Abstract
Recent research in rodents has demonstrated that exposure to bacterial endotoxin during the neonatal period alters the development of the hypothalamic-pituitary-adrenal axis resulting in hypersecretion of corticosterone after stress-exposure in adulthood. Given the known interactions between glucocorticoids and the immune system it was hypothesized that such alterations may impact on immune outcomes. Fischer 344 rats were treated with endotoxin (50 μg/kg Salmonella enteritidis, i.p.) or the vehicle on postpartum d 1, 3, 5, and 7. In adulthood, animals were subjected to chronic stress (6 × 10 h/d restraint stress), and the effect on resistance to tumor colonization (experiment 1) and natural killer cell activity (experiment 2) was assessed. Experiment 3 assessed corticosterone responses to acute stress in adulthood after neonatal endotoxin or saline treatment. Neonatal endotoxin exposure resulted in a 2-fold increase in tumor colonization (p < 0.001) and a significant impairment in the activity of natural killer cells (p < 0.01), cells critically involved in the surveillance and eradication of tumor cells. Neonatal endotoxin exposure also resulted in a significant decrease in gain weight that persisted into adulthood (p < 0.05), and potentiation of corticosterone responses to acute stress in adulthood (p < 0.05). We conclude that neonatal endotoxin exposure produces long-term changes in the hypothalamic-pituitary-adrenal axis, and has significant long-term effects on immune function, specifically in terms of resistance to tumor colonization in adulthood.
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Abbreviations
- CBG:
-
corticosteroid-binding globulin
- E:T:
-
effector to target
- HPA:
-
hypothalamic-pituitary-adrenal
- LPS:
-
lipopolysaccharide
- NK:
-
natural killer
References
Akana SF, Cascio CS, Shinsako J, Dallman MF 1985 Corticosterone: narrow range required for normal body and thymus weight and ACTH. Am J Physiol 249: R527–R532
Pierpaoli W, Kopp HG, Muller J, Keller M 1997 Interdependence between neuroendocrine programming and the generation of immune recognition in ontogeny. Cell Immunol 29: 16–27
O'Grady MP, Hall NRS 1991 Long-term effects of neuroendocrine-immune interactions during early development. In: Ader R, Felton DL, Cohen N (eds) Psychoneuroimmunology, 2nd Ed. Academic Press, San Diego, 561–572.
Reul JM, Stec I, Weigers GJ, Labeur MS, Linthorst AC, Arzt E, Holsboer F 1994 Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. J Clin Invest 93: 2600–2607
Granger DA, Hood KE, Ikeda SC, Reed CL, Block ML 1996 Neonatal endotoxin exposure alters the development of social behaviour and the hypothalamic pituitary adrenal axis in selectively bred mice. Brain Behav Immun 10: 249–259
Plotsky PM, Meaney MJ 1993 Early postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 18: 195–200
Shanks N, Larocque S, Meaney MJ 1995 Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. J Neurosci 15: 376–384
Shanks N, Meaney MJ 1994 Hypothalamic pituitary adrenal activation following endotoxin administration in the developing rat: a CRH-mediated effect. J Neuroendocrinol 6: 375–383
Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, Lightman SL 2000 Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc Natl Acad Sci USA 97: 5645–5650
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ 1997 Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277: 1659–1662
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM 1996 Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 18: 49–72
Stanton ME, Gutierrez YR, Levine S 1988 Maternal deprivation potentiates pituitary adrenal stress response in infant rats. Behav Neurosci 102: 692–700
Suchecki D, Mozaffarian D, Gross G, Rosenfeld P, Levine S 1993 Effects of maternal deprivation on the ACTH stress response in the infant rat. Neuroendocrinology 57: 204–212
Witek-Janusek L 1988 Pituitary-adrenal response to bacteria in developing rats. Am J Physiol 255: E525–E530
Munck A, Guyre PM, Holbrook NJ 1984 Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5: 25–44
Dhabhar FS, Miller AH, McEwen BS, Spencer RL 1995 Effects of stress on immune cell distribution: dynamic and hormonal mechanisms. J Immunol 154: 5511–5527
Buckingham JC, Christian HC, Gillies GE, James GP 1996 The hypothalamo-pituitary-adrenocortical immune axis. In: Marsh JA, Kendall MD (eds) The Physiology of Immunity. CRC Press, Boca Raton, FL, 331–355.
