Abstract
Background: Cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, that are released in response to injury are thought to inhibit growth and cause muscle wasting, at least in part by inhibiting anabolic hormones such as insulin-like growth factor I (IGF-I). Because critical illness in humans is accompanied by high circulating concentrations of growth hormone (GH), which is the main stimulus for IGF-I production by the liver, resistance to GH is thought to contribute to the IGF-I decline observed in catabolic diseases. While TNF-α seems to cause GH resistance mainly through downregulation of liver GH receptor expression, IL-6 may inhibit the GH-stimulated Janus kinase and signal transducer and activator of transcription pathways by induction of suppressors of cytokine signaling proteins. Elevations in circulating IGF binding protein-1 levels, as observed in many catabolic situations, may play a role in the decline in muscle mass by decreasing the rate of protein synthesis in skeletal muscle. Furthermore, the increase in local muscle cytokines produced during inflammation makes the muscle GH-resistant and reduces its own IGF-I production. Finally, not only decreased IGF-I production by muscle, but also decreased muscle sensitivity to the anabolic effects of IGF-I, may contribute to muscle wasting observed in response to severe stress. Conclusions: Taken together, proinflammatory cytokines may contribute to the growth retardation and muscle wasting that occur after injury by impairing the GH/IGF-I axis at several levels.
References
1.
Ballinger AB, Azooz O, El Haj T, Poole S, Farthing MJ: Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis. Gut 2000;46:694–700.
2.
Spate U, Schulze PC: Proinflammatory cytokines and skeletal muscle. Curr Opin Clin Nutr Metab Care 2004;7:265–269.
3.
Baker J, Liu JP, Robertson EJ, Efstratiadis A: Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993;75:73–82.
4.
Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N: Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 2001;27:195–200.
5.
Briard N, Guillaume V, Frachebois C, Rico-Gomez M, Sauze N, Oliver C, Dutour A: Endotoxin injection increases growth hormone and somatostatin secretion in sheep. Endocrinology 1998;139:2662–2669.
6.
Daniel JA, Elsasser TH, Martinez A, Steele B, Whitlock BK, Sartin JL: Interleukin-1beta and tumor necrosis factor-alpha mediation of endotoxin action on growth hormone. Am J Physiol Endocrinol Metab 2005;289:E650–E657.
7.
Gong FY, Deng JY, Shi YF: Stimulatory effect of interleukin-1beta on growth hormone gene expression and growth hormone release from rat GH3 cells. Neuroendocrinology 2005;81:217–228.
8.
Soto L, Martín AI, Millán S, Vara E, López-Calderón A: Effects of endotoxin lipopolysaccharide administration on the somatotropic axis. J Endocrinol 1998;159:239–246.
9.
Wada Y, Sato M, Niimi M, Tamaki M, Ishida T, Takahara J: Inhibitory effects of interleukin-1 on growth hormone secretion in conscious male rats. Endocrinology 1995;136:3936–3941.
10.
Peisen JN, McDonnell KJ, Mulroney SE, Lumpkin MD: Endotoxin-induced suppression of the somatotropic axis is mediated by interleukin-1beta and corticotrophin-releasing factor in the juvenile rat. Endocrinology 1995;136:3378–3390.
11.
Hataya Y, Akamizu T, Hosoda H, Kanamoto N, Moriyama K, Kangawa K, Takaya K, Nakao K: Alterations of plasma ghrelin levels in rats with lipopolysaccharide-induced wasting syndrome and effects of ghrelin treatment on the syndrome. Endocrinology 2003;144:5365–5371.
12.
Van den Berghe G, De Zegher F, Veldhuis JD, Wouters P, Awouters M, Verbruggen W, Schetz M, Verwaest C, Lauwers P, Bouillon R, Bowers CY: The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion. J Clin Endocrinol Metab 1997;82:590–599.
13.
Dahn MS, Lange MP, Jacobs LA: Insulin-like growth factor-I production is inhibited in human sepsis. Arch Surg 1988;123:1409–1414.
14.
Defalque D, Brandt N, Ketelslegers JM, Thissen JP: GH insensitivity induced by endotoxin injection is associated with decreased liver GH receptors. Am J Physiol 1999;276:E565–E572.
15.
Bergad PL, Schwarzenberg SJ, Humbert JT, Morrison M, Amarasinghe S, Towle HC, Berry SA: Inhibition of growth hormone action in models of inflammation. Am J Physiol Cell Physiol 2000;279:C1906–C1917.
16.
Denson LA, Held MA, Menon RK, Frank SJ, Parlow AF, Arnold DL: Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Am J Physiol Gastrointest Liver Physiol 2003;284:G646–G654.
17.
Difedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, Menon RK, Denson LA: Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis. Gastroenterology 2005;128:1278–1291.
18.
Schaefer F, Chen Y, Tsao T, Nouri P, Rabkin R: Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. J Clin Invest 2001;108:467–475.
19.
Waxman DJ, Ram PA, Park S-H, Choi HK: Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular regulator of male-specific liver gene transcription. J Biol Chem 1995;270:13262–13270.
20.
Davey HW, Xie T, McLachlan MJ, Wilkins RJ, Waxman DJ, Grattan DR: STAT5b is required for GH-induced liver Igf-I gene expression. Endocrinology 2001;142:3836–3841.
21.
Woelfle J, Rotwein P: In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. Am J Physiol Endocrinol Metab 2004;286:E393–E401.
22.
Yumet G, Shumate ML, Bryant P, Lin CM, Lang CH, Cooney RN: Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis. Am J Physiol Endocrinol Metab 2002;283:E472–E481.
23.
Mao YL, Ling PR, Fitzgibbons TP, McCowen KC, Frick GP, Bistrian BR, Smith RJ: Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo. Endocrinology 1999;140:5505–5515.
24.
Wolf M, Böhm S, Brand M, Kreymann G: Proinflammatory cytokines interleukin 1b and tumor necrosis factor a 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 1996;135:729–737.
25.
Thissen JP, Verniers J: Inhibition by interleukin-1b and tumor necrosis factor-a of the insulin-like growth factor I messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology 1997;138:1078–1084.
26.
Boisclair YR, Wang JR, Shi JR, Hurst KR, Ooi GT: Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1b on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. J Biol Chem 2000;275:3841–3847.
27.
Lelbach A, Scharf JG, Ramadori G: Regulation of insulin-like growth factor-I and of insulin-like growth factor binding protein-1, -3 and -4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6. J Hepatol 2001;35:558–567.
28.
Fan J, Char D, Bagby GJ, Gelato MC, Lang CH: Regulation of insulin-like growth factor-I (IGF-I) and IGF binding proteins by tumor necrosis factor. Am J Physiol 1995;269:R1204–R1212.
29.
Lang CH, Fan J, Cooney R, Vary TC: IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis. Am J Physiol Endocrinol Metab 1996;270:E430–E437.
30.
Denson LA, Menon RK, Shaufl A, Bajwa HS, Williams CR, Karpen SJ: TNF-a downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding. J Clin Invest 2001;107:1451–1458.
31.
Ram PA, Waxman DJ: SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 1999;274:35553–35561.
32.
Colson A, Le Cam A, Maiter D, Edery M, Thissen JP: Potentiation of growth hormone-induced liver suppressors of cytokine signaling messenger ribonucleic acid by cytokines. Endocrinology 2000;141:3687–3695.
33.
Lang CH, Hong-Brown L, Frost RA: Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. Pediatr Nephrol 2005;20:306–312.
34.
De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, Martini A, Ciliberto G, Fattori E: 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. J Clin Invest 1997;99:643–650.
35.
Frystyk J, Gronbæk H, Skjærbæk C, Flyvbjerg A, Orskov H, Baxter RC: Developmental changes in serum levels of free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and the acid-labile subunit in rats. Endocrinology 1998;139:4286–4292.
36.
Binoux M, Hossenlopp P: Insulin-like growth factor (IGF) and IGF-binding proteins: comparison of human serum and lymph. J Clin Endocrinol Metab 1988;67:509–514.
37.
Bar RS, Clemmons DR, Boes M, Busby WH, Booth BA, Dake BL, Sandra A: Transcapillary permeability and subendothelial distribution of endothelial and amniotic fluid insulin-like growth factor binding proteins in the rat heart. Endocrinology 1990;127:1078–1086.
38.
Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev 1995;16:3–34.
39.
Elgin RG, Busby WHJ, Clemmons DR: An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I. Proc Natl Acad Sci USA 1987;84:3254–3258.
40.
Blum WF, Jenne EW, Reppin F, Kietzmann K, Ranke MB, Bierich JR: Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I. Endocrinology 1989;125:766–772.
41.
