Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 15;99(4):643–650. doi: 10.1172/JCI119207

Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation.

F De Benedetti 1, T Alonzi 1, A Moretta 1, D Lazzaro 1, P Costa 1, V Poli 1, A Martini 1, G Ciliberto 1, E Fattori 1
PMCID: PMC507846  PMID: 9045866

Abstract

Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL-6 and stunted growth. In this study we found that NSE/hIL-6 transgenic mouse lines expressing high levels of circulating IL-6 since early after birth presented a reduced growth rate that led to mice 50-70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine IL-6 receptor partially reverted the growth defect. In NSE/hIL-6 transgenic mice, circulating IGF-I levels were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL-6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with systemic juvenile rheumatoid arthritis, circulating IL-6 levels were negatively correlated with IGF-I levels. Our findings suggest that IL-6-mediated decrease in IGF-I production represents a major mechanism by which chronic inflammation affects growth.

Full Text

The Full Text of this article is available as a PDF (294.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ANSELL B. M., BYWATERS E. G. Growth in Still's disease. Ann Rheum Dis. 1956 Dec;15(4):295–319. doi: 10.1136/ard.15.4.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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 Sep-Oct;7(5):557–561. [PubMed] [Google Scholar]
  3. Allen R. C., Jimenez M., Cowell C. T. Insulin-like growth factor and growth hormone secretion in juvenile chronic arthritis. Ann Rheum Dis. 1991 Sep;50(9):602–606. doi: 10.1136/ard.50.9.602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arcone R., Pucci P., Zappacosta F., Fontaine V., Malorni A., Marino G., Ciliberto G. Single-step purification and structural characterization of human interleukin-6 produced in Escherichia coli from a T7 RNA polymerase expression vector. Eur J Biochem. 1991 Jun 15;198(3):541–547. doi: 10.1111/j.1432-1033.1991.tb16048.x. [DOI] [PubMed] [Google Scholar]
  5. Baker J., Liu J. P., Robertson E. J., Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993 Oct 8;75(1):73–82. [PubMed] [Google Scholar]
  6. Baumann H., Gauldie J. The acute phase response. Immunol Today. 1994 Feb;15(2):74–80. doi: 10.1016/0167-5699(94)90137-6. [DOI] [PubMed] [Google Scholar]
  7. Bennett A. E., Silverman E. D., Miller J. J., 3rd, Hintz R. L. Insulin-like growth factors I and II in children with systemic onset juvenile arthritis. J Rheumatol. 1988 Apr;15(4):655–658. [PubMed] [Google Scholar]
  8. Bithoney W. G., Dubowitz H., Egan H. Failure to thrive/growth deficiency. Pediatr Rev. 1992 Dec;13(12):453–460. [PubMed] [Google Scholar]
  9. Brewer E. J., Jr, Bass J., Baum J., Cassidy J. T., Fink C., Jacobs J., Hanson V., Levinson J. E., Schaller J., Stillman J. S. Current proposed revision of JRA Criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of The Arthritis Foundation. Arthritis Rheum. 1977 Mar;20(2 Suppl):195–199. [PubMed] [Google Scholar]
  10. Campbell I. L., Abraham C. R., Masliah E., Kemper P., Inglis J. D., Oldstone M. B., Mucke L. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10061–10065. doi: 10.1073/pnas.90.21.10061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cazzola M., Ponchio L., de Benedetti F., Ravelli A., Rosti V., Beguin Y., Invernizzi R., Barosi G., Martini A. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood. 1996 Jun 1;87(11):4824–4830. [PubMed] [Google Scholar]
  12. Dahn M. S., Lange M. P., Jacobs L. A. Insulinlike growth factor 1 production is inhibited in human sepsis. Arch Surg. 1988 Nov;123(11):1409–1414. doi: 10.1001/archsurg.1988.01400350123019. [DOI] [PubMed] [Google Scholar]
  13. 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 Jan;21(1):153–158. [PubMed] [Google Scholar]
  14. De Benedetti F., Massa M., Pignatti P., Albani S., Novick D., Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. 1994 May;93(5):2114–2119. doi: 10.1172/JCI117206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. De Benedetti F., Robbioni P., Massa M., Viola S., Albani S., Martini A. Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol. 1992 Sep-Oct;10(5):493–498. [PubMed] [Google Scholar]
  16. DiCosmo B. F., Geba G. P., Picarella D., Elias J. A., Rankin J. A., Stripp B. R., Whitsett J. A., Flavell R. A. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest. 1994 Nov;94(5):2028–2035. doi: 10.1172/JCI117556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fattori E., Cappelletti M., Costa P., Sellitto C., Cantoni L., Carelli M., Faggioni R., Fantuzzi G., Ghezzi P., Poli V. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med. 1994 Oct 1;180(4):1243–1250. doi: 10.1084/jem.180.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fattori E., Della Rocca C., Costa P., Giorgio M., Dente B., Pozzi L., Ciliberto G. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood. 1994 May 1;83(9):2570–2579. [PubMed] [Google Scholar]
  19. Fattori E., Lazzaro D., Musiani P., Modesti A., Alonzi T., Ciliberto G. IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur J Neurosci. 1995 Dec 1;7(12):2441–2449. doi: 10.1111/j.1460-9568.1995.tb01042.x. [DOI] [PubMed] [Google Scholar]
  20. Gershenwald J. E., Fong Y. M., Fahey T. J., 3rd, Calvano S. E., Chizzonite R., Kilian P. L., Lowry S. F., Moldawer L. L. Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4966–4970. doi: 10.1073/pnas.87.13.4966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jones J. I., Clemmons D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3–34. doi: 10.1210/edrv-16-1-3. [DOI] [PubMed] [Google Scholar]
  22. Kent S., Rodriguez F., Kelley K. W., Dantzer R. Reduction in food and water intake induced by microinjection of interleukin-1 beta in the ventromedial hypothalamus of the rat. Physiol Behav. 1994 Nov;56(5):1031–1036. doi: 10.1016/0031-9384(94)90339-5. [DOI] [PubMed] [Google Scholar]
  23. Kirschner B. S., Sutton M. M. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology. 1986 Oct;91(4):830–836. doi: 10.1016/0016-5085(86)90683-9. [DOI] [PubMed] [Google Scholar]
  24. Laursen E. M., Juul A., Lanng S., Høiby N., Koch C., Müller J., Skakkebaek N. E. Diminished concentrations of insulin-like growth factor I in cystic fibrosis. Arch Dis Child. 1995 Jun;72(6):494–497. doi: 10.1136/adc.72.6.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lazzaro D., Price M., de Felice M., Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development. 1991 Dec;113(4):1093–1104. doi: 10.1242/dev.113.4.1093. [DOI] [PubMed] [Google Scholar]
  26. Libert C., Vink A., Coulie P., Brouckaert P., Everaerdt B., Van Snick J., Fiers W. Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. Eur J Immunol. 1992 Oct;22(10):2625–2630. doi: 10.1002/eji.1830221023. [DOI] [PubMed] [Google Scholar]
  27. Mangge H., Kenzian H., Gallistl S., Neuwirth G., Liebmann P., Kaulfersch W., Beaufort F., Muntean W., Schauenstein K. Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. Arthritis Rheum. 1995 Feb;38(2):211–220. doi: 10.1002/art.1780380209. [DOI] [PubMed] [Google Scholar]
  28. Mitsuyama K., Sata M., Tanikawa K. Significance of interleukin-6 in patients with inflammatory bowel disease. Gastroenterol Jpn. 1991 Feb;26(1):20–28. doi: 10.1007/BF02779504. [DOI] [PubMed] [Google Scholar]
  29. Motil K. J., Grand R. J., Davis-Kraft L., Ferlic L. L., Smith E. O. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology. 1993 Sep;105(3):681–691. doi: 10.1016/0016-5085(93)90883-e. [DOI] [PubMed] [Google Scholar]
  30. Oldenburg H. S., Rogy M. A., Lazarus D. D., Van Zee K. J., Keeler B. P., Chizzonite R. A., Lowry S. F., Moldawer L. L. Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6. Eur J Immunol. 1993 Aug;23(8):1889–1894. doi: 10.1002/eji.1830230824. [DOI] [PubMed] [Google Scholar]
  31. Pomeroy C., Eckert E., Hu S., Eiken B., Mentink M., Crosby R. D., Chao C. C. Role of interleukin-6 and transforming growth factor-beta in anorexia nervosa. Biol Psychiatry. 1994 Dec 15;36(12):836–839. doi: 10.1016/0006-3223(94)90594-0. [DOI] [PubMed] [Google Scholar]
  32. Reinecker H. C., Steffen M., Witthoeft T., Pflueger I., Schreiber S., MacDermott R. P., Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993 Oct;94(1):174–181. doi: 10.1111/j.1365-2249.1993.tb05997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rooney M., David J., Symons J., Di Giovine F., Varsani H., Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol. 1995 May;34(5):454–460. doi: 10.1093/rheumatology/34.5.454. [DOI] [PubMed] [Google Scholar]
  34. Ross R., Miell J., Freeman E., Jones J., Matthews D., Preece M., Buchanan C. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I. Clin Endocrinol (Oxf) 1991 Jul;35(1):47–54. doi: 10.1111/j.1365-2265.1991.tb03495.x. [DOI] [PubMed] [Google Scholar]
  35. SPROUL A., HUANG N. GROWTH PATTERNS IN CHILDREN WITH CYSTIC FIBROSIS. J Pediatr. 1964 Nov;65:664–676. doi: 10.1016/s0022-3476(64)80151-7. [DOI] [PubMed] [Google Scholar]
  36. Stevens C., Walz G., Singaram C., Lipman M. L., Zanker B., Muggia A., Antonioli D., Peppercorn M. A., Strom T. B. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci. 1992 Jun;37(6):818–826. doi: 10.1007/BF01300378. [DOI] [PubMed] [Google Scholar]
  37. Sturge R. A., Beardwell C., Hartog M., Wright D., Ansell B. M. Cortisol and growth hormone secretion in relation to linear growth: patients with Still's disease on different therapeutic regimens. Br Med J. 1970 Sep 5;3(5722):547–551. doi: 10.1136/bmj.3.5722.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Turksen K., Kupper T., Degenstein L., Williams I., Fuchs E. Interleukin 6: insights to its function in skin by overexpression in transgenic mice. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5068–5072. doi: 10.1073/pnas.89.11.5068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Underwood L. E., Thissen J. P., Lemozy S., Ketelslegers J. M., Clemmons D. R. Hormonal and nutritional regulation of IGF-I and its binding proteins. Horm Res. 1994;42(4-5):145–151. doi: 10.1159/000184187. [DOI] [PubMed] [Google Scholar]
  40. Yang Z. J., Meguid M. M. Continuous systemic interleukin-1 alpha infusion suppresses food intake without increasing lateral hypothalamic dopamine activity. Brain Res Bull. 1995;36(4):417–420. doi: 10.1016/0361-9230(94)00212-j. [DOI] [PubMed] [Google Scholar]
  41. de Benedetti F., Massa M., Robbioni P., Ravelli A., Burgio G. R., Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1158–1163. doi: 10.1002/art.1780340912. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES