Cytokines and Appetite

  • Wolfgang Langhans
  • Brian J. Hrupka
Part of the Neurobiological Foundation of Aberrant Behaviors book series (NFAB, volume 7)


Cytokines are known to orchestrate non-specific and specific immune reactions and are broadly categorized as being pro-inflammatory or antiinflammatory. In addition to their pleiotropic effects in the immune system, cytokines affect other physiologic functions and cause CNS-mediated effects such as fever, sleep, and an activation of the hypothalamic-pituitary-adrenal axis. Moreover, several pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, IL-8, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) suppress appetite. The cytokine-induced suppression of appetite, i.e. the resulting anorexia and hypermetabolism are major contributors to the cachexia of chronic diseases, and part of the organism’s acute phase response to various immune stimuli. Acute, short-term anorexia during an immune challenge is considered to be beneficial for the host. For example, force-feeding experimentally infected mice to the control levels reduced survival time and increased mortality (1). Sustained cytokine-mediated anorexia, however, which occurs during chronic infections, cancer and other chronic diseases can compromise the host’s ability to fight disease. Cytokines also presumably contribute to the anorexia and cachexia that promote fragility in aging people. Thus, the appetite suppressing effect of cytokines is a practically relevant and scientifically interesting research problem with various facets.


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  1. 1.
    Murray, M.J., Murray, A.B. Anorexia of infection as a mechanism of host defense. Am J Clin Nutr 1979; 32:593–596.PubMedGoogle Scholar
  2. 2.
    Langhans, W., Hrupka, B. Interleukins and tumor necrosis factor as inhibitors of food intake. Neuropeptides 1999; 33:415–424.PubMedGoogle Scholar
  3. 3.
    Plata-Salamàn, .CR. Interferons and central regulation of feeding. Am J Physiol 1992; 263:R1222–R1227.PubMedGoogle Scholar
  4. 4.
    Plata-Salamàn, C.R. Cytokines and feeding suppression: An integrative view from neurologic to molecular levels. Nutrition 1995; 11:674–677.PubMedGoogle Scholar
  5. 5.
    Plata-Salamàn, C.R. Anorexia during acute and chronic disease. Nutrition 1996; 12:69–78.PubMedGoogle Scholar
  6. 6.
    Kent, S., BretDibat, .L., Kelley, K.W., et al. Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev 1996; 20:171–175.PubMedGoogle Scholar
  7. 7.
    Plata-Salamàn, C.R., FfrenchMullen, J.M.H. Intracerebro ventricular administration of a specific IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1 beta. Physiol Behav 1992; 51:1277–1279.PubMedGoogle Scholar
  8. 8.
    Aubert, A., Goodall, G., Dantzer, R. Compared effects of cold ambient temperature and cytokines on macronutrient intake in rats. Physiol Behav 1995; 57:869–873.PubMedGoogle Scholar
  9. 9.
    Winograd, C.H., Brown, E.M. Aggressive oral refeeding in hospitalized-patients. Am J Clin Nutr 1990; 52:967–968.PubMedGoogle Scholar
  10. 10.
    Bauer, C., Weingarten, S., Senn, M., Langhans W. Limited importance of a learned aversion in the hypophagic effect of interleukin-1 beta. Physiol Behav 1995; 57:1145–1153.PubMedGoogle Scholar
  11. 11.
    Bernstein, I.L. Neural mediation of food aversions and anorexia induced by tumor necrosis factor and tumors. Neurosci Biobehav Rev 1996; 20:177–181.PubMedGoogle Scholar
  12. 12.
    Goehler, L.E., Busch, C.R., Tartaglia, N., et al. Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: Further evidence for vagal mediation of immune-brain communication. Neurosci Lett 1995; 185:163–166.PubMedGoogle Scholar
  13. 13.
    Lennie, T.A. Relationship of body energy status to inflammation-induced anorexia and weight loss. Physiol Behav 1998; 64:475–481.PubMedGoogle Scholar
  14. 14.
    Mrosovsky, N., Molony, L.A., Conn, C.A., et al. Anorexic effects of interleukin 1 in the rat. Am J Physiol 1989;257:R1315-R1321.PubMedGoogle Scholar
  15. 15.
    Porter, M.H., Arnold, M., Langhans, W. TNF-alpha tolerance blocks LPS-induced hypophagia but LPS tolerance fails to prevent TNF-alpha-induced hypophagia. Am J Physiol 1998; 274:R741-R745.PubMedGoogle Scholar
  16. 16.
    Weingarten, S., Savoldelli, D., Langhans, W. Enhancement or loss of the hypophagic effect of interleukin-1 upon chronic administration. Physiol Behav 1992; 52:831–837.PubMedGoogle Scholar
  17. 17.
    Fraker, D.L., Stovroff, M.C., Merino, M.J., et al. Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity. J Exp Med 1988; 168:95–105.PubMedGoogle Scholar
  18. 18.
    Takahashi, N., Brouckaert, P., Fiers, W. Mechanism of tolerance to tumor necrosis factor: Receptor-specific pathway and selectivity. Am J Physiol 1995; 269:R398–R405.PubMedGoogle Scholar
  19. 19.
    Plata-Salamàn, C.R., Sonti, G., Borkoski, J.P., et al. Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol Behav 1996; 60:867–875.PubMedGoogle Scholar
  20. 20.
    Segall, M.A., Crnic, L.S. An animal model for the behavioral effects of interferon. Behav Neurosci 1990; 104:612–618.PubMedGoogle Scholar
  21. 21.
    Langstein, H.N., Doherty, G.M., Fraker, D.L., et al. The roles of gamm-interferon and tumor-necrosis-factor-alpha in an experimental rat model of cancer cachexia. Cancer Res 1991; 51:2302–2306.PubMedGoogle Scholar
  22. 22.
    Sonti, G., Ilyin, S.E., Plata-Salamàn, C.R. Anorexia induced by cytokine interactions at pathophysiological concentrations. Am J Physiol 1996; 270:R1394–R1402.PubMedGoogle Scholar
  23. 23.
    Plata-Salamàn, C.R. Meal patterns in response to the intracerebroventricular administration of interleukin-1 beta in rats. Physiol Behav 1994; 55:727–733.PubMedGoogle Scholar
  24. 24.
    Debonis, D., Meguid, M.M., Laviano, A., et al. Temporal changes in meal number and meal size relationship in response to rHu IL-1 alpha. Neuroreport 1995; 6:1752–1756.PubMedGoogle Scholar
  25. 25.
    Langhans, W., Savoldelli, D., Weingarten, S. Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-1 beta. Physiol Behav 1993; 53:643–649.PubMedGoogle Scholar
  26. 26.
    Langhans, W., Balkowski, G., Savoldelli, D. Further characterization of the feeding responses to interleukin and tumor necrosis factor. In: Murison, R., (ed.) Endocrine and Nutritional Control of Basic Biological Functions. Hogrefe & Huber Publishers, Toronto (1992) pp. 137–144.Google Scholar
  27. 27.
    Angele, M.K., Knoferl, M.W., Schwacha, M.G., et al. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol 1999; 277:C35–C42.PubMedGoogle Scholar
  28. 28.
    Li, Z.G., Danis, V.A., Brooks, P.M. Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol 1993; 11:157–162.PubMedGoogle Scholar
  29. 29.
    Lynch, E.A., Dinarello, C.A., Cannon, J.G. Gender differences in IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist secretion from mononuclear cells and urinary excretion. J Immunol 1994; 153:300–306.PubMedGoogle Scholar
  30. 30.
    Schwarz, E., Schafer, C., Bode, J.C., et al. Influence of the menstrual cycle on the LPS-induced cytokine response of monocytes. Cytokine 2000; 12:413–416.PubMedGoogle Scholar
  31. 31.
    Geary, N. Sex differences in disease anorexia. Nutrition 2001; 17:499–507.PubMedGoogle Scholar
  32. 32.
    Mouihate, A., Chen, X., Pittman, Q.J. Interleukin-1 beta fever in rats: gender difference and estrous cycle influence. Am J Physiol 1998; 275:R1450-R1454.PubMedGoogle Scholar
  33. 33.
    Ikejima, K., Enomoto, N., Iimuro, Y., et al. Estrogen increases sensitivity of Kupffer cells to endotoxin. Alcoholism - Clin Exp Res 1998; 22:768–769.Google Scholar
  34. 34.
    Butera, P.C., Doerflinger, A.L., Roberto, F. Cyclic estradiol treatmet enhances the effects of interluekin-lbeta on food intake in female rats. Brain Behav Immun 2002; 16:275–281.PubMedGoogle Scholar
  35. 35.
    VanderMeer, M.J.M., Sweep, C.G.J.F., Pesman, G.J., et al. Synergism between IL-1 beta and TNF-alpha on the activity of the pituitary-adrenal axis and on food intake of rats. Am J Physiol 1995; 268.E551–E557.Google Scholar
  36. 36.
    Yang, Z.J., Koseki, M., Meguid, M.M., et al. Synergistic effect of rhTNF-alpha and rhIL-1 alpha in inducing anorexia in rats. Am J Physiol 1994; 267:R1056-R1064.PubMedGoogle Scholar
  37. 37.
    Plata-Salamàn, C.R., Turrin, N.P. Cytokine interactions and cytokine balance in the brain: relevance to neurology and psychiatry. Mol Psychiatry 1999; 4:303–306.Google Scholar
  38. 38.
    Alheim, K., Chai, Z., Fantuzzi, G., et al. Hyperresponsive febrile reactions to interleukin (IL) 1 alpha and IL-1 beta, and altered brain cytokine mRNA and serum cytokine levels, in IL-1 beta-deficient mice. Proc Natl Acad Sci USA 1997; 94:2681–2686.PubMedGoogle Scholar
  39. 39.
    Chai, Z., Gatti, S., Toniatti, C., et al. Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipolysaccharide or IL-1 beta: A study on IL-6-deficient mice. J Exp Med 1996; 183:311–316.PubMedGoogle Scholar
  40. 40.
    Arsenijevic, D., Girardier, L., Seydoux, J., et al. Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii. Am J Physiol 1997; 272:E908–E917.PubMedGoogle Scholar
  41. 41.
    Arsenijevic, D., Onuma, H., Pecqueur, C., et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genetics 2000; 26:435–439.PubMedGoogle Scholar
  42. 42.
    Wusteman, M., Wight, D.G.D., Elia, M. Protein-metabolism after injury within turpentine - A rat model for clinical trauma. Am J Physiol 1990; 259:E763–E769.PubMedGoogle Scholar
  43. 43.
    Cooper, A.L., Brouwer, S., Turnbull, A.V., et al. Tumor necrosis factor-alpha and fever after peripheral inflammation in the rat. Am J Physiol 1994; 36:R1431–R1436.Google Scholar
  44. 44.
    Kopf, M., Baumann, H., Freer, G., et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994; 368:339–342.PubMedGoogle Scholar
  45. 45.
    Kozak, W., Poli, V., Soszynski, D., et al. Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis. Am J Physiol 1997; 272:R621–R630.PubMedGoogle Scholar
  46. 46.
    Leon, L.R., Conn, C.A., Glaccum, M., et al. IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice. Am. J. Physiol. 1996; 271:R1668–R1675.PubMedGoogle Scholar
  47. 47.
    Oldenburg, H.S.A., Rogy, M.A., Lazarus, D.D., et al. Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6. Eur J Immunol 1993; 23:1889–1894.PubMedGoogle Scholar
  48. 48.
    Gee, M.I., Grace, M.G.A., Wensel, R.H., et al. Protein-energy malnutrition in gastroeneterology outpatients — Increased risk in Crohns-disease. J Am Diet Assoc 1985;85:1466–1474.PubMedGoogle Scholar
  49. 49.
    Mchugh, K., Castonguay, T.W., Collins, S.M., et al. Characterization of suppression of food intake following acute colon inflammation in the rat. Am J Physiol 1993; 265.R1001–R1005.PubMedGoogle Scholar
  50. 50.
    Rachmilewitz, D., Simon, P.L., Schwartz, L.W., et al. Inflammatory mediators of experimental colitis in rats. Gastroenterol 1989; 97:326–337.Google Scholar
  51. 51.
    Mchugh, K.J., Collins, S.M., Weingarten, H.P. Central interleukin-1 receptors contribute to suppression of feeding after acute colitis in the rat. Am J Physiol 1994; 266:R1659–R1663.PubMedGoogle Scholar
  52. 52.
    Abram, M., Vuckovic, D., Wraber, B., et al. Plasma cytokine response in mice with bacterial infection. Med Inflamm 2000; 9:229–234.Google Scholar
  53. 53.
    Imanishi, J. Expression of cytokines in bacterial and viral infections and their biochemical aspects. J Biochem 2000; 127:525–530.PubMedGoogle Scholar
  54. 54.
    Poveda, F., Camacho, J., Arnalich, F.,et al. Circulating cytokine concentrations in tuberculosis and other chronic bacterial infections. Infection 1999; 27:272–274.PubMedGoogle Scholar
  55. 55.
    Rietschel, E.T., Schletter, J., Weidemann, B., El S.V., et al. Lipopolysaccharide and peptidoglycan: CD14-dependent bacterial inducers of inflammation. Microb Drug Resist 1998; 4:37–44.PubMedGoogle Scholar
  56. 56.
    Akira, S. Toll-like receptors: lessons from knockout mice. Biochem Soc Trans 2000; 28 Part 5:551–556.PubMedGoogle Scholar
  57. 57.
    Beutler, B. Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity. Curr Opin Microbiol 2000; 3:23–28.PubMedGoogle Scholar
  58. 58.
    Muzio, M., Mantovani, A. Toll-like receptors. Microbes Inf 2000; 2:251–255.Google Scholar
  59. 59.
    Arsenijevic, D., Garcia, I., Vesin, C, et al. Differential roles of tumor necrosis factor-alpha and interferon-gamma in mouse hypermetabolic and anorectic responses induced by LPS. Eur Cytok Netw 2000; 11:662–668.Google Scholar
  60. 60.
    Bluthe, R.M., Laye, S., Michaud, B., et al. 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 2000; 12:4447–4456.PubMedGoogle Scholar
  61. 61.
    Kozak, W., Zheng, H., Conn, C.A., et al. Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice. Am J Physiol 1995; 269:R969–R977.PubMedGoogle Scholar
  62. 62.
    Leon, L.R., Kozak, W., Peschon, J., et al. Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice. Am J Physiol 1997; 272:R563–R569.PubMedGoogle Scholar
  63. 63.
    Bluthe, R.M., Michaud, B., Poli, V., et al. Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol Behav 2000; 70:367–373.PubMedGoogle Scholar
  64. 64.
    Leon, L.R., White, A.A., Kluger, M.J. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 1998; 275:R269–R277.PubMedGoogle Scholar
  65. 65.
    Matsuda, T., Hirano, T. IL-6. In: Oppenheim JJ, Feldmann M, editors. Cytokine Reference, Volume 1: Ligands. San Diego: Academic Press, 2001: 537–563.Google Scholar
  66. 66.
    Billiau, A., Vendenbroeck, K. INF-gamma. In: Oppenheim JJ, Feldmann M, editors. Cytokine Reference, Volume 1: Ligands. San Diego: Academic Press, 2001: 641–688.Google Scholar
  67. 67.
    Beutler, B. TLR4: central component of the sole mammalian LPS sensor. Curr Opin Immunol 2000; 12:20–26.PubMedGoogle Scholar
  68. 68.
    Doherty, G.M., Lange, J.R., Langstein, H.N., et al. Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. J Immunol 1992; 149:1666–1670.PubMedGoogle Scholar
  69. 69.
    Chang, H.R., Bistrian, B. The role of cytokines in the catabolic consequences of infection and injury. J Parent Enteral Nutr 1998; 22:156–166.Google Scholar
  70. 70.
    Porter, M.H., Hrupka, B.J., Altreuther, G., et al. Inhibition of TNF-? production contributes to the attenuation of LPS-induced hypophagia by pentoxifylline. Am J Physiol 2000; 279:R2113–R2120.Google Scholar
  71. 71.
    Swiergiel, A.H., Dunn, A.J. The roles of IL-1, IL-6, and TNF alpha in the feeding responses to endotoxin and influenza virus infection in mice. Brain Behav Immun 1999; 13:252–265.PubMedGoogle Scholar
  72. 72.
    Barton, B.E. IL-6-like cytokines and cancer cachexia - Consequences of chronic inflammation. Immunol Res 2001; 23:41–58.PubMedGoogle Scholar
  73. 73.
    Bossola, M., Muscaritoli, M., Bellantone, R., et al. Serum tumour necrosis factor-alpha levels in cancer patients are discontinuous and correlate with weight loss. Eur J Clin Invest 2000; 30:1107–1112.PubMedGoogle Scholar
  74. 74.
    Ikemoto, S., Sugimura, K., Yoshida, N., et al. TNF alpha, IL-1 beta and IL-6 production by peripheral blood monocytes in patients with renal cell carcinoma. Anticancer Res 2000; 20:317–321.PubMedGoogle Scholar
  75. 75.
    Mantovani, G., Maccio, A., Mura, L., et al. Serum levels of leptin and pro-inflamatory cytokines in patients with advanced-stage cancer at different sites. J Mol Med-Jmm 2000; 78:554–561.Google Scholar
  76. 76.
    Okada, S., Okusaka, T., Ishii, H., et al. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jap J Clin Oncol 1998; 28:12–15.Google Scholar
  77. 77.
    Plata-Salamàn, C.R., Ilyin, S.E., Gayle, D. Brain cytokine mRNAs in anorectic rats bearing prostate adenocarcinoma tumor cells. Am J Physiol 1998; 275:R566–R573.PubMedGoogle Scholar
  78. 78.
    Zhang, G.J., Adachi, I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 1999; 19:1427–1432.PubMedGoogle Scholar
  79. 79.
    Cahlin, C., Korner, A., Axelsson, H., et al. Experimental cancer cachexia: The role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res 2000; 60:5488–5493.PubMedGoogle Scholar
  80. 80.
    Molotkov, A., Satoh, M., Tohyama, C. Tumor growth and food intake in interleukin-6 gene knock-out mice. Cancer Lett 1998; 132:187–192.PubMedGoogle Scholar
  81. 81.
    Laviano, A., Renvyle, T., Meguid, M.M., et al. Relationship between interleukin-1 and cancer anorexia. Nutrition 1995; 11:680–683.PubMedGoogle Scholar
  82. 82.
    Smith, B.K., Kluger, M.J. Anti-TNF-alpha antibodies normalized body temperature and enhanced food intake in tumor-bearing rats. Am J Physiol 1993; 265:R615–R619.PubMedGoogle Scholar
  83. 83.
    Torelli, G.F., Meguid, M.M., Moldawer, L.L., et al. Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. Am J Physiol 1999; 277:R850–R855.PubMedGoogle Scholar
  84. 84.
    Moldawer, L.L., Rogy, M.A., Lowry, S.F. The role of cytokines in cancer cachexia. J Parent Ent Nutr 1992; 16 Suppl:43S–49S.Google Scholar
  85. 85.
    Noguchi, Y., Yoshikawa, T., Matsumoto, A., et al. Are cytokines possible mediators of cancer cachexia? Surg Today 1996; 26:467–475.PubMedGoogle Scholar
  86. 86.
    Nakatani S, Iwagaki H, Okabayashi T, Isozaki H, Takakura N, Tanaka N. Is increased IL-1 beta mRNA expression in spleen of tumor- bearing mice relevant to cancer cachexia? Res Comm Mol Pathol Pharmacol 1998; 102:241–249.Google Scholar
  87. 87.
    Strassmann, G., Fong, M., Kenney, J.S., et al. Evidence for involvement of interleukin-6 in experimental cancer cachexia. J Clin Invest 1992; 89:1681–1684.PubMedGoogle Scholar
  88. 88.
    Malaguarnera, L., Ferlito, L., Imbesi, R.M., et al. Immunosenescence: a review. Arch Gerontol Geriat 2001; 32:1–14.Google Scholar
  89. 89.
    Bruunsgaard, H., Pedersen, A.N., Schroll, M., et al. TNF-alpha, leptin, and lymphocyte function in human aging. Life Sci 2000; 67:2721–2731.PubMedGoogle Scholar
  90. 90.
    Pedersen, B.K., Bruunsgaard, H., Ostrowski, K., et al. Cytokines in aging and exercise. Int J Sports Med 2000; 21:S4-S9.PubMedGoogle Scholar
  91. 91.
    Saurwein, T.M., Blasko, I., Zisterer, K., et al. An imbalance between pro- and antiinflammatory cytokines, a characteristic feature of old age. Cytokine 2000; 12:1160–1161.Google Scholar
  92. 92.
    Yeh, S.S., Schuster, M.W. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 1999;70:183–197.PubMedGoogle Scholar
  93. 93.
    Paolisso, G., Rizzo, M.R., Mazziotti, G., et al. Advancing age and insulin resistance: role of plasma tumor necrosis factor-alpha. Am J Physiol 1998; 275:E294–E299.PubMedGoogle Scholar
  94. 94.
    Ostrowski, K., Rohde, T., Asp, S., et al. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol London 1999; 515:287–291.PubMedGoogle Scholar
  95. 95.
    Ostrowski, K., Schjerling, P., Pedersen, B.K. Physical activity and plasma interleukin-6 in humans - effect of intensity of exercise. Eur J Appl Physiol 2000; 83:512–515.PubMedGoogle Scholar
  96. 96.
    Pedersen, B.K. Exercise and cytokines. Immunol Cell Biol 2000; 78:532–535.PubMedGoogle Scholar
  97. 97.
    Baum, M., MullerSteinhardt, M., Liesen, H., et al. Moderate and exhaustive endurance exercise influences the interferon-gamma levels in whole-blood culture supernatants. Eur J Appl Physiol 1997; 76:165–169.Google Scholar
  98. 98.
    Starkie, R.L., Angus, D.J., Rolland, J., et al. Effect of prolonged, submaximal exercise and carbohydrate ingestion on monocyte intracellular cytokine production in humans. J Physiol London 2000; 528:647–655.PubMedGoogle Scholar
  99. 99.
    Ostrowski, K., Rohde, T., Zacho, M., et al. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J Physiol London 1998; 508:949–953.PubMedGoogle Scholar
  100. 100.
    Jeukendrup, A.E., Vet, J.K., Sturk, A., et al. Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. Clin Sci 2000; 98:47–55.PubMedGoogle Scholar
  101. 101.
    Hotamisligil, G.S., Arner, P., Caro, J.F., et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95:2409–2415.PubMedGoogle Scholar
  102. 102.
    Kern, P.A., Saghizadeh, M., Ong, J.M., et al. The expression of tumor necrosis factor in human adipose tissue - Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995; 95:2111–2119.PubMedGoogle Scholar
  103. 103.
    Hotamisligil, G.S., Shargill, N.S., Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259:87–91.PubMedGoogle Scholar
  104. 104.
    Brand, E., Schorr, U., Kunz, I., et al. Tumor necrosis factor-alpha-308 G/A polymorphism in obese Caucasians. Int J Obes 2001; 25:581–585.Google Scholar
  105. 105.
    Morin, C.L., Pagliassotti, M.J., Windmiller, D., et al. Adipose tissue-derived tumor necrosis factor-alpha activity is elevated in older rats. J Gerontol Series A Biol Sci Med Sci 1997; 52.B190–B195.Google Scholar
  106. 106.
    Morin, C.L., Eckel, R.H., Marcel, T., et al. High fat diets elevate adipose tissue-derived tumor necrosis factor-alpha activity. Endocrinol 1997; 138:4665–4671.Google Scholar
  107. 107.
    Hotamisligil, G.S., Budavari, A., Murray, D., et al. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 1994; 94:1543–1549.PubMedGoogle Scholar
  108. 108.
    Kern, P.A. Potential role of TNF alpha and lipoprotein lipase as candidate genes for obesity. J Nutr 1997; 127:S1917–S1922.Google Scholar
  109. 109.
    Tanaka, T., Itoh, H., Doi, K., et al. Down regulation of peroxisome proliferator-activated receptor gamma expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 1999; 42:702–710.8PubMedGoogle Scholar
  110. 110.
    Dandona, P., Weinstock, R., Thusu, K., et al. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998; 83:2907–2910.PubMedGoogle Scholar
  111. 111.
    Tsigos, C, Kyrou, L., Chala, E., et al. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metabolism 1999; 48:1332–1335.PubMedGoogle Scholar
  112. 112.
    Mohamed-Ali, V., Goodrick, S., Rawesh, A., et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metabol 1997; 82:4196–4200.Google Scholar
  113. 113.
    Kirchgessner, T.G., Uysal, K., Wiesbrock, S.M., et al. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest 1997; 100:2777–2782.PubMedGoogle Scholar
  114. 114.
    Unger, R.H. Leptin physiology: a second look. Regul Peptides 2000; 92:87–95.Google Scholar
  115. 115.
    Uysal, K.T., Wiesbrock, S.M., Marino, M.W., et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389:610–614.PubMedGoogle Scholar
  116. 116.
    Bastard, J.P., Jardel, C., Bruckert, E., et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metabol 2000; 85:3338–3342.Google Scholar
  117. 117.
    McCarty, M.F. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. MedHypoth 1999; 52:465–477.Google Scholar
  118. 118.
    Raymond, N.C., Dysken, M., Bettin, K., et al. Cytokine production in patients with anorexia nervosa, bulimia nervosa, and obesity. Int J Eating Disord 2000; 28:293–302.Google Scholar
  119. 119.
    Bruun, J.M., Pedersen, S.B., Richelsen, B. Regulation of interleukin 8 production and gene expression in human adipose tissue in vitro. J Clin Endocrinol Metabol 2001; 86:1267–1273.Google Scholar
  120. 120.
    Montuschi, P., Tringali, G., Mirtella, A., et al. Interleukin-lbeta release from rat gastric fundus. Am J Physiol 1996; 271:G275–G281.PubMedGoogle Scholar
  121. 121.
    Youngman, K.R., Simon, P.L., West, G. A., et al. Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells. Gastroenterol 1993; 104:749–758.Google Scholar
  122. 122.
    Deitch, E.A. Bacterial translocation — The influence of dietary variables. Gut 1994; 35:S23–S27.PubMedGoogle Scholar
  123. 123.
    Hansen, K., Sickelmann, F., Pietrowsky, R., et al. Systemic immune changes following meal intake in humans. Am J Physiol 1997; 273:R548–R553.PubMedGoogle Scholar
  124. 124.
    Hansen, M.K., Taishi, P., Chen, Z.T., et al. Cafeteria feeding induces interleukin-1 beta mRNA expression in rat liver and brain. Am J Physiol 1998; 274.R1734–R1739.PubMedGoogle Scholar
  125. 125.
    Kurosawa, M., UvnasMoberg, K., Miyasaka, K., et al. Interleukin-1 increases activity of the gastric vagal afferent nerve partly via stimulation of type A CCK receptor in anesthetized rats. J Auton Nerv Syst 1997; 62:72–78.PubMedGoogle Scholar
  126. 126.
    Niijima, A. The afferent discharges from sensors for interleukin-lbeta in the hepatoportal system in the anesthetized rat. J Auton Nerv Syst 1996; 61:287–291.PubMedGoogle Scholar
  127. 127.
    Hansen, M.K., Krueger, J.M. Subdiaphragmatic vagotomy blocks the sleep- and fever-promoting effects of interleukin-1 beta. Am J Physiol 1997; 273:R1246–R1253.PubMedGoogle Scholar
  128. 128.
    Pu, S.Y., Anisman, H., Merali, Z. Central infusion of interleukin-I receptor antagonist fails to alter feeding and weight gain. Neuroreport 2000; 11:1699–1702.PubMedGoogle Scholar
  129. 129.
    Floyd, R.A., Krueger, J.M. Diurnal variation of TNF alpha in the rat brain. Neuroreport 1997; 8:915–918.PubMedGoogle Scholar
  130. 130.
    Holden, R.J., Pakula, I.S. The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity. Med Hypoth 1996; 47:423–438.Google Scholar
  131. 131.
    Brambilla, F., Bellodi, L., Brunetta, M., et al. Plasma concentrations of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha in Anorexia and Bulimia Nervosa. Psychoneuroendocrinol 1998; 23:439–447.Google Scholar
  132. 132.
    Nakai, Y., Hamagaki, S., Takagi, R., et al. Plasma concentrations of tumor necrosis factor-alpha (TNF- alpha) and soluble TNF receptors in patients with bulimia nervosa. Clin Endocrinol 2000; 53:383–388.Google Scholar
  133. 133.
    Vitkovic, L., Bockaert, J., Jacque, C. Inflammatory cytokines: Neuromodulators in normal brain? J Neurochem 2000; 74:457–471.PubMedGoogle Scholar
  134. 134.
    Rothwell, N.J. Cytokines - killers in the brain? J Physiol London 1999; 514:3–17.PubMedGoogle Scholar
  135. 135.
    Pan, W., Zadina, J.E., Harlan, R.E., et al. Tumor necrosis factor-alpha: a neuromodulator in the CNS. Neurosci Biobehav Rev 1997; 21:603–613.PubMedGoogle Scholar
  136. 136.
    Konsman, J.P., Tridon, V., Dantzer, R. Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS. Neuroscience 2000; 101:957–967.PubMedGoogle Scholar
  137. 137.
    Ericsson, A., Liu, C., Hart, R.P., et al. Type-1 interleukin receptor in the rat brain -Distribution, regulation, and relationship to sites IL-1-induced cellular activation. J Comp Neurol 1995; 361:681–698.PubMedGoogle Scholar
  138. 138.
    Zhang, J., Rivest, S. A functional analysis of EP4 receptor-expressing neurons in mediating the action of prostaglandin E-2 within specific nuclei of the brain in response to circulating interleukin-1 beta. J Neurochem 2000; 74:2134–2145.PubMedGoogle Scholar
  139. 139.
    Gabellec, M.M., Griffais, R., Fillion, G., et al. Expression of interleukin 1 alpha, interleukin 1 beta and interleukin 1 receptor antagonist mRNA in mouse brain: Regulation by bacterial lipopolysaccharide (LPS) treatment. Mol Brain Res 1995; 31:122–130.PubMedGoogle Scholar
  140. 140.
    Gayle, D., Ilyin, S.E., Plata, S.C. Central nervous system IL-1 beta system and neuropeptide Y mRNAs during IL-1 beta-induced anorexia in rats. Brain Res Bull 1997;44:311–317.PubMedGoogle Scholar
  141. 141.
    Haour, F., Marquette, C., Ban, E., et al. Receptors for interleukin-1 in the central nervous and neuroendocrine systems - Role in infection and stress. Ann D Endocrinol 1995;56:173–179.Google Scholar
  142. 142.
    Marquette, C., VanDam, A.M., Ban, E., et al. Rat interleukin-1 beta binding sites in rat hypothalamus and pituitary gland. Neuroendocrinal 1995; 62:362–369.Google Scholar
  143. 143.
    Wong, M.L., Bongiorno, P.B., Rettori, V., et al. Interleukin (IL) 1 beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: Pathophysiological implications. Proc Natl Acad Sci USA 1997; 94:227–232.PubMedGoogle Scholar
  144. 144.
    Cartmell, T., Luheshi, G.N., Rothwell, N.J. Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat. J Physiol London 1999; 518:585–594.PubMedGoogle Scholar
  145. 145.
    Kakizaki, Y., Watanobe, H., Kohsaka, A., et al. Temporal profiles of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in the plasma and hypothalamic paraventricular nucleus after intravenous or intraperitoneal administration of lipopolysaccharide in the rat: Estimation by push-pull perfusion. Endocrine J 1999; 46:487–496.Google Scholar
  146. 146.
    Eriksson, C., Nobel, S., Winblad, B., et al. Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopoly saccharides. Cytokine 2000; 12:423–431.PubMedGoogle Scholar
  147. 147.
    Quan, N., Stern, E.L., Whiteside, M.B., et al. Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 1999; 93:72–80.PubMedGoogle Scholar
  148. 148.
    Konsman, J.P., Kelley, K., Dantzer, R. Temporal and spatial relationships between lipopolysaccharide-induced expression of fos, interleukin-1 beta and inducible nitric oxide synthase in rat brain. Neuroscience 1999; 89:535–548.PubMedGoogle Scholar
  149. 149.
    VanDam, A.M., Brouns, M., Louisse, S., et al. 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 1992; 588:291–296.Google Scholar
  150. 150.
    Breder, C.D., Hazuka, C., Ghayur, T., et al. Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc Natl Acad Sci USA 1994; 91:11393–11397.PubMedGoogle Scholar
  151. 151.
    Banks, W.A., Kastin, A.J., Gutierrez, E.G. Interleukin-1 alpha in blood has direct access to cortical brain cells. Neurosci Lett 1993; 163:41–44.PubMedGoogle Scholar
  152. 152.
    Turrin, N.P., Gayle, D., Ilyin, S.E., et al. Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide. Brain Res Bull 2001; 54:443–453.PubMedGoogle Scholar
  153. 153.
    Burgess, W., Gheusi, G., Yao, J.H., et al. Interleukin-1 beta-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia. Am J Physiol 1998; 274:R1829–R1833.PubMedGoogle Scholar
  154. 154.
