Cytokines and the Anorexia of Infection: Potential Mechanisms and Treatments

Abstract

Anorexia during infection is thought to be mediated by immunoregulatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. This article reviews the potential mechanisms of action by which these cytokines are thought to suppress food intake during infection and examines the proposition that blocking of cytokine activity might be one approach to improving food intake of the infected host.

Keywords

Animal models interleukin-1alpha interleukin-1beta interleukin-6 tumor necrosis factor alpha anorexia infection lipopolysaccharide

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References

Arsenijevic D , Girardier L , Seydoux J , Chang HR , Dulloo AG . 1997. Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii. Am J Physiol 272:E908-E917.

Banks WA , Kastin AJ , Broadwell RD . 1995. Passage of cytokines across the blood-brain barrier [Review]. Neuroimmunomodulation 2:241-248.

Banks WA , Kastin AJ , Huang W , Jaspan JB , Maness LM . 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305-311.

Berkowitz DE , Brown D , Lee KM , Emala C , Palmer D , An Y , Breslow M . 1998. Endotoxin-induced alteration in the expression of leptin and beta3-adrenergic receptor in adipose tissue. Am Psychol 274:E992-E997.

Bernardis LL , Bellinger LL . 1996. The lateral hypothalamic area revisited: ingestive behavior. Neurosci Behav Rev 20:189-287.

Bessesen DH , Faggioni R . 1998. Recently identified peptides involved in the regulation of body weight [Review]. Semin Oncol 25:28-32.

Biberstine KJ , Darr DS , Rosenthal RS . 1996. Tolerance to appetite suppression induced by peptidoglycan. Infect Immunol 64:3641-3645.

Blatteis CM , Sehic E . 1997. Fever: how may circulating pyrogens signal the brain? News Physiol Sci 12:1-9.

Blundell JE , Halford JC . 1994. Regulation of nutrient supply: the brain and appetite control [Review]. Proc Nutr Soc 53:407-418.

10.

Bluthé RM , Michaud B , Kelley KW , Dantzer R . 1996. Vagotomy blocks behavioral effects of interleukin-1 injected via the i.p. route but not via other systemic routes. Neuroreport 7:2823-2827.

11.

Bret-Dibat JL , Bluthé RM , Kent S , Kelley KW , Dantzer R . 1995. Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immunol 9:242-246.

12.

Brobeck JR . 1948. Food intake as a mechanism of temperature regulation. Yale J Biol Med 20:545-552.

13.

Bucinskaite V , Kurosawa M , Miyasaka K , Funakoshi A , Lundeberg T . 1997. Neurosci Lett 229:33-36.

14.

Burgess W , Gheusi G , Yao J , Johnson RW , Dantzer R , Kelley KW . 1998. Interleukin-1 β-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia. Am J Physiol 274:R1829-R1833.

15.

Carlson GL . 1997. Nutrient induced thermogenesis. Baillieres Clin Endocrinol Metab 11:603-615.

16.

Chang HR , Bistrian B . 1998. The role of cytokines in the catabolic consequences of infection and injury. JPEN J Parenter Enteral Nutr 22:156-166.

17.

Coimbra CR , Plourde V . 1996. Abdominal surgery-induced inhibition of gastric emptying is mediated in part by interleukin-1beta. Am J Physiol 270:R556-R560.

18.

Dantzer R , Bluthé RM , Gheusi G , Cremona S , Laye S , Parnet P , Kelley KW . 1998. Molecular basis of sickness behavior. Ann N Y Acad Sci 856:132-138.

19.

Daun JM , McCarthy DO . 1993. The role of cholecystokinin in Interleukin-1 induced anorexia. Physiol Behav 54:237-241.

20.

Ek M , Kurosawa M , Lundeberg T , Ericsson A . 1998. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 18:9471-9479.

21.

Elmquist JK , Scammell TE , Saper CB . 1997. Mechanisms of CNS response to systemic immune challenge: the febrile response [Review]. Trends Neurosci 20:565-570.

22.

Faggioni R , Fantuzzi G , Fuller J , Dinarello CA , Feingold KR , Grunfeld C . 1998. IL-1 beta mediates leptin induction during inflammation. Am J Physiol 274:R204-R208.

23.

Faggioni R , Fantuzzi G , Gabay C , Moser A , Dinarello CA , Feingold KR , Grunfeld C . 1999. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol 276:R136-R142.

