Derangement of the interaction between the immune and neuroendocrine systems represent one of the major mechanisms in the development of chronic fatigue syndrome. Induction of chronic fatigue syndrome by i.p. administration of the synthetic double-stranded RNA poly I:C provides a suitable experimental model for studying these mechanisms. We report here our studies of changes in the intensity of the cytotoxic and proliferative activities of splenocytes, changes in the intensity of immunomodulatory cytokine signal transduction via the sphingomyelin pathway in the P2 membrane fraction of the cerebral cortex, and changes in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHACS) during development of chronic fatigue syndrome in rats. Suppression of both cytotoxic and proliferative activity was demonstrated in rat splenocytes during the formation of experimental chronic fatigue syndrome. Important data showing suppression of the activity of neutral sphingomyelinase (N-SMase) activity were obtained, this being a key enzyme in the sphingomyelin cascade, in cerebral cortex cells three days after animals were given Poly I:C. Injections of poly I:C were followed by impairment of HHACS function in rats, with decreases in corticosterone concentrations in standard functional tests in which animals were given ACTH and hydrocortisone. The results lead to the conclusion that impairments to the interaction between the immune and neuroendocrine systems during development of chronic fatigue, including changes in HHACS activity, are mediated both at the level of changes in the activity of immunocompetent cells and directly on brain cell membranes.
Similar content being viewed by others
References
N. G. Artsimovich and T. S. Galushina, Chronic Fatigue Syndrome [in Russian], Novyi Mir, Moscow (2002).
N. P. Goncharov, V. I. Vorontsov, G. K. Kadiya, A. V. Antonichev, and V. N. Butnev, “Studies of adrenal and sex gland hormone functions in experiment on monkeys,” Vestn. Adak. Med. Nauk. SSSR, 8, 13–20 (1997).
I. V. Nesterova, I. P. Balmasova, V. A. Kozlov, E. S. Malova, and R. I. Sepiashvili, “Chronic fatigue syndrome in patients with recurrent viral infections: clinical immunological features and characteristics of serotoninergic regulation,” Tsitok. Vospal., 5, No. 2, 3–14 (2006).
E. G. Rybakina, N. N. Nalivaeva, I. Yu. Pivanovich, S. N. Shanin, I. A. Kozinets, and E. A. Korneva, “The role of neutral sphingomyelinase in interleukin-1-beta signal transduction in mouse brain cells,” Ros. Fiziol. Zh. im. I. M. Sechenova, 86, No. 3, 303–311 (2000).
E. G. Rybakina and E. A. Korneva, “The physiological role of interleukin-1 in the mechanisms of development of stress reactions,” Med. Akad. Zh., 2, No. 2, 4–17 (2002).
E. G. Rybakina and E. A. Korneva, “Transduction of the interleukin-1 signal in the interaction of the nervous and immune systems,” Vestn. Ros. Akad. Med. Nauk., 7, 3–8 (2005).
E. E. Fomicheva, S. N. Shanin, and E. G. Rybakina, “Impairments to the interaction of the hypothalamo-hypophyseal-adrenocortical and immune systems as one of the mechanisms underlying the development of chronic fatigue syndrome,” Neiroimmunologiya, 6, No. 1–2, 4–12 (2008).
P. de Becker, M. McGregor, and K. de Meirleir, “Possible triggers and mode of onset of chronic fatigue syndrome,” J. Chronic Fatigue Syndrome, 10, 3–18 (2002).
A. J. Cleare, “The neuroendocrinology of chronic fatigue syndrome,” Endocr. Rev., 24, No. 2, 236–252 (2003).
A. J. Cleare, “The HPA axis and the genesis of chronic fatigue syndrome,” Trends Endocrinol. Metab., 15, 55–59 (2004).
T. G. Dinan, T. Majeed, E. Lavelle, L. V. Scott, C. Berti, and P. Behan, “Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome,” Psychoneuroendocrinology, 22, 261–267 (1997).
K. Fukuda, S. E. Straus, I. Hickie, et al., “The chronic fatigue syndrome: a comprehensive approach to its definition and study,” Ann. Intern. Med., 121, 953–959 (1994).
C. J. Gamard, G. S. Dbaibo, B. Lin, L. M. Obeid, and Y. A. Hannun, “Selective involvement of ceramide in cytokine-induced apoptosis. Ceramide inhibits phorbol ester activation of nuclear factor kappa B,” J. Biol. Chem., 272, No. 26, 16474–16481 (1997).
