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.
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References
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
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
Langhans W, Hrupka BJ (2003) Cytokines and appetite. In: Kronfol Z (ed) Cytokines and mental health. Kluwer/Academic Publishers, Boston, pp 167–224
Plata-Salamàn CR (1995) Cytokines and feeding suppression: an integrative view from neurologic to molecular levels. Nutrition 11:674–677
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
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
Geary N (2001) Sex differences in disease anorexia. Nutrition 17:499–507
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
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
Vitkovic L, Bockaert J, Jacque C (2000) ‘Inflammatory’ cytokines: neuromodulators in normal brain? J Neurochem 74:457–471
Plata-Salamàn CR, Turrin NP (1999) Cytokine interactions and cytokine balance in the brain: relevance to neurology and psychiatry. Mol Psychiatry 4:303–306
Rothwell NJ (1999) Cytokines—killers in the brain? J Physiol 514:3–17
Laviano A, Renvyle T, Meguid MM et al (1995) Relationship between interleukin-1 and cancer anorexia. Nutrition 11:680–683
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
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
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
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
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
Langhans W (2002) Peripheral mechanisms involved with catabolism. Curr Opin Clin Nutr Metab Care 5:419–426
Langhans W (2000) Anorexia of infection: current prospects. Nutrition 16:996–1005
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
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
Banks WA, Kastin AJ (1996) Passage of peptides across the blood-brain barrier: pathophysiological perspectives. Life Sci 59:1923–1943
Bierhaus A, Chen J, Liliensiek B, Nawroth PP (2000) LPS and cytokine-activated endothelium. Semin Thromb Hemost 26:571–587
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
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
Kalaria RN (1999) Cerebral endothelial activation and signal transduction mechanisms during inflammation and infectious disease. Am J Pathol 154:1311–1314
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
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
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
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
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
Langhans W, Savoldelli D, Weingarten S (1993) Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-lbeta. Physiol Behav 53:643–649
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
Reyes TM, Sawchenko PE (2002) Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia. J Neurosci 22:5091–5099
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
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
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
Marks DL, Butler AA, Turner R et al (2003) Differential role of melanocortin receptor subtypes in cachexia. Endocrinology 144:1513–1523
Wisse BE, Schwartz MW, Cummings DE (2003) Melanocortin signaling and anorexia in chronic disease states. Ann NY Acad Sci 994:275–281
Heisler LK, Cowley MA, Kishi T et al (2003) Central serotonin and melanocortin pathways regulating energy homeostasis. Ann NY Acad Sci 994:169–174
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
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
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
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
Pi-Sunyer FX (2000) Overnutrition and undernutrition as modifiers of metabolic processes in disease states. Am J Clin Nutr 72:533S–537S
Caldwell FT, Graves DB, Wallace BH (1998) Studies on the mechanism of fever after intravenous administration of endotoxin. J Trauma 44:304–312
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
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
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
Blatteis CM, Sehic E, Li SX (2000) Pyrogen sensing and signaling: old views and new concepts. Clin Infect Dis 31(Suppl 5):S168–S177
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
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
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
Szekely M, Balasko M, Kulchitsky VA et al (2000) Multiple neural mechanisms of fever. Auton Neurosci 85:78–82
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
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
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
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
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
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
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
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
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
Yudkin JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes 27:S25–S28
Das UN (2001) Is obesity an inflammatory condition? Nutrition 17:953–966
Schmidt MI, Duncan BB (2003) Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med41:1120–1130
Kern PA (1997) Potential role of TNF alpha and lipoprotein lipase as candidate genes for obesity. J Nutr 127:S1917–S1922
Hostamisligil GS (1999) Mechanisms of TNF-alphainduced insulin resistance. Exp Clin Endocrinol Diabetes 107:119–125
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
Hotamisligil GS (2000) Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes 24:S23–S27
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
Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784–2789
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
Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51:3391–3399
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
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
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
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
Sonnenberg GE, Krakower GR, Kissebah AH (2004) A novel pathway to the manifestations of metabolic syndrome. Obes Res 12:180–186
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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
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DOI: https://doi.org/10.1007/978-88-470-0552-5_22
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