Ernst M, Rodan GA: Increased activity of insulin-like growth factor (IGF) in osteoblastic cells in the presence of growth hormone (GH): positive correlation with the presence of the GH-induced IGF-binding protein BP-3. Endocrinology 1990;127:807–814.
42.
Burch WW, Correa J, Shively JE, Powell DR: The 25-kilodalton insulin-like growth factor (IGF)-binding protein inhibits both basal and IGF-I-mediated growth of chick embryo pelvic cartilage in vitro. J Clin Endocrinol Metab 1990;70:173–180.
43.
Ross M, Francis GL, Szabo L, Wallace JC, Ballard FJ: Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-I and IGF-II but not des-(1–3)-IGF-I. Biochem J 1989;258:267–272.
44.
De Mellow JS, Baxter RC: Growth hormone dependent insulin-like growth factor binding protein both inhibits and potentiates IGF-I stimulated DNA synthesis in skin fibroblasts. Biochem Biophys Res Commun 1988;156:199–204.
45.
Fan J, Molina PE, Gelato MC, Lang CH: Differential tissue regulation of insulin-like growth factor-I content and binding proteins after endotoxin. Endocrinology 1994;134:1685–1692.
46.
Lang CH, Fan J, Frost RA, Gelato MC, Sakurai Y, Herndon DN, Wolfe RR: Regulation of the insulin-like growth factor system by insulin in burn patients. J Clin Endocrinol Metab 1996;81:2474–2480.
47.
Davenport ML, Isley WL, Pucilowska JB, Pemberton LB, Lyman B, Underwood LE, Clemmons DR: Insulin-like growth factor binding protein-3 proteolytic activity is induced following elective surgery. J Clin Endocrinol Metab 1992;75:590–595.
48.
Timmins AC, Cotterill AM, Hughes SC, Holly JM, Ross RJ, Blum W, Hinds CJ: Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease. Crit Care Med 1996;24:1460–1466.
49.
Skjaerbaek C, Frystyk J, Orskov H, Kissmeyer-Nielsen P, Jensen MB, Laurberg S, Moller N, Flyvbjerg A: Differential changes in free and total insulin-like growth factor I after major, elective abdominal surgery: the possible role of insulin-like growth factor-binding protein-3 proteolysis. J Clin Endocrinol Metab 1998;83:2445–2449.
50.
Fan J, Char D, Kolasa AJ, Pan W, Maitra SR, Patlak CS, Spolarics Z, Gelato MC, Lang CH: Alterations in hepatic production and peripheral clearance of IGF-I after endotoxin. Am J Physiol Endocrinol Metab 1995;269:E33–E42.
51.
Thissen JP, Davenport ML, Pucilowska J, Miles MV, Underwood LE: Increased serum clearance and degradation of 125I-labeled IGF-I in protein-restricted rats. Am J Physiol 1992;262:E406–E411.
52.
Frost RA, Nystrom GJ, Lang CH: Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1b: requirement of the mitogen-activated protein kinase pathway. Endocrinology 2000;141:3156–3164.
53.
Lang CH, Vary TC, Frost RA: Acute in vivo elevation of insulin-like growth factor (IGF) binding protein-1 decreases plasma free IGF-I and muscle protein synthesis. Endocrinology 2003;144:3922–3933.
54.
Lang CH, Pollard V, Fan J, Traber LD, Traber DL, Frost RA, Gelato MC, Prough DS: Acute alterations in growth hormone insulin-like growth factor axis in humans injected with endotoxin. Am J Physiol Regul Integr Comp Physiol 1997;273:R371–R378.
55.
Schulze PC, Gielen S, Adams V, Linke A, Mobius-Winkler S, Erbs S, Kratzsch J, Hambrecht R, Schuler G: Muscular levels of proinflammatory cytokines correlate with a reduced expression of insulinlike growth factor-I in chronic heart failure. Basic Res Cardiol 2003;98:267–274.
56.
Fernandez-Celemin L, Pasko N, Blomart V, Thissen JP: Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab 2002;283:E1279–E1290.
57.
Hong-Brown LQ, Brown CR, Cooney RN, Frost RA, Lang CH: Sepsis-induced muscle growth hormone resistance occurs independent of STAT5 phosphorylation. Am J Physiol Endocrinol Metab 2003;285:E63–E72.
58.
Frost RA, Nystrom GJ, Lang CH: Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2002;283:R698–R709.
