Skip to main content

Cytokines in Chronic Inflammation

  • Chapter

Abstract

With the tremendous increase in scientific knowledge about cytokines and their immune functions, it has also become clear that cytokines have systemic and local effects that are only partly related to their coordinating functions in the immune system. Thus, proinflammatory cytokines are the major endogenous mediators of anorexia and cachexia during chronic diseases. They have substantial hypermetabolic effects, which are at the core of the organism’s fever reaction, and, last but not least, they are implicated in the metabolic disturbances and several other comorbidities of obesity, in particular by contributing to insulin resistance. This chapter summarises current knowledge of these effects: it describes studies including different levels of scientific analysis, from the molecular through cellular to the systemic and behavioural levels, which reveal interesting features of the role of cytokines in these phenomena.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Oppenheim JJ, Feldmann M (2001) Introduction to the role of cytokines in innate host defense and adaptive immunity. In: Oppenheim JJ, Feldmann M (eds) Cytokine Reference, Volume 1: Ligands. Academic Press, San Diego, pp 3–20

    Google Scholar 

  2. Feldmann M, Saklatvala J (2001) Proinflammatory cytokines. In: Oppenheim JJ, Feldmann M (eds) Cytokine Reference, Volume 1: Ligands. Academic Press, San Diego, pp 291–305

    Google Scholar 

  3. Langhans W, Hrupka BJ (2003) Cytokines and appetite. In: Kronfol Z (ed) Cytokines and mental health. Kluwer/Academic Publishers, Boston, pp 167–224

    Google Scholar 

  4. Plata-Salamàn CR (1995) Cytokines and feeding suppression: an integrative view from neurologic to molecular levels. Nutrition 11:674–677

    PubMed  Google Scholar 

  5. Langhans W (2004) Anorexia during disease. Neurobiology of food and fluid intake. In: Stricker E, Woods SC (eds) Handbook of Behavioral Neurobiology, 2nd ed. Kluwer Academic/Plenum Publishers, London, pp 347–379

    Google Scholar 

  6. Butera PC, Doerflinger AL, Roberto F (2002) Cyclic estradiol treatment enhances the effects of interleukin-1 beta on food intake in female rats. Brain Behav Immun 16:275–281

    Article  PubMed  CAS  Google Scholar 

  7. Geary N (2001) Sex differences in disease anorexia. Nutrition 17:499–507

    Article  PubMed  CAS  Google Scholar 

  8. Merali Z, Brennan K, Brau P, Anisman H (2003) Dissociating anorexia and anhedonia elicited by interleukin-1 beta: antidepressant and gender effects on responding for ‘free chow’ and ‘earned’ sucrose intake. Psychopharmacology (Berl) 165:413–418

    CAS  Google Scholar 

  9. Gayle D, Ilyin SE, Plata-Salamàn CR (1997) Interleukin-1 receptor type mRNA levels in brain regions from male and female rats. Brain Res Bull 42:463–467

    Article  PubMed  CAS  Google Scholar 

  10. Vitkovic L, Bockaert J, Jacque C (2000) ‘Inflammatory’ cytokines: neuromodulators in normal brain? J Neurochem 74:457–471

    Article  PubMed  CAS  Google Scholar 

  11. Plata-Salamàn CR, Turrin NP (1999) Cytokine interactions and cytokine balance in the brain: relevance to neurology and psychiatry. Mol Psychiatry 4:303–306

    Article  Google Scholar 

  12. Rothwell NJ (1999) Cytokines—killers in the brain? J Physiol 514:3–17

    Article  PubMed  CAS  Google Scholar 

  13. Laviano A, Renvyle T, Meguid MM et al (1995) Relationship between interleukin-1 and cancer anorexia. Nutrition 11:680–683

    PubMed  CAS  Google Scholar 

  14. Mchugh KJ, Collins SM, Weingarten HP (1994) Central interleukin-1 receptors contribute to suppression of feeding after acute colitis in the rat. Am J Physiol 266:R1659–R1663

    PubMed  CAS  Google Scholar 

  15. Plata-Salamàn CR, Ilyin SE, Gayle D (1998) Brain cytokine mRNAs in anorectic rats bearing prostate adenocarcinoma tumor cells. Am J Physiol 44:R566–R573

