Pediatric Nephrology

, Volume 20, Issue 3, pp 306–312 | Cite as

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

  • Charles H. Lang
  • Ly Hong-Brown
  • Robert A. Frost


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.


Sepsis Endotoxin Tumor necrosis factor-α Insulin-like growth factor-I Muscle JNK 



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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Copyright information

© IPNA 2004

Authors and Affiliations

  • Charles H. Lang
    • 1
  • Ly Hong-Brown
    • 1
  • Robert A. Frost
    • 1
  1. 1.Department of Cellular and Molecular PhysiologyPennsylvania State University College of MedicineHersheyUSA

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