24.

Faggioni R , Fantuzzi G , Villa P , Buurman W , van Tits LJ , Ghezzi P . 1995. Independent down-regulation of central and peripheral tumor necrosis factor production as a result of lipopolysaccharide tolerance in mice. Infect Immun 63:1473-1477.

25.

Faggioni R , Fuller J , Moser A , Feingold KR , Grunfeld C . 1997. LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Am J Physiol 273:R181-R186.

26.

Fantino M , Wieteska L . 1993. Evidence for a direct central anorectic effect of tumor-necrosis-factor-alpha in the rat. Brain Res 53:477-483.

27.

Fantuzzi G , Dinarello CA . 1996. The inflammatory response in interleukin-1 beta-deficient mice: comparison with other cytokine-related knock-out mice. J Leukoc Biol 59:489-493.

28.

Fantuzzi G , Zheng H , Faggioni R , Benigni F , Ghezzi P , Sipe JD , Shaw AR , Dinarello CA . 1996. Effect of endotoxin in IL-1 beta-deficient mice. J Immunol 157:291-296.

29.

Fargeas MJ , Fioramonti J , Bueno L . 1984. Prostaglandin E2: a neuromodulator in the central control of gastrointestinal motility and feeding behavior by calcitonin. Science 225:1050-1052.

30.

Fattori E , Cappelletti M , Costa P , Sellitto C , Cantoni L , Carelli M , Faggioni R , Fantuzzi G , Ghezzi P , Poli V . 1994. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med 180:1243-1250.

31.

Feleder C , Refojo D , Nacht S , Moguilevsky JA . 1998. Interleukin-1 stimulates hypothalamic inhibitory amino acid neurotransmitter release. Neuroimmunomodulation 5:1-4.

32.

Gabay C , Kushner I . 1999. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448-454.

33.

Gallaher DD . 1992. Animal models in human nutrition research. Nutr Clin Prac 7:37-39.

34.

Gatti S , Bartfai T . 1993. Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res 624:291-294.

35.

Gayle D , Ilyin SE , Flynn MC , Plata-Salamán CR . 1998. Lipopolysaccharide (LPS)-and muramyl dipeptide (MDP)-induced anorexia during refeeding following acute fasting: characterization of brain cytokine and neuropeptide systems m RNA. Brain Res 795:77-86.

36.

Gayle D , Ilyin SE , Plata-Salamán CR . 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.

37.

Giner M , Laviano A , Meguid MM , Gleason JR . 1996. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition 12:23-29.

38.

Greig PD , Askanazi J , Elwyn DH , Kinney JM . 1984. Metabolic effects of increasing nitrogen intake during total parenteral nutrition in sepsis. JPEN J Parenter Enteral Nutr 8:87-94.

39.

Hansen MK , Taishi P , Chen Z , Krueger JM . 1998. Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta. J Neurosci 18:2247-2253.

40.

Hart BL . 1988. Biological basis of the behavior of sick animals [Review]. Neurosci Biobehav Rev 12:123-137.

41.

Haslett PA . 1998. Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol 25:53-57.

42.

Hill AG , Siegel J , Rounds J , Wilmore D . 1997. Metabolic responses to interleukin-1. Ann Surg 225:246-251.

43.

Huang QH , Hruby VJ , Tatro JB . 1999. Role of central melanocortins in endotoxin-induced anorexia. Am J Physiol 276:R864-R871.

44.

Ilyin SE , Gayle D , Flynn MC , Plata-Salamán CR . 1998. Interleukin-1beta system (ligand, receptor type I, receptor accessory protein and receptor antagonist), TNF-alpha, TGF betal and neuropeptide Y mRNAs in specific brain regions during bacterial LPS-induced anorexia. Brain Res Bull 45:507-515.

45.

Johnson RW . 1998. Immune and endocrine regulation of food intake in sick animals. Domest Anim Endocrinol 15:309-319.

46.

Kent S , Bluthé R , Dantzer R , Hardwick, AJ , Kelley KW , Rothwell NJ , Vannice JL . 1992. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci U S A 89:9117-9120.

47.

Kent S , Rodriguez F , Kelley KW , Dantzer R . 1994. Reduction in food and water intake induced by microinjection of interleukin-1 β in the ventromedial hypothalamus of the rat. Brain Res 56:1031-1036.

48.

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.

49.