Barlozzari T, Leonhardt J, Wiltrout RH, Herberman RB, Reynolds CW 1985 Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol 134: 2783–2789
Ben-Eliyahu S, Page GG 1992 In vivo assessment of natural killer cell activity in rats. Prog Neuroendocrinol 5: 199–214
Ben-Eliyahu S 1998 Stress, natural killer cell activity and tumor metastasis: the role of catecholamines and corticosteroids. In: Levi A, Grauer E, Ben-Nathan D, De-Kloet ER (eds) The New Frontiers in Stress Research: Modulation of Brain Function. Harwood Academic Publishers, Amsterdam, 203–215.
Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G 1999 Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 80: 880–888
Hodgson DM, Taylor AN, Chiappelli F, Kung M, Morrow NS 1996 Impact of acute food restriction on the colonization of MADB106 tumor cells to the lungs of Fischer 344 rats. Neuroimmunomodulation 3: 371–381
Ben-Eliyahu S, Page GG, Shakhar G, Taylor AN 1996 Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: possible role of oestradiol and natural killer cells. Br J Cancer 74: 1900–1907
Meaney MJ, Aitken DH, Sapolsky RM 1987 Thyroid hormones influence the development of hippocampal glucocorticoid receptors in the rat: a mechanism for the effects of postnatal handling on the development of the adrenocortical stress response. Neuroendocrinology 45: 278–283
Ogawa T, Mikuni M, Kuroda Y, Muneoka K, Mori K, Takahashi K 1994 Periodic maternal deprivation alters stress response in adult offspring: potentiates the negative feedback regulation of restraint stress-induced adrenocortical response and reduces the frequencies of open field-induced behaviors. Pharmacol Biochem Behav 49: 961–967
Viau V, Sharma S, Plotsky PM, Meaney MJ 1993 Increased plasma ACTH responses to stress in nonhandled compared with handled rats require basal levels of corticosterone and are associated with increased levels of ACTH secretagogues in the median eminence. J Neurosci 13: 1097–1105
Shakhar G, Ben-Eliyahu S 1998 In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol 160: 3251–3258
Ferdynand JK, Engelman EG 1996 Immune regulation: a critical link between NK cells and CTLs. Immunol Today 17: 174–176
Peisen JN, McDonnell KV, Mulroney SE, Lumpkin MD 1995 Endotoxin-induced suppression of the somatotropic axis is mediated by interleukin-1 (beta) and corticotropin releasing factor in the juvenile rat. Comp Biochem Physiol C Pharmacol Toxicol 136: 3378–3389
Kumar BA, Leibowitz SF 1988 Impact of acute corticosterone administration on feeding and macronutrient self selection patterns. Am J Physiol 254: R222–R228
Kumar BA, Papamichael M, Leibowitz SF 1988 Feeding and macronutrient selection patterns in rats: adrenalectomy and chronic corticosterone replacement. Physiol Behav 42: 581–589
Devenport L, Thomas T, Knehans A, Sundstrom A 1990 Acute, chronic, and interactive effects of type I and II corticosterone receptor stimulation of feeding and weight gain. Physiol Behav 47: 1221–1228
Barker DJP 1999 The fetal origins of type 2 diabetes mellitus. Ann Intern Med 130: 322–324
Acknowledgements
The authors thank the expert technical assistance of Elly Huber and Mike Newton and the guidance and support of Professor Roger Smith.
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Supported by RMC grant No. 2821078 from The University of Newcastle, Australia.
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Hodgson, D., Knott, B. & Walker, F. Neonatal Endotoxin Exposure Influences HPA Responsivity and Impairs Tumor Immunity in Fischer 344 Rats in Adulthood. Pediatr Res 50, 750–755 (2001). https://doi.org/10.1203/00006450-200112000-00020
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DOI: https://doi.org/10.1203/00006450-200112000-00020
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