayner T E, Andress D L, Belford D A. Regulation of insulin-like growth factor-binding protein-5 by insulin-like growth factor I and interleukin-1α in ovine articular chondrocytes.  Endocrinology. 1998;  139 2356-2362
    CrossrefPubMedGoogle Scholar
  • 33 Olney R C, Tsuchiya K, Wilson D M, Mohtai M, Maloney W J, Schurman D J, Smith R L. Chondrocytes from osteoarthritic cartilage have increased expression of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and -5, but not IGF-II or IGFBP-4.  J Clin Endocr Metab. 1996;  81 1096-1103
    CrossrefPubMedGoogle Scholar
  • 34 Tardif G, Reboul P, Pelletier J P, Geng C, Cloutier J M, Martel Pelletier J. Normal expression of type 1 insulin-like growth factor receptor by human osteoarthritic chondrocytes with increased expression and synthesis of insulin-like growth factor binding proteins.  Arthritis Rheum. 1996;  39 968-978
    PubMedGoogle Scholar
  • 35 Whellams E J, Maile L A, Fernihough J K, Billinham M EJ, Holly J M. Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint.  J Endocrinol. 2000;  165 537-544
    CrossrefPubMedGoogle Scholar
  • 36 Oh Y. IGFBPs and neoplasic models.  Endocrine. 1997;  7 111-113
    PubMedGoogle Scholar
  • 37 Rosen C J, Pollak M. Circulating IGF-I: New perspectives for a new century.  Trends Endocrin Metab. 1999;  10 136-141
    PubMedGoogle Scholar
  • 38 Brauer R, Kette H, Henzgen S, Thoss K. Influence of cyclosporin A on cytokine levels in synovial fluid and serum of rats with antigen-induced arthritis.  Agents Act. 1994;  41 96-98
    PubMedGoogle Scholar
  • 39 Fan J, Char D, Bagby G J, Gelato M C, Lang C H. Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor.  Am J Physiol. 1995;  269 1204-1212
    PubMedGoogle Scholar
  • 40 Benbassat C A, Lazarus D D, Cichy S B, Evans T M, Moldawer L L, Lowry S F. Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro.  Horm Metab Res. 1999;  31 209-215
    PubMedGoogle Scholar

A. López-Calderón

Departamento de Fisiología
Facultad de Medicina
Universidad Complutense

28040 Madrid
Spain


Phone: + 34 (91) 3941491

Fax: + 34 (91) 3941628

Email: ALC@eucmax.sim.ucm.es

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