Kopf M , Baumann H , Freer G , Freudenberg M , Lamers M , Kishimoto T , Zinkernagel R , Bluethmann H , Kohler G . 1994. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339-342.

50.

Kozak W , Kluger MJ , Soszynski D , Conn CA , Rudolph K , Leon LR , Zheng H . 1998. IL-6 and IL-1 beta in fever. Studies using cytokine-deficient (knockout) mice. Ann N Y Acad Sci 856:33-47.

51.

Kurosawa M , Uvnas-Moberg K , Miyasaka K , Lundeberg T . 1997. Interleukin-1 increases activity of the gastric vagal afferent nerve partly via stimulation of type ACC Kreceptor in anesthetized rats. J Auton Nerv Syst 62:72-78.

52.

Langhans W . 1996. Bacterial products and the control of ingestive behavior: clinical implications. Nutrition 12:303-315.

53.

Langhans W , Harlacher R , Balkowski G , Scharrer E . 1990. Comparison of the effects of bacterial lipopolysaccharide and muramyl dipeptide on food intake. Physiol Behav 47:805-813.

54.

Langhans W , Savoldelli D , Weingarten S . 1993. Comparison of the feeding responses to bacterial lipopolysaccharide. Physiol Behav 53:643-649.

55.

Larson SJ , Collins SM , Weingarten HP . 1996. Dissociation of temperature changes and anorexia after experimental colitis and LPS administration in rats. Am J Physiol 271:R967-R972.

56.

Laviano A , Yang ZJ , Meguid MM , Koseki M , Beverly JL . 1995. Hepatic vagus does not mediate IL-1 alpha induced anorexia. Neuroreport 6:1394-1396.

57.

Laye S , Bluthé RM , Kent S , Combe C , Medine C , Parnet P , Kelly K , Dantzer R . 1995. Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS. Am J Physiol 268:R1327-R1331.

58.

Laye S , Parnet P , Goujon E , Dantzer R . 1994. Peripheral administration of lipopolysaccharide induces the expression of cytokinetranscripts in the brain and pituitary of mice. Brain Res 27:157-162.

59.

Leon LR , Conn CA , Glaccum M , Kluger MJ . 1996. IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice. Am J Physiol 271:R1668-R1675.

60.

Levine AS , Billington CJ . 1997. Why do we eat? A neural systems approach. Annu Rev Nutr 17:597-619.

61.

Ling PR , Schwartz H , Bistrian BR . 1997. Mechanisms of host wasting induced by administration of cytokines in rats. Am J Physiol 272:E333-E339.

62.

Long NC . 1996. Evolution of infectious disease: how evolutionary forces shape physiological responses to pathogens. News Physiol Sci 11:83-90.

63.

Luheshi GN , Gardner JD , Rushforth DA , Loudon AS , Rothwell NJ . 1999. Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl Acad Sci U S A 96:7047-7052.

64.

Lutz CA , Przytulski KR . 1997. Nutrition and diet therapy. 2d ed. Philadelphia: F. A. Davis.

65.

Mahony SM , Tisdale MJ . 1989. Role of prostaglandins in tumour necrosis factor induced weight loss. Br J Cancer 60:51-55.

66.

Maier SF , Goehler LE , Fleshner M , Watkins LR . 1998. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289-300.

67.

McCarthy DO . In press. Tumor necrosis factor-alpha and interleukin-6 have differential effects on food intake and gastric emptying in fasted rats. Res Nurs Health.

68.

McCarthy DO , Daun JM . 1992. The role of prostaglandins in interleukin-1 induced gastroparesis. Physiol Behav 52:351-353.

69.

McCarthy DO , Kluger MJ , Vander AJ . 1984. The role of fever in appetite suppression after endotoxin administration. Am J Clin Nutr 40:310-316.

70.

McCarthy DO , Kluger MJ , Vander AJ . 1986. Effect of centrally administered interleukin-1 and endotoxin on food intake of fasted rats. Physiol Behav 36:745-749.

71.

McCarthy HD , Dryden S , Williams G . 1995. Interleukin-1 betainduced anorexia and pyrexia in rat: relationship to hypothalamic neuropeptide Y. Am J Physiol 269:E852-E857.

72.

Moldawer LL , Copeland EM III . 1998. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options [Review]. Cancer 79:1828-1839.

73.

Montuschi P , Preziosi P , Navarra P . 1993. Interleukin-1 β and tumour necrosis factor inhibit rat gastric fundus motility in vitro. Eur J Pharmacol 233:303-304.