T. R. Gerrity, D. A. Papanicolaou, J. D. Amsterdam, S. Bingham, A. Grossman, T. Hedrick, R. B. Herberman, G. Krueger, S. Levine, N. Mohagheghpour, R. C. Moore, J. Oleske, and C. R. Snell, “Immunologic aspects of chronic fatigue syndrome,” Neuroimmunomod., 11, No. 6, 351–357 (2004).
R. Glaser, D. A. Padgett, M. L. Litsky, et al., “Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implication for chronic fatigue syndrome and cancer,” Brain Behav. Immun., 19, 91–103 (2005).
K. Inoue, H. Yamazaki, Y. Manabe, C. Fukuda, K. Hanai, and T. Fushiki, “Transforming growth factor beta activated during exercise in brain depresses spontaneous motor activity of animals,” Brain Res., 846, 145–153 (1999).
T. Katafuchi, K. Kondo, T. Yasaka, K. Kubo, S. Take, and M. Yoshimura, “Prolonged effects of polyriboinosinic:polyribocylidylic acid on spontaneous running wheel activity and brain interferon alpha mRNA in rats: a model for immunologically induced fatigue,” Neurosci., 120, 837–845 (2003).
T. Katafuchi, T. Kondo, S. Take, and M. Yoshimura, “Enhanced expression of brain interferon-α and serotonin transporter in immunologically induced fatigue in rats,” Eur. J. Neurosci., 22, 2817–2826 (2005).
R. Kolesnick, “Signal transduction through the sphingomyelin pathway,” Mol. Chem. Neuropathol., 21, 287–297 (1984).
E. G. Lapetina, E. F. Soto, and E. De Robertis, “Gangliosides and Nacetyl-cholinesterase in isolated membranes in the rat brain cortex,” Biochem. Biophys Acta, 135, 33–43 (1967).
A. M. Lerner, S. H. Beqaj, R. G. Deeter, and J. T. Fitzgerald, “IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with chronic fatigue syndrome,” In vivo, 18, 101–106 (2004).
Q. Li, C. Wichems, A. Heils, L. D. Van De Kar, K. P. Lesch, and D. L. Murphy, “Reduction of 5-hydroxytryptamine (5-HT)1A-mediated temperature and neuroendocrine responses and (5-HT)1A binding sites in 5-HT transporter knockout mice,” J. Pharmacol. Exp. Ther., 291, 999–1007 (1999).
B. Liu, L. M. Obeid, and Y. A. Hannun, “Sphingomyelin in cell regulation,” Seminars Cell. Dev. Biol., 8, 311–322 (1997).
M. Lyall, M. Peakman, and S. Wessely, “A systematic review and critical evaluation of the immunology of chronic fatigue syndrome,” J. Psychosom. Res., 55, 79–90 (2003).
S. Mathias, A. Younes, C. C. Kan, I. Orlow, C. Joseph, and R. N. Kolesnick, “Activation of the sphingomyelin signalling pathway in intact EL4 cells and in a cell-free system by IL-1 beta,” Science, 259, 519–522 (1993).
M. Narita, N. Nishigami, N. Narita, K. Yamaguti, N. Okado, Y. Watanabe, and H. Kuratsune, “Association between serotonin transporter gene polymorphism and chronic fatigue syndrome,” Biochem. Biophys. Res. Commun., 311, 264–266 (2003).
J. B. Prins, J. W. M. Van der Meer, and G. Bleijenberg, “Chronic fatigue syndrome,” Lancet, 367, 246–355 (2006).
B. G. Rao and M. W. Spence, “Sphingomyelinase activity at pH 7.4 in human brain and a comparison to activity at pH 5,” J. Lipid Res., 17, 506–515 (1976).
E. G. Rybakina and E. A. Korneva, “Interleukin-1β signal transduction via the sphingomyelin pathway in brain cells,” in: NeuroImmune Biology, Vol. 6, Cytokines and the Brain, C. Phelps and E. Korneva (eds.), Elsevier B. V. (2008), pp. 79–91.
L. V. Scott, S. Medbak, and T. G. Dinan, “Blunted adrenocorticotropin and cortisol response to corticotropin-releasing hormone stimulation in chronic fatigue syndrome,” Acta Psychiatr. Scand., 97, 450–457 (1998).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 95, No. 12, pp. 1324–1335, December, 2009.
Rights and permissions
About this article
Cite this article
Rybakina, E.G., Shanin, S.N., Fomicheva, E.E. et al. Cellular and Molecular Mechanisms of the Interaction between the Immune and Neuroendocrine Systems in Experimental Chronic Fatigue Syndrome. Neurosci Behav Physi 41, 198–205 (2011). https://doi.org/10.1007/s11055-011-9400-2
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-011-9400-2