59.
Hambrecht R, Schulze PC, Gielen S, Linke A, Mobius WS, Yu JT, Kratzsch J, Baldauf G, Busse MW, Schubert A, Adams V, Schuler G: Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure. J Am Coll Cardiol 2002;39:1175–1181.
60.
Frost RA, Nystrom GJ, Lang CH: Tumor necrosis factor-alpha decreases insulin-like growth factor-I messenger ribonucleic acid expression in C2C12 myoblasts via a Jun N-terminal kinase pathway. Endocrinology 2003;144:1770–1779.
61.
Ding H, Gao XL, Hirschberg R, Vadgama JV, Kopple JD: Impaired actions of insulin-like growth factor 1 on protein synthesis and degradation in skeletal muscle of rats with chronic renal failure. Evidence for a postreceptor defect. J Clin Invest 1996;97:1064–1075.
62.
Fang CH, Li BG, Sun X, Hasselgren PO: Insulin-like growth factor I reduces ubiquitin and ubiquitin-conjugating enzyme gene expression but does not inhibit muscle proteolysis in septic rats. Endocrinology 2000;141:2743–2751.
63.
Vary TC, Dardevet D, Grizard J, Voisin L, Buffiere C, Denis P, Breuille D, Obled C: Differential regulation of skeletal muscle protein turnover by insulin and IGF-I after bacteremia. Am J Physiol Endocrinol Metab 1998;275:E584–E593.
64.
Fang CH, Li BG, Wang JJ, Fischer JE, Hasselgren PO: Treatment of burned rats with insulin-like growth factor I inhibits the catabolic response in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 1998;275:R1091–R1098.
65.
Fang CH, Li BG, James JH, King JK, Evenson AR, Warden GD, Hasselgren PO: Protein breakdown in muscle from burned rats is blocked by IGF-I and GSK-3{β} inhibitors. Endocrinology 2005;146:3141–3149.
66.
Broussard SR, McCusker RH, Novakofski JE, Strle K, Hong SW, Johnson RW, Freund GG, Dantzer R, Kelley KW: Cytokine-hormone interactions: tumor necrosis factor alpha impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. Endocrinology 2003;144:2988–2996.
67.
Broussard SR, McCusker RH, Novakofski JE, Strle K, Shen WH, Johnson RW, Dantzer R, Kelley KW: IL-1beta impairs insulin-like growth factor-induced differentiation and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. J Immunol 2004;172:7713–7720.
68.
Frost RA, Lang CH, Gelato MC: Transient exposure of human myoblasts to tumor necrosis factor-a inhibits serum and insulin-like growth factor-I stimulated protein synthesis. Endocrinology 1997;138:4153–4159.
69.
Strle K, Broussard SR, MCusker RH, Shen WH, Johnson RW, Freund GG, Dantzer R, Kelley KW: Proinflammatory cytokine impairment of IGF-I-induced protein synthesis in skeletal muscle myoblasts requires ceramide. Endocrinology 2004;145:4592–4602.
70.
Layne MD, Farmer SR: Tumor necrosis factor-a and basic fibroblast growth factor differentially inhibit the insulin-like growth factor-I induced expression of myogenin in C2C12 myoblasts. Exp Cell Res 1999;249:177–187.
71.
Langen RC, Schols AM, Kelders MC, Wouters EF, Janssen-Heininger YM: Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor- kappa B. FASEB J 2001;15:1169–1180.
72.
Fang CH, Li BG, Wray CJ, Hasselgren PO: Insulin-like growth factor-I inhibits lysosomal and proteasome-dependent proteolysis in skeletal muscle after burn injury. J Burn Care Rehabil 2002;23:318–325.
73.
Schulze PC, Fang J, Kassik KA, Gannon J, Cupesi M, Macgillivray C, Lee RT, Rosenthal N: Transgenic overexpression of locally acting insulin-like growth factor-1 inhibits ubiquitin-mediated muscle atrophy in chronic left-ventricular dysfunction. Circ Res 2005;97:418–426.
74.
Schakman O, Gilson H, de Coninck V, Lause P, Verniers J, Havaux X, Ketelslegers JM, Thissen JP: Insulin-like growth factor-I gene transfer by electroporation prevents skeletal muscle atrophy in glucocorticoid-treated rats. Endocrinology 2005;146:1789–1797.
75.
Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P: Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 2005;115:451–458.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