74.

Montuschi P , Tringali G , Currò , Ciabattoni G , Parente L , Preziosi P , Navarra P . 1994. Evidence that interleukin-1 β and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygenase pathway. Eur J Pharmacol 252:253-260.

75.

Mugridge KG , Perretty M , Ghiara P , Parente L . 1991. a-Melanocytestimulating hormone reduces interleukin-1 β effects on rat stomach preparations possibly through interference with a type I receptor. Eur J Pharmacol 197:151-155.

76.

Murray MJ , Murray AB . 1979. Anorexia of infection as a mechanism of host defense. Am J Clin Nutr 32:593-596.

77.

Patton JS , Peters PM , McCabe J , Crase D , Hansen S , Chen AB , Liggitt D . 1987. Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-β in rodents. J Clin Invest 80:1587-1596.

78.

Pittet D , Harbarth S , Ruef C , Francioli P , Sudre P . Petignat C , Trampuz A . 1999. Prevalence and risk factors for nosocomial infections in four university hospitals in Switzerland. Infect Control Hosp Epidemiol 20:37-42.

79.

Plata-Salamán CR . 1994. Meal patterns in response to the intracerebroventricular administration of interleukin-1 β in rats. Physiol Behav 55:727-733.

80.

Plata-Salamán CR . 1995. Strategies for potential manipulation of anorexia during acute and chronic disease. Nutrition 11:702-704.

81.

Plata-Salamán CR . 1998a. Cytokine-induced anorexia, behavioral, cellular, and molecular mechanisms. Ann N Y Acad Sci 856:160-170.

82.

Plata-Salamán CR . 1998b. Cytokines and feeding. News Physiol Sci 13:298-304.

83.

Plata-Salamán CR , Borkoski JP . 1993. Centrally administered bacterial lipopolysaccharide depresses feeding in rats. Pharmacol Biochem Behav 46:787-791.

84.

Plata-Salamán CR , French-Mullen JMH . 1992. Intracerebroventricular administration of a specific IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1 β. Physiol Behav 51:1277-1279.

85.

Plata-Salamán CR , Vasselli JR , Sonti G . 1997. Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia. Obes Res 5:36-42.

86.

Porter MH , Arnold M , Langhans W . 1998. TNF-alpha tolerance blocks LPS-induced hypophagia but LPS tolerance fails to prevent TNF-alpha-induced hypophagia. Am J Physiol 274:R741-R745.

87.

Porter MH , Hrupka BJ , Langhans W , Schwartz GJ . 1998. Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS, and MDP. Am J Physiol 275:R384-E389.

88.

Riquelme R , Torres A , el-Ebiary M , Mensa J , Estruch R , Ruiz M , Augrill J , Soler N . 1997. Community-acquired pneumonia in the elderly: clinical and nutritional aspects. Am J Respir Crit Care Med 156:1908-1914.

89.

Roth J , Aslan T , Storr B , Luheshi GN , Zeisberger E . 1997. Lack of cross tolerance between LPS and muramyl dipeptide in induction of circulating TNF-alpha and IL-6 in guinea pigs. Am J Physiol 273:R1529-R1533.

90.

Rothe J , Lesslauer W , Lotscher H , Lang Y , Koebel P , Kontgen F , Althage A , Zinkernagel R , Steinmetz M , Bluethmann H . 1993. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364:798-802.

91.

Rowland NE , Morien A , Li B-H . 1996. The physiology and brain mechanisms of feeding. Nutrition 12:626-639.

92.

Rynbergen HJ . 1938. The place of nutrition in the nursing curriculum. J Am Diet Assoc 14:492-499.

93.

Sarraf P , Frederich RC , Turner EM , Ma G , Jaskowiak NT , Rivet DJ III , Flier JS , Lowell BB , Fraker DL , Alexander HR . 1997. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 185:171-175.

94.

Schumann D . 1996. Reducing post critical care infection. Med Surg Nurs 5:169-176.

95.

Schwartz GJ , Plata-Salamán CR , Langhans W . 1997. Subdiaphragmatic vagal deafferentation fails to block feeding suppressive effects of LPS and IL-1 beta in rats. Am J Physiol 273:R1193-R1198.

96.