    Google Scholar 

  16. Arsenijevic D, Garcia I, Vesin C et al (2000) Differential roles of tumor necrosis factor-alpha and interferon-gamma in mouse hypermetabolic and anorectic responses induced by LPS. Eur Cytokine Netw 11:662–668

    PubMed  CAS  Google Scholar 

  17. Eriksson C, Nobel S, Winblad B, Schultzberg M (2000) Expression of interleukin-1 alpha and beta, and interleukin-1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides. Cytokine 12:423–431

    Article  PubMed  CAS  Google Scholar 

  18. Haour F, Marquette C, Ban E et al (1995) Receptors for interleukin-1 in the central nervous and neuroendocrine systems—role in infection and stress. Ann Endocrinol (Paris) 56:173–179

    CAS  Google Scholar 

  19. Langhans W (2002) Peripheral mechanisms involved with catabolism. Curr Opin Clin Nutr Metab Care 5:419–426

    Article  PubMed  CAS  Google Scholar 

  20. Langhans W (2000) Anorexia of infection: current prospects. Nutrition 16:996–1005

    Article  PubMed  CAS  Google Scholar 

  21. Lugarini F, Hrupka BJ, Schwartz GJ et al (2005) Acute and chronic administrtion of immunomodultors induces anorexia in obese (fa/fa) and lean (fa/?) Zucker rats. Physiol Behav 84:165–173

    Article  PubMed  CAS  Google Scholar 

  22. Grunfeld C, Zhao C, Fuller J et al (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters—A role for leptin in the anorexia of infection. J Clin Invest 97:2152–2157

    PubMed  CAS  Google Scholar 

  23. Banks WA, Kastin AJ (1996) Passage of peptides across the blood-brain barrier: pathophysiological perspectives. Life Sci 59:1923–1943

    Article  PubMed  CAS  Google Scholar 

  24. Bierhaus A, Chen J, Liliensiek B, Nawroth PP (2000) LPS and cytokine-activated endothelium. Semin Thromb Hemost 26:571–587

    Article  PubMed  CAS  Google Scholar 

  25. Laflamme N, Lacroix S, Rivest S (1999) An essential role of interleukin-1 beta in mediating NF-kappa B activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci 19:10923–10930

    PubMed  CAS  Google Scholar 

  26. Cao CY, Matsumura K, Yamagata K, Watanabe Y (1996) Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res 733:263–272

    Article  PubMed  CAS  Google Scholar 

  27. Kalaria RN (1999) Cerebral endothelial activation and signal transduction mechanisms during inflammation and infectious disease. Am J Pathol 154:1311–1314

    PubMed  CAS  Google Scholar 

  28. Lacroix S, Rivest S (1998) Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J Neurochem 70:452–466

    Article  PubMed  CAS  Google Scholar 

  29. Nadeau S, Rivest S (1999) Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 93:1449–1464

    Article  PubMed  CAS  Google Scholar 

  30. Cahlin C, Korner A, Axelsson H et al (2000) Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferongamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res 60:5488–5493

    PubMed  CAS  Google Scholar 

  31. Lugarini F, Hrupka BJ, Schwartz GJ et al (2002) A role for cyclooxygenase-2 in lipopolysaccharideinduced anorexia in rats. Am J Physiol 283:R862–R868

    CAS  Google Scholar 

  32. Swiergiel AH, Dunn AJ (2002) Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. J Pharmacol Exp Ther 302:1031–1036

    Article  PubMed  CAS  Google Scholar 

  33. Langhans W, Savoldelli D, Weingarten S (1993) Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-lbeta. Physiol Behav 53:643–649

    Article  PubMed  CAS  Google Scholar 

  34. Herkenham M, Lee HY, Baker RA (1998) Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood-brain barrier. J Comp Neurol 400:175–196

    Article  PubMed  CAS  Google Scholar 

  35. Reyes TM, Sawchenko PE (2002) Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia. J Neurosci 22:5091–5099

    PubMed  CAS  Google Scholar 

  36. Ericsson A, Arias C, Sawchenko PE (1997) Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 17:7166–7179

    PubMed  CAS  Google Scholar 

  37. El Haj T, Poole S, Farthing MJG, Ballinger AB (2002) Anorexia in a rat model of colitis: interaction of interleukin-1 and hypothalamic serotonin. Brain Res 927:1–7