    Yao, J.H., Ye, S.M., Burgess, W., et al. Mice deficient in interleukin-1 beta converting enzyme resist anorexia induced by central lipopolysaccharide. Am J Physiol 1999; 277:R1435–R1443.PubMedGoogle Scholar
  155. 155.
    Bluthe, R.M., Dantzer, R., Kelley, K.W. Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 1992; 573:318–320.PubMedGoogle Scholar
  156. 156.
    Laye, S., Gheusi, G., Cremona, S., et al. Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression. Am J Physiol 2000; 279:R93-R98.Google Scholar
  157. 157.
    Brochu, S., Olivier, M., Rivest, S.. Neuronal activity and transcription of pro-inflamatory cytokines, I kappa B alpha, and iNOS in the mouse brain during acute endotoxemia and chronic infection with Trypanosoma brucei brucei. J Neurosci Res 1999;57:801–816.PubMedGoogle Scholar
  158. 158.
    Quan, N., Mhlanga, J.D.M., Whiteside, M.B., et al. Chronic overexpression of pro-inflamatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. J Comp Neurol 1999; 414:114–130.PubMedGoogle Scholar
  159. 159.
    Callahan, T.A., Piekut, D.T. Differential Fos expression induced by IL-1 beta and IL-6 in rat hypothalamus and pituitary gland. J Neuroimmunol 1997; 73:207–211.PubMedGoogle Scholar
  160. 160.
    Wan, W.H., Wetmore, L., Sorensen, C.M., et al. Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Res Bull 1994; 34:7–14.PubMedGoogle Scholar
  161. 161.
    Goehler, L.E., Gaykema, R.P.A., Nguyen, K.T., et al. Interleukin-1 beta in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci 1999; 19:2799–2806.PubMedGoogle Scholar
  162. 162.
    Miller, A.J., Hopkins, S.J., Luheshi, G.N. Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat. Br J Pharmacol 1997; 120:1274–1279.PubMedGoogle Scholar
  163. 163.
    Dantzer, R., Konsman, J.P., Bluthe, R.M., et al. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci Basic and Clin 2000; 85:60–65.Google Scholar
  164. 164.
    BretDibat, J.L., Bluthe, R.M., Kent, S., et al. Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun 1995; 9:242–246.Google Scholar
  165. 165.
    BretDibat, J.L., Creminon, C., Couraud, J.Y., et al. Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1 beta. Brain Res Bull 1997; 42:443–449.Google Scholar
  166. 166.
    Porter, M.H., Hrupka, B.J., Langhans, W., et al. Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1 beta, LPS, and MDP. Am J Physiol 1998; 275:R384-R389.PubMedGoogle Scholar
  167. 167.
    Faggioni, R., Fantuzzi, G., Fuller, J., et al. IL-1 beta mediates leptin induction during inflammation. Am J Physiol 1998; 274:R204–R208.PubMedGoogle Scholar
  168. 168.
    Finck, B.N., Kelley, K.W., Dantzer, R., et ak. In vivo and in vitro evidence for the involvement of tumor necrosis factor-alpha in the induction of leptin by lipopolysaccharide. Endocrinology 1998; 139:2278–2283.PubMedGoogle Scholar
  169. 169.
    Grunfeld, C., Zhao, C., Fuller, J., et al. 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 1996; 97:2152–2157.PubMedGoogle Scholar
  170. 170.
    Sarraf, P., Frederich, R.C., Turner, E.M., et al. Multiple cytokines and acute inflammation raise mouse leptin levels: Potential role in inflammatory anorexia. J Exp Med 1997; 185:171–175.PubMedGoogle Scholar
  171. 171.
    Faggioni, R., Fuller, J., Moser, A., et al. LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Am J Physiol 1997; 273:R181-R186.PubMedGoogle Scholar
  172. 172.
    Bomstein, S.R., Preas, H.L., Chrousos, G.P., et al. Circulating leptin levels during acute experimental endotoxemia andanti-inflammatory therapy in humans. J Infect Dis 1998; 178:887–890.Google Scholar
  173. 173.
    Granowitz, E.V., Porat, R., Dinarello, C.A. Circulating leptin during experimental endotoxemia in humans. J Infect Dis 1999; 179:1313–1314.PubMedGoogle Scholar
  174. 174.
    Vaselli, J.R., Casey, D. Increased responseiveness of Zucker obese rats to the feeding-inhibitory effect of systemic TNFalpha. FASEB J 1996; 10: A823.Google Scholar
  175. 175.
    Langhans, W., Lugarini, F., Hrupka, B.J., et al. Chronic lipopolysaccharide (LPS) anorexia is unaltered in obese Zucker rats, but leptin enhances acute LPS anorexia in normal rats. Soc Neurosci Abstr 2000; 26:1071.Google Scholar
  176. 176.
    Banks, W.A., Kastin, A.J. Passage of peptides across the blood-brain barrier: Pathophysiological perspectives. Life Sci 1996; 59:1923–1943.PubMedGoogle Scholar
  177. 177.
    Stitt, J.T. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol Lond 1985; 368:501–511.PubMedGoogle Scholar
  178. 178.
    Ota, K., Katafuchi, T., Takaki, A., et al. AV3V neurons that send axons to hypothalamic nuclei respond to the systemic injection of IL-lbeta. Am J Physiol 1997; 272:R532–R540.PubMedGoogle Scholar
  179. 179.
    Ericsson, A., Arias, C., Sawchenko, P.E. Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 1997; 17:7166–7179.PubMedGoogle Scholar
  180. 180.
    Kastin, A.J., Pan, W., Maness, L.M., et al. Peptides crossing the blood-brain barrier: some unusual observations. Brain Res 1999; 848:96–100.PubMedGoogle Scholar
  181. 181.
    DeVries, H.E., BlomRoosemalen, M.C.M., vanOosten, M., et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol 1996; 64:37–43.Google Scholar
  182. 182.
    Licinio, J., Wong, M.L. Pathways and mechanisms for cytokine signaling of the central nervous system. J Clin Invest 1997; 100:2941–2947.PubMedGoogle Scholar
  183. 183.
    Herkenham, M., Lee, H.Y., Baker, RA. 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 1998; 400:175–196.PubMedGoogle Scholar
  184. 184.
    Quan, N., Whiteside, M., Herkenham, M. Time course and localization patterns of interleukin-1 beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide. Neurosci 1998; 83:281–293.Google Scholar
  185. 185.
    Bierhaus, A., Chen, J., Liliensiek, B., et al. LPS and cytokine-activated endothelium. Sent Thromb Hemost 2000; 26:571–587.Google Scholar
  186. 186.
    Deckert-Schluter, M., Bluethmann, H., Kaefer, N., et al. Interferon-gamma receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis. Am J Pathol 1999; 154:1549–1561.PubMedGoogle Scholar
  187. 187.
    Nadeau, S., Rivest, S. 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. Neurosci 1999; 93:1449–1464.Google Scholar
  188. 188.
    VanDam, A.M., DeVries, H.E., Kuiper, J., et al. Interleukin-1 receptors on rat brain endothelial cells: A role in neuroimmune interaction? FASEB J 1996; 10:351–356.Google Scholar
  189. 189.
    Cao, C., Matsumura, K., Yamagata, K., et al. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response. Brain Res 1995; 697:187–196.PubMedGoogle Scholar
  190. 190.
    Cao, C.Y., Matsumura, K., Yamagata, K., et al. 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 1996; 733:263–272.PubMedGoogle Scholar
  191. 191.
    Rivest, S. What is the cellular source of prostaglandins in the brain in response to systemic inflammation? Facts and controversies. Mol Psychiatry 1999; 4:501–507.Google Scholar
  192. 192.
    VanDam, A.M., Brouns, M., Manahing, W., et al. Immunocytochemical detection of prostaglandin-E(2) in microvasculature and in neurons of rat brain after administration of bacterial endotoxin. Brain Res 1993; 613:331–336.Google Scholar
  193. 193.
    Cao, C.Y., Matsumura, K., Yamagata, K., et al. Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. Mol Brain Res 1998; 56:45–56.PubMedGoogle Scholar
  194. 194.
    Lacroix, S., Rivest, S. 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 1998; 70:452–466.PubMedGoogle Scholar
  195. 195.
    Perkins, D.J., Kniss, D.A. Tumor necrosis factor-alpha promotes sustained cyclooxygenase-2 expression: Attenuation by dexamethasone and NSAIDs. Prostaglandins 1997; 54:727–743.PubMedGoogle Scholar
  196. 196.
    Quan, N., Whiteside, M., Herkenham, M. Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide. Brain Res 1998; 802:189–197.PubMedGoogle Scholar
  197. 197.
    Kalaria RN. Cerebral endothelial activation and signal transduction mechanisms during inflammation and infectious disease. Am J Pathol 1999; 154:1311–1314.PubMedGoogle Scholar
  198. 198.
    Elmquist, J.K., Breder, C.D., Sherin, J.E., et al. Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 1997; 381:119–129.PubMedGoogle Scholar
  199. 199.
    Laflamme, N., Lacroix, S., Rivest, S. 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 1999; 19:10923–10930.PubMedGoogle Scholar
  200. 200.
    de Vries, H.E., Hoogendoorn, K.H., van Dijk, J., et al. Eicosanoid production by rat cerebral endothelial cells: stimulation by lipopolysaccharide, interleukin-1 and interleukin-6. J Neuroimmunol 1995; 59:1–8.PubMedGoogle Scholar
  201. 201.
    Langhans, W., Harlacher, R., Scharrer, E. Verapamil and indomethacin attenuate endotoxin-induced anorexia. Physiol Behav 1989; 46:535–539.PubMedGoogle Scholar
  202. 202.
    Swiergiel, A.H., Smagin, G.N., Dunn, A.J. Influenza virus infection of mice induces anorexia: Comparison with endotoxin and interleukin-1 and the effects of indomethacin. Pharmacol Biochem Behav 1997; 57:389–396.PubMedGoogle Scholar
  203. 203.
    Lacroix, S., Rivest, S. Functional circuitry in the brain of immune-challenged rats: Partial involvement of prostaglandins. J Comp Neurol 1997; 387:307–324.PubMedGoogle Scholar
  204. 204.
    Simmons, D.L., Wagner, D., Westover, K. Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever. Clin Inf Dis 2000; 31 Suppl 5:S211-S218.Google Scholar
  205. 205.
    Li, S., Wang, Y., Matsumura, K., et al. The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice. Brain Res 1999; 825:86–94.PubMedGoogle Scholar
  206. 206.
    Matsumura, K., Kaihatsu, S., Imai, H., et al. Cyclooxygenase in the vagal afferents: is it involved in the brain prostaglandin response evoked by lipopolysaccharide? Auton Neurosci 2000; 85:88–92.PubMedGoogle Scholar
  207. 207.
    Cao, C.Y., Matsumura, K., Ozaki, M., et al. Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells. J Neurosci 1999; 19:716–725.PubMedGoogle Scholar
  208. 208.
    Cao, C.Y., Matsumura, K., Shirakawa, N., et al. Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors. Eur J Neurosci 2001; 13:1781–1790.PubMedGoogle Scholar
  209. 209.
    Elmquist, J.K., Saper, C.B. Activation of neurons projecting to the paraventricular hypothalamic nucleus by intravenous lipopolysaccharide. J Comp Neurol 1996; 374:315–331.PubMedGoogle Scholar
  210. 210.
    MolinaHolgado, F., Borrell, J., Guaza, C. Effect of endotoxin and interleukin-1 beta on corticotropin-releasing factor and prostaglandin release by rat brainstem slices. J Neuroendocrinol 1998; 10:429–436.Google Scholar
  211. 211.
    Ericsson, A., Kovacs, K.J., Sawchenko, P.E. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J Neurosci 1994; 14:897–913.PubMedGoogle Scholar
  212. 212.
    Simansky, K.J. Serotonergic control of the organization of feeding and satiety. Behav Brain Res 1996;73:37–42.PubMedGoogle Scholar
  213. 213.
    Cunningham, E.T., Wada, E., Carter, D.B., et al. Insitu histochemical-localization of type-I interleukin-1 receptor messenger mRNA in the central-nervous-system, pituitary, and adrenal-gland of the mouse. J Neurosci 1992; 12:1101–1114.PubMedGoogle Scholar
  214. 214.
    Clement, H.W., Buschmann, J., Rex, S., et al. Effects of interferon-gamma, interleukin-1 beta, and tumor necrosis factor-alpha on the serotonin metabolism in the nucleus raphe dorsalis of the rat. J Neur Transmission 1997; 104:981–991.Google Scholar
  215. 215.
    Gemma, C., Imeri, L., DeSimoni, M.G., et al. Interleukin-1 induces changes in sleep, brain temperature, and serotonergic metabolism. Am J Physiol 1997; 41:R601–R606.Google Scholar
  216. 216.
    Mohankumar, P.S., Thyagarajan, S., Quadri, S.K. Interleukin-1-beta Increases 5-hydroxyindoleacetic acid release in the hypothalamus in vivo. Brain Res Bull 1993; 31:745–748.PubMedGoogle Scholar
  217. 217.
    Gemma, C., Ghezzi, P., De-Simoni, M.G. Activation of the hypothalamic serotoninergic system by central interleukin-1. Eur J Pharmacol 1991; 209:139–140.PubMedGoogle Scholar
  218. 218.
    Ballinger, A., El Haj, T., Perrett, D., et al. The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis. Gastroenterol 2000; 118:544–553.Google Scholar
  219. 219.
    MohanKumar, S.M.J., Mohankumar, P.S., Quadri, S.K. Lipopolysaccharide-induced changes in monoamines in specific areas of the brain: blockade by interleukin-1 receptor antagonist. Brain Res 1999; 824:232–237.PubMedGoogle Scholar
  220. 220.
    MohanKumar, S.M.J., Mohankumar, P.S., Quadri, S.K. Effects of bacterial lipopolysaccharide on central monoamines and fever in the rat: involvement of the vagus. Neurosci Lett 2000; 284:159–162.PubMedGoogle Scholar
  221. 221.
    Hrupka, B.J., Langhans, W. A role for serotonin in lipopolysaccharide-induced anorexia in rats. Pharmacol Biochem Behav 2001; 68:355–362.PubMedGoogle Scholar
  222. 222.
    Swiergiel, A.H., Dunn, A.J. Lack of evidence for a role of serotonin in interleukin-1 -induced hypophagia. Pharmacol Biochem Behav 2000; 65:531–537.PubMedGoogle Scholar
  223. 223.
    Laviano, A., Cangiano, C., Preziosa, I., et al. Serotoninergic block in the ventromedial nucleus of hypothalamus improves food intake in anorectic tumor bearing rats. Adv Exp Med Biol 1996; 398:551–553.PubMedGoogle Scholar
  224. 224.
    Chance, W.T., von Meyenfeldt, M., Fischer, J.E. Serotonin depletion by 5,7-dihydroxytryptamine or para-chloroamphetamine does not affect cancer anorexia. Pharmacol Biochem Behav 1983; 18:115–121.PubMedGoogle Scholar
  225. 225.
    Rinaman, L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am J Physiol 1999; 277:R582–R590.PubMedGoogle Scholar
  226. 226.
    Comer, J., Rinaman, L. Role of central glucagon-like peptide-1 receptor signaling in lipopolysaccharide-induced fever and anorexia. FASEB J 2000; 14:A87.Google Scholar
  227. 227.
    Rinaman, L., Comer, J. Antagonism of central glucagon-like peptide-1 receptors enhances lipopolysaccharide-induced fever. Auton Neurosci 2000; 85:98–101.PubMedGoogle Scholar
  228. 228.
    Katafuchi, T., Motomura, K., Baba, S., et al. Differential effects of tumor necrosis actor-alpha and -beta on rat ventromedial hypothalamic neurons in vitro. Am J Physiol 1997; 272:R1966-R1971.PubMedGoogle Scholar
  229. 229.
    Plata-Salaman, C.R., FfrenchMullen, J.M.H. Interleukin-1 beta inhibits Ca2+ channel currents in hippocampal neurons through protein kinase. C. Eur J Pharmacol 1994; 266:1–10.PubMedGoogle Scholar
  230. 230.
    Suda, T., Tozawa, F., Ushiyama, T., et al. Interleukin-1 stimulates corticotropin-releasing factor gene expression in rat hypothalamus. Endocrinol 1990; 126:1223–1228.Google Scholar
  231. 231.
    Uehara, A., Sekiya, C., Takasugi, Y., et al. Anorexia induced by interleukin 1: involvement of corticotropin-releasing factor. Am J Physiol 1989; 257:R613–R617.PubMedGoogle Scholar
  232. 232.
    Watanabe, T., Morimoto, A., Sakata, Y., et al. ACTH response induced by interleukin-1 is mediated by CRF secretion stimulated by hypothalamic PGE. Experientia 1990; 46:482–484.Google Scholar
  233. 233.
    Sonti, G., Ilyin, S.E., Plata-Salamàn, C.R. Neuropeptide Y blocks and reverses interleukin-1 beta-induced anorexia in rats. Peptides 1996; 17:517–520.PubMedGoogle Scholar
  234. 234.
    Chance, W.T., Balasubramaniam, A., Fischer, J.E. Neuropeptide Y and the development of cancer anorexia. Ann Surg 1995; 221:579–587.PubMedGoogle Scholar
  235. 235.
    Kang, M., Yoshimatsu, H., Chiba, S., et al. Hypothalamic neuronal histamine modulates physiological responses induced by interleukin-1 beta. Am J Physiol 1995; 38:R1308–R1313.Google Scholar
  236. 236.
    McCarthy, H.D., McKibbin, P.E., Perkins, A.V., et al. Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats. Am J Physiol 1993; 264:E638–E643.PubMedGoogle Scholar
  237. 237.
    Inui, A. Cancer anorexia-cachexia syndrome: Are neuropeptides the key? Cancer Res 1999;59:4493–4501.PubMedGoogle Scholar
  238. 238.
    Swiergiel, A.H., Burunda, T., Patterson, B., et al. Endotoxin- and interleukin-1-induced hypophagia are not affected by adrenergic, dopaminergic, histaminergic, or muscarinic antagonists. Pharmacol Biochem Behav 1999; 63:629–637.PubMedGoogle Scholar
  239. 239.
    Catania, A., Lipton, J.M. The neuropeptide alpha-melanocyte-stimulating hormone: a key component of neuroimmunomodulation. Neuroimmunomodulation 1994; 1:93–99.PubMedGoogle Scholar
  240. 240.
    Catania, A., Suffredini, A.F., Lipton, J.M. Endotoxin causes release of alpha-melanocyte-stimulating hormone in normal human subjects. Neuroimmunomodulation 1995; 2:258–262.PubMedGoogle Scholar
  241. 241.
    Lipton, J.M., Catania, A. Mechanisms ofanti-inflammatory action of the neuroimmunomodulatory peptide alpha-MSH. Ann N Y Acad Sci 1998; 840:373–380.PubMedGoogle Scholar
  242. 242.
    Tritos, N.A., Maratos-Flier, E. Two important systems in energy homeostasis: melanocortins and melanin-concentrating hormone. Neuropeptides 1999; 33:339–349.PubMedGoogle Scholar
  243. 243.
    Fan, W., Boston, B.A., Kesterson, R.A., et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385:165–168.PubMedGoogle Scholar
  244. 244.
    Huang, Q.H., Hruby, V.J., Tatro, J.B. Role of central melanocortins in endotoxin-induced anorexia. Am J Physiol 1999; 276:R864–R871.PubMedGoogle Scholar
  245. 245.
    Marks, D.L., Ling, N., Cone, R.D. Role of the central melanocortin system in cachexia. Cancer Res 2001; 61:1432–1438.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2003

Authors and Affiliations

  • Wolfgang Langhans
    • 1
  • Brian J. Hrupka
    • 1
  1. 1.Institute of Animal Sciences, Swiss Federal Institute of Technology (ETH)ZurichSwitzerland

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