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Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance

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Abstract

Growth hormone (GH) and insulin-like growth factor (IGF)-I are potent regulators of muscle mass in health and disease. This somatomedin axis is markedly deranged in various catabolic conditions in which circulating and tissue levels of inflammatory cytokines are elevated. The plasma concentration of IGF-I, which is primarily determined by hepatic synthesis and secretion of the peptide hormone, is dramatically decreased during catabolic and inflammatory conditions. Moreover, many of these conditions are also associated with an inability of GH to stimulate hepatic IGF-I synthesis. This defect results from an impaired phosphorylation and activation of the traditional JAK2/STAT5 signal transduction pathway. Numerous lines of evidence support the role of tumor necrosis factor (TNF)-α as a prominent but probably not the sole mediator of the sepsis-induced impairment in basal and GH-stimulated IGF-I synthesis in liver. Additionally, catabolic conditions produce comparable alterations in skeletal muscle. However, in contrast to liver, the GH resistance in muscle is not mediated by a defect in STAT5 phosphorylation. Muscle is now recognized to respond to infectious stimuli with the production of numerous inflammatory cytokines, including TNF-α. Furthermore, myocytes cultured with TNF-α are GH resistant and this defect appears mediated via a STAT5-independent but JNK-dependent mechanism. Collectively, these changes act to limit IGF-I availability in muscle, which disturbs protein balance and results in the loss of protein stores in catabolic and inflammatory conditions.

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References

  1. Frost RA, Lang CH (2003) Regulation of insulin-like growth factor-I in skeletal muscle and muscle cells. Minerva Endocrinol 28:53–73

    CAS  PubMed  Google Scholar 

  2. Conney RN, Kimball SR, Vary TC (1997) Regulation of skeletal muscle protein turnover during sepsis: mechanisms and mediators. Shock 7:1–16

    PubMed  Google Scholar 

  3. Hasselgren PO (1993) Protein metabolism in sepsis. CRC Press, Boca Raton

  4. Kotler DP, Tierney AR, Wang J, Pierson RN (1989) Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50:444–447

    CAS  PubMed  Google Scholar 

  5. Sharma R, Florea VG, Bolger AP, Doehner W, Florea ND, Coasts AJS, Hodson ME, Anker SD, Henein MY (2001) Wasting as an independent predictor of mortality in patients with cystic fibrosis. Thorax 56:746–750

    Article  CAS  PubMed  Google Scholar 

  6. Lang CH, Fan J, Cooney RN, Vary TC (1996) Interleukin-1 receptor antagonist attenuates sepsis-induced alterations in the insulin-like growth factor system and protein synthesis. Am J Physiol Endocrinol Metab 270:E430–E437

    CAS  Google Scholar 

  7. Svanberg E, Frost RA, Lang CH, Isgaard J, Jefferson LS, Kimball SR, Vary TC (2000) IGF-I/IGFBP-3 binary complex attenuates sepsis-induced inhibition of protein synthesis in skeletal muscle. Am J Physiol Endocrinol Metab 279:E1145–E1158

    CAS  PubMed  Google Scholar 

  8. Lang CH, Frost RA, Jefferson LS, Kimball SR, Vary TC (2000) Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I. Am J Physiol Endocrinol Metab 278:E1133–E1143

    CAS  PubMed  Google Scholar 

  9. Lang CH, Frost R, Nairn A, MacLean DA, Vary TC (2002) TNFα impairs heart and skeletal muscle protein synthesis by altering translation initiation. Am J Physiol Endocrinol Metab 282:E336–E347

    CAS  PubMed  Google Scholar 

  10. Zoico E, Roubenoff R (2002) The role of cytokines in regulating protein metabolism and muscle function. Nutr Rev 60:39–51

    Article  PubMed  Google Scholar 

  11. Fong Y, Moldawer LL, Marano M, Wei H, Barber A, Manogue K, Tracey KJ, Kuo G, Fischman DA, Cerami A, Lowry SR (1989) Cachectin/TNF or IL-1α induces cachexia with redistribution of body proteins. Am J Physiol Regul Integr Comp Physiol 256:R659–R665

    CAS  Google Scholar 

  12. Cooney R, Kimball SR, Eckman R, Maish G, Shumate M, Vary TC (1999) TNF-binding protein ameliorates inhibition of skeletal muscle protein synthesis during sepsis. Am J Physiol Endocrinol Metab 276:E611–E619

    CAS  Google Scholar 

  13. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E, Suzuki K, Tanaka K, Katsume A, Ohsugi Y, Shiozaki H, Monden M (1996) Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 97:244–249

    CAS  PubMed  Google Scholar 

  14. Frost RA, Lang CH (1998) Growth factors in critical illness: regulation and therapeutic aspects. Curr Opin Clin Nutr Metab Care 1:195–204