    Article  PubMed  CAS  Google Scholar 

  38. Bluthe RM, Laye S, Michaud B et al (2000) Role of interleukin-1 beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 12:4447–4456

    Article  PubMed  CAS  Google Scholar 

  39. Marks DL, Butler AA, Turner R et al (2003) Differential role of melanocortin receptor subtypes in cachexia. Endocrinology 144:1513–1523

    Article  PubMed  CAS  Google Scholar 

  40. Wisse BE, Schwartz MW, Cummings DE (2003) Melanocortin signaling and anorexia in chronic disease states. Ann NY Acad Sci 994:275–281

    PubMed  CAS  Google Scholar 

  41. Heisler LK, Cowley MA, Kishi T et al (2003) Central serotonin and melanocortin pathways regulating energy homeostasis. Ann NY Acad Sci 994:169–174

    PubMed  CAS  Google Scholar 

  42. Herx LM, Rivest S, Yong VW (2000) Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol 165:2232–2239

    PubMed  CAS  Google Scholar 

  43. Lambert PD, Anderson KD, Sleeman MW et al (2001) Ciliary neurotrophic factor activates leptinlike pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 98:4652–4657

    Article  PubMed  CAS  Google Scholar 

  44. Xu B, Dube MG, Kalra PS et al (1998) Anorectic effects of the cytokine, ciliary neurotropic factor, are mediated by hypothalamic neuropeptide Y: Comparison with leptin. Endocrinology 139:466–473

    Article  PubMed  CAS  Google Scholar 

  45. Gayle D, Ilyin SE, Plata SC (1997) Central nervous system IL-1 beta system and neuropeptide Y mRNAs during IL-1 beta-induced anorexia in rats. Brain Res Bull 44:311–317

    Article  PubMed  CAS  Google Scholar 

  46. Pi-Sunyer FX (2000) Overnutrition and undernutrition as modifiers of metabolic processes in disease states. Am J Clin Nutr 72:533S–537S

    PubMed  CAS  Google Scholar 

  47. Caldwell FT, Graves DB, Wallace BH (1998) Studies on the mechanism of fever after intravenous administration of endotoxin. J Trauma 44:304–312

    PubMed  CAS  Google Scholar 

  48. Jansky L, Vybiral S, Pospisilova D et al (1995) Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever. Neuroendocrinology 62:55–61

    PubMed  CAS  Google Scholar 

  49. Kluger MJ, Kozak W, Leon LR, Conn CA (1998) The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol 25:141–144

    Article  PubMed  CAS  Google Scholar 

  50. Cartmell T, Poole S, Turnbull AV et al (2000) Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol 526:653–661

    Article  PubMed  CAS  Google Scholar 

  51. Blatteis CM, Sehic E, Li SX (2000) Pyrogen sensing and signaling: old views and new concepts. Clin Infect Dis 31(Suppl 5):S168–S177

    Article  PubMed  CAS  Google Scholar 

  52. Miller AJ, Hopkins SJ, Luheshi GN (1997) Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat. Br J Clin Pharmacol 120:1274–1279

    CAS  Google Scholar 

  53. Netea MG, Kullberg BJ, Van Der Meer JW (1999) Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis. Eur J Clin Invest 29:351–356

    Article  CAS  Google Scholar 

  54. Gaykema RPA, Goehler LE, Hansen MK et al (2000) Subdiaphragmatic vagotomy blocks interleukin-1 beta-induced fever but does not reduce IL-1 beta levels in the circulation. Auton Neurosci 85:72–77

    Article  PubMed  CAS  Google Scholar 

  55. Szekely M, Balasko M, Kulchitsky VA et al (2000) Multiple neural mechanisms of fever. Auton Neurosci 85:78–82

    Article  PubMed  CAS  Google Scholar 

  56. Watkins LR, Goehler LE, Relton JK et al (1995) Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune brain communication. Neurosci Lett 183:27–31

    Article  PubMed  CAS  Google Scholar 

  57. Caldwell FT, Graves DB, Wallace BH (1999) Humoral versus neural pathways for fever production in rats after administration of lipopolysaccharide. J Trauma 47:120–129