Segretti J , Gheusi G , Dantzer R , Kelley KW , Johnson RW . 1997.Defect in interleukin-1 beta secretion prevents sickness behavior in C3H/HeJ mice. Physiol Behav 61:873-878.

97.

Shimizu H , Uehara Y , Shimomura Y , Kobayashi I . 1991. Central administration of ibuprofen failed to block the anorexia induced by interleukin-1. Eur J Pharmacol 195:281-284.

98.

Sonti G , Flynn MC , Plata-Salamán CR . 1997. Interleukin-1 (IL-1) receptor type I mediates anorexia but not adipsia induced by centrally administered IL-1beta. Physiol Behav 62:1179-1183.

99.

Sonti G , Ilyin SE , Plata-Salamán CR . 1996. Neuropeptide Y blocks and reverses interleukin-1 beta-induced anorexia in rats. Peptides 17:517-520.

100.

Souba WW . 1994. Cytokine control of nutrition and metabolism in critical illness [Review]. Curr Probl Surg 31:577-643.

101.

Stein J , Zeuzem S , Uphoff K , Laube H . 1994. Effects of prostaglandins and indomethacin on gastric emptying in the rat. Prostaglandins 47:31-40.

102.

Strassman G , Fong M , Windsor S , Neta R . 1993. The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production, in vivo. Cytokine 5:285-290.

103.

Sütõ G , Király A , Plourde V , Taché Y . 1996. Intravenous interleukin-1-beta-induced inhibition of gastric emptying: involvement of central corticotrophin-releasing factor and prostaglandin pathways in rats. Digestion 57:135-140.

104.

Sütõ G , Király á , Taché Y . 1994. Interleukin 1 β inhibits gastric emptying in rats: mediation through prostaglandin and corticotropin-releasing factor. Gastroenterology 106:1568-1575.

105.

Swiergiel AH , Smagin GN , Johnson LJ , Dunn AJ . 1997. The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra). Brain Res 776:96-104.

106.

Takahashi N , Waelput W , Guisez Y . 1999. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor. J Exp Med 189:207-212.

107.

Tompkins RG . 1997. The role of proinflammatory cytokines in inflammatory and metabolic responses. Ann Surg 225:243-245.

108.

Uehara Y , Shimizu H , Shimomura Y , Negishi M , Kobayashi I , Kobayashi S . 1990. Effects of recombinant human interleukins on food intake of previously food-deprived rats. Proc Soc Exp Biol Med 195:197-201.

109.

van Dam A-M , Brouns M , Louisse S , Berkenbosch F . 1992. Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res 588:291-296.

110.

van der Meer MJM , Sweep CGJF , Pesman GJ , Borm GF , Hermus ARMM . 1995. Synergism between IL-1 β and TNF-β on the activity of the pituitary-adrenal axis and on food intake of rats. Am J Physiol 268:E551-E557.

111.

van Miert ASJPAM , van Duin CTM . 1998. Pharmacological and pathophysiological modulation of food intake and forestomach motility in small ruminants. J Vet Pharmacol ther 21:1-17.

112.

Verity S . 1996. Nutrition and its importance to intensive care patients. Intensive Crit Care Nurs 12:71-78.

113.

Weingarten HP . 1996. Cytokines and food intake: the relevance of the immune system to the student of ingestive behavior. Neurosci Biobehav Rev 120:163-170.

114.

Wing EJ , Young JB . 1980. Acute starvation protects mice against Listeria monocytogenes. Infect Immunol 28:771-776.

115.

Wolf G . 1997. Neuropeptides responding to leptin. Nutr Rev 55:85-88.

116.

Woodroofe MN . 1995. Cytokine production in the central nervous system. Neurology 45:S6-S10.

117.

Yang ZJ , Blaha V , Meguid MM , Laviano A , Oler A , Zadak Z . 1999. Interleukin-1 alpha injection into ventromedial hypothalamic nucleus of normal rats depresses food intake and increases release of dopamine and serotonin. Pharmacol Biochem Behav 62:61-65.

118.

Yang ZJ , Koseki M , Meguid MM , Gleason JR , Debonis D . 1994. Synergistic effect of rhTNF-1 β in inducing anorexia in rats. Am J Physiol 267:R1056-R1064.

119.

Zheng H , Fletcher D , Kozak W , Jiang M , Hofmann KJ , Conn CA , Soszynski D , Grabiec C , Trimbauer ME , Shaw A . 1995. Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice. Immunity 3:9-19.