    Article  CAS  PubMed  Google Scholar 

  15. Fan J, Char D, Kolasa AJ, Pan W, Maitra SR, Patlak CS, Spolarics Z, Gelato MC, Lang CH (1995) Alterations in hepatic production and peripheral clearance of IGF-I after endotoxin. Am J Physiol Endocrinol Metab 269:E33–E42

    CAS  Google Scholar 

  16. Fan J, Bagby GJ, Gelato MC, Lang CH (1995) Regulation of IGF-I content and IGF-binding proteins by tumor necrosis factor. Am J Physiol Regul Integr Comp Physiol 269:R1204–R1212

    CAS  Google Scholar 

  17. Fan J, Wojnar MM, Theodorakis M, Lang CH (1996) Regulation of IGF-I mRNA and peptide, and IGF binding proteins by interleukin-1. Am J Physiol Regul Integr Comp Physiol 270:R621–R629

    CAS  Google Scholar 

  18. Wojnar MM, Fan J, Frost RA, Gelato MC, Lang CH (1995) Alterations in the IGF system in trauma patients. Am J Physiol Regul Integr Comp Physiol 268:R970–R977

    CAS  Google Scholar 

  19. Lang CH, Fan J, Frost RA, Gelato MC, Sakurai Y, Herndon DN, Wolfe RR (1996) Regulation of the insulin-like growth factor system by insulin in burn patients. J Clin Endocrinol Metab 81:2474–2480

    Article  CAS  PubMed  Google Scholar 

  20. Lang CH, Pollard V, Traber LD, Traber DL, Frost RA, Gelato MC, Prough DS (1997) Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin. Am J Physiol Regul Integr Comp Physiol 273:R371–R378

    CAS  Google Scholar 

  21. Lang CH, Nystrom GJ, Frost RA (2002) Burn-induced changes in IGF-I and IGF-binding proteins are partially glucocorticoid dependent. Am J Physiol Regul Integr Comp Physiol 282:R207–R215

    CAS  PubMed  Google Scholar 

  22. Thissen J-P, Davenport ML, Pucilowska JB, Miles MV, Underwood LE (1992) increased serum clearance and degradation of 125I-labeled IGF-I in protein-restricted rats. Am J Physiol Endocrinol Metab 262:E406–E411

    CAS  Google Scholar 

  23. Lang CH, Nystrom GJ, Frost RA (2001) Tissue-specific regulation of IGF-I and IGF-binding proteins in response to TNFα. Growth Horm IGF Res 11:250–260

    Article  CAS  PubMed  Google Scholar 

  24. Lang CH, Frost RA, Ejiofor J, Lacy DB, McGuinness OP (1998) Hepatic production and intestinal uptake of IGF-I: response to infection. Am J Physiol Gastrointest Liver Physiol 275:G1291–G1298

    CAS  Google Scholar 

  25. Colson A, Wilems B, Thissen J-P (2003) Inhibition of TNF-α production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I. J Endocrinol 178:101–109

    CAS  PubMed  Google Scholar 

  26. Fan J, Li YH, Bagby GJ, Lang CH (1995) Modulation of inflammation-induced changes in IGF-I and IGF binding protein-1 by anti-TNF antibody. Shock 4:21

    CAS  PubMed  Google Scholar 

  27. Bereket A, Lang CH, Blethen SL, Gelato Mc, Fan J, Frost R, Wilson TA (1995) Effect of insulin on the alterations of growth hormone-IGF axis in children with new onset insulin dependent diabetes mellitus. J Clin Endocrinol Metab 80:1312–1317

    Article  CAS  PubMed  Google Scholar 

  28. Frost RA, Fuhrer J, Mariuz P, Lang CH, Gelato MC (1996) Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin-like growth factor system. Clin Endocrinol (Oxf) 44:501–514

    Google Scholar 

  29. Dahn MS, Lange MP (1998) Systemic and splanchnic metabolic response to exogenous human growth hormone. Surgery 123:528–538

    Article  CAS  PubMed  Google Scholar 

  30. Cooney RN (2002) Suppressors of cytokine signaling (SOCS): inhibitors of the JAK/STAT pathway. Shock 17:83–90

    Article  PubMed  Google Scholar 

  31. Zhu T, Goh ELK, Graichen R, Ling L, Lobie PE (2001) Signal transduction via the growth hormone receptor. Cell Signal 13:599–616

    Article  CAS  PubMed  Google Scholar 

  32. Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW (1997) Requirement of Stat5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 94:7239–7244

    Article  CAS  PubMed  Google Scholar 

  33. Woelfle J, Billiard J, Rotwein P (2003) Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. J Biol Chem 278:22696–22702

    Article  CAS  PubMed  Google Scholar 

  34. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG (2003) Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 349:1139–1147

    Article  CAS  PubMed  Google Scholar 

  35. Mao Y, Ling P, Fitzgibbons T, McCowen KC, Frick CP, Bistrian BR, Smith RJ (1999) Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo. Endocrinology 140:5505–5515

    Article  CAS  PubMed  Google Scholar 

  36. Hong-Brown LQ, Brown CR, Cooney RN, Frost RA, Lang CH (2003) Sepsis-induced muscle growth hormone resistance occurs independently of STAT5 phosphorylation. Am J Physiol Endocrinol Metab 285:E63–E72

    CAS  PubMed  Google Scholar 

  37. Yumet G, Shumate ML, Bryant P, Lin C-M, Lang CH, Cooney RN (2002) Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis. Am J Physiol Endocrinol Metab 283:E472–E481

    CAS  PubMed  Google Scholar 

  38. Denson LA, Matthew AH, Menon RK, Frank SJ, Parlow AF, Arnold DL (2002) Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Am J Physiol Gastrointest Liver Physiol 284:G646–G654

    Google Scholar 

  39. Bergad PL, Schwarzenberg SJ, Humbert JT, Morrison M, Amarasinghe S, Towle HC, Berry SA (2000) Inhibition of growth hormone action in models of inflammation. Am J Physiol Cell Physiol 279:C1906–C1917

    CAS  PubMed  Google Scholar 

  40. Defalque D, Brandt N, Ketelslegers JM, Thissen J-P (1999) GH insensitivity induced by endotoxin injection is associated with decreased liver GH receptors. Am J Physiol Endocrinol Metab 276:E565–E572

    CAS  Google Scholar 

  41. Denson LA, Menon RK, Shaufl A, Bajwa HS, Williams CR, Karpen SJ (2001) TNF-α downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding. J Clin Invest 107:1451–1458

    CAS  PubMed  Google Scholar 

  42. Wolf M, Bohm S, Brand M, Kreymann G (1996) Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 135:729–737

    CAS  PubMed  Google Scholar 

  43. Lang CH, Silvis C, Deshpande N, Nystrom GJ, Frost RA (2003) Endotoxin stimulates in vivo expression of inflammatory cytokines TNFα, IL-1β, IL-6 and HMGB1 in skeletal muscle. Shock 19:538–546

    Article  CAS  PubMed  Google Scholar 

  44. Thissen J-P, Verniers J (1997) Inhibition by interleukin-1β and tumor necrosis factor-α of the insulin-like growth factor-I messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology 138:1078–1084

    Article  CAS  PubMed  Google Scholar 

  45. Mann DL (1996) Stress activated cytokines and the heart. Cytokine Growth Factor Rev 7:341–354

    Article  CAS  PubMed  Google Scholar 

  46. Frost RA, Nystrom GJ, Lang CH (2002) Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. Am J Physiol Regul Integr Comp Physiol 283:R698–R709

    CAS  PubMed  Google Scholar 

  47. Frost RA, Nystrom GJ, Lang CH (2002) Regulation of IGF-I mRNA and signal transducers and activators of transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 myoblasts. Endocrinology 143:492–503

    Article  CAS  PubMed  Google Scholar 

  48. Florini JR, Ewton DZ, Coolican SA (1996) Growth hormone and the IGF system in myogenesis. Endocr Rev 17:481–517

    Article  CAS  PubMed  Google Scholar 

  49. Frost RA, Lang CH, Gelato MC (1997) Transient exposure of human myoblasts to tumor necrosis factor-α inhibits serum and insulin-like growth factor-I stimulated protein synthesis. Endocrinology 138:4153–4159

    Article  CAS  PubMed  Google Scholar 

  50. Broussard SR, McCusker RH, Novakofski JE, Strle K, Shen WH, Johnson RW, Freund GG, Dantzer R, Kelley KW (2003) Cytokine-hormone interactions: tumor necrosis factor α impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor. Endocrinology 144:2988–2996

    Article  CAS  PubMed  Google Scholar 

  51. Sadowski CL, Wheeler TT, Wang LH, Sadowski HB (2001) GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. Endocrinology 142:3890–3900

    Article  CAS  PubMed  Google Scholar 

  52. Frost RA, Nystrom GJ, Lang CH (2003) TNFα decreases IGF-I mRNA expression C2C12 myoblasts via Jun N-terminal kinase pathway. Endocrinology 144:1770–1779

    Article  CAS  PubMed  Google Scholar 

  53. Hwa V, Little B, Kofoed EM, Rosenfeld RG (2004) Transcriptional regulation of insulin-like growth factor-I by interferon-γ requires STAT-5b. J Biol Chem 279:2728–2736

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by National Institutes of Health grant GM38032. Additionally, we thank our collaborators Drs. Robert Cooney, Gladys Yumet, and Margaret Shumate.

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Authors and Affiliations

  1. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA

    Charles H. Lang, Ly Hong-Brown & Robert A. Frost

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  1. Charles H. Lang
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  2. Ly Hong-Brown
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  3. Robert A. Frost
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Correspondence to Charles H. Lang.

Additional information

This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany

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Lang, C.H., Hong-Brown, L. & Frost, R.A. Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. Pediatr Nephrol 20, 306–312 (2005). https://doi.org/10.1007/s00467-004-1607-9

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  • DOI: https://doi.org/10.1007/s00467-004-1607-9

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