    Article  PubMed  CAS  Google Scholar 

  58. Luheshi GN, Bluthe RM, Rushforth D et al (2000) Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats. Auton Neurosci 85:127–132

    Article  PubMed  CAS  Google Scholar 

  59. Goldbach JM, Roth J, Zeisberger E (1997) Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration. Am J Physiol 41:R675–R681

    Google Scholar 

  60. Romanovsky AA, Simons CT, Szekely M, Kulchitsky VA (1997) The vagus nerve in the thermoregulatory response to systemic inflammation. Am J Physiol 42:R407–R413

    Google Scholar 

  61. Arsenijevic D, de Bilbao F, Giannkopoulos P et al (2002) Role for interferon-gamma in the hypermetabolic response to murine toxoplasmosis. Eur Cytokine Netw 12:518–527

    Google Scholar 

  62. Busquets S, Alvarez B, Van Royen M et al (2001) Increased uncoupling protein-2 gene expression in brain of lipopolysaccharide-injected mice: role of tumour necrosis factor-alpha? Biochim Biophys Acta 1499:249–256

    Article  PubMed  CAS  Google Scholar 

  63. Masaki T, Yoshimatsu H, Kakuma T et al (1999) Induction of rat uncoupling protein-2 gene treated with tumour necrosis factor alpha in vivo. Eur J Clin Invest 29:76–82

    Article  PubMed  CAS  Google Scholar 

  64. Puigserver P, Rhee J, Lin JD et al (2001) Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPAR gamma coactivator-1. Mol Cell 8:971–982

    Article  PubMed  CAS  Google Scholar 

  65. Yudkin JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes 27:S25–S28

    Article  CAS  Google Scholar 

  66. Das UN (2001) Is obesity an inflammatory condition? Nutrition 17:953–966

    Article  PubMed  CAS  Google Scholar 

  67. Schmidt MI, Duncan BB (2003) Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med41:1120–1130

    Article  PubMed  CAS  Google Scholar 

  68. Kern PA (1997) Potential role of TNF alpha and lipoprotein lipase as candidate genes for obesity. J Nutr 127:S1917–S1922

    Google Scholar 

  69. Hostamisligil GS (1999) Mechanisms of TNF-alphainduced insulin resistance. Exp Clin Endocrinol Diabetes 107:119–125

    Article  Google Scholar 

  70. Uysal KT, Wiesbrock SM, Hotamisligil GS (1998) Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139:4832–4838

    Article  PubMed  CAS  Google Scholar 

  71. Hotamisligil GS (2000) Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes 24:S23–S27

    Article  CAS  Google Scholar 

  72. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614

    Article  PubMed  CAS  Google Scholar 

  73. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784–2789

    Article  PubMed  CAS  Google Scholar 

  74. Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784

    Article  PubMed  CAS  Google Scholar 

  75. Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51:3391–3399

    Article  PubMed  CAS  Google Scholar 

  76. Senn JJ, Klover PJ, Nowak IA et al (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278:13740–13746

    Article  PubMed  CAS  Google Scholar 

  77. Fasshauer M, Kralisch S, Klier M et al (2004) Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factorand Jak/Stat-signaling pathways in 3T3-L1 adipocytes. J Endocrinol 181:129–138

    Article  PubMed  CAS  Google Scholar 

  78. Mooney RA, Senn J, Cameron S et al (2001) Suppressors of cytokine signaling-1 and-6 associate with and inhibit the insulin receptor—A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem 276:25889–25893

    Article  PubMed  CAS  Google Scholar 

  79. Kaser S, Kaser A, Sandhofer A et al (2003) Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 309:286–290

    Article  PubMed  CAS  Google Scholar 

  80. Sonnenberg GE, Krakower GR, Kissebah AH (2004) A novel pathway to the manifestations of metabolic syndrome. Obes Res 12:180–186

    Article  PubMed  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer-Verlag Italia

About this chapter

Cite this chapter

Langhans, W. (2006). Cytokines in Chronic Inflammation. In: Mantovani, G., et al. Cachexia and Wasting: A Modern Approach. Springer, Milano. https://doi.org/10.1007/978-88-470-0552-5_22

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-0552-5_22

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-0471-9

  • Online ISBN: 978-88-470-0552-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics