Abstract
Lipopolysaccharide (LPS) is a proinflammatory and depressogenic agent whereas thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an endogenous antidepressant and neuroprotective peptide. LPS and TRH also have opposing effects on K+ channel conductivity. We hypothesized that LPS can modulate the expression and release of not only TRH but also TRH-like peptides with the general structure pGlu-X-Pro-NH2, where “X” can be any amino acid residue. The response might be “homeostatic,” that is, LPS might increase TRH and TRH-like peptide release, thereby moderating the cell damaging effects of this bacterial cell wall constituent. On the other hand, LPS might impair the synthesis and release of these neuropeptides, thus facilitating the induction of early response genes, cytokines, and other downstream biochemical changes that contribute to the “sickness syndrome.”
Sprague-Dawley rats (300 g) received a single intraperitoneal injection of 100 µg/kg LPS. Animals were then decapitated 0, 2, 4, 8, and 24 h later. Serum cytokines and corticosterone peaked 2 h after intraperitoneal LPS along with a transient decrease in serum T3. TRH and TRH-like peptides were measured by a combination of high-performance liquid chromatography and radioimmunoassay. TRH declined in the nucleus accumbens and amygdala in a manner consistent with LPS-accelerated release and degradation. Various TRH-like peptide levels increased at 2 h in the anterior cingulate, hippocampus, striatum, entorhinal cortex, posterior cingulate, and cerebellum, indicating decreased release and clearance of these peptides. These brain regions are part of aneuroimmunomodulatory system that coordinates the behavioral, endocrine, and immune responses to the stresses of sickness, injury, and danger. A sustained rise in TRH levels in pancreatic β-cells accompanied LPS-impaired insulin secretion. TRH and Leu-TRH in prostate and TRH in epididymis remained elevated 2-24h after intraperitoneal LPS. We conclude that these endogenous neuroprotective and antidep resant-like peptides both mediate and moderate some of the behavioral and toxic effects of LPS.
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Alesci S., Martinez P. E., Kelkar S., et al. (2005) Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J. Clin. Endocrinol. Metab. 90, 2522–2530.
Allen J. A., Diemer T., Janus P., Hales K. H., and Hales D. B. (2004) Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria. Endocrine 25, 265–275.
Anisman H., Merali Z., Poulter M. O., and Hayley S. (2005) Cytokines as a precipitant of depressive illness: animal and human studies. Curr. Plarin. Des. 11, 963–972.
Arai H., Furuya T., Yasuda T., Miura M., Mizuno Y., and Mochizuki H. (2004) Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1 beta, and expression of caspase-11 in mice. J. Biol. Chem. 279, 51,647–51,653.
Barrientos R. M., Sprunger D. B., Campeau S., Watkins L. R., Rudy J. W., and Maier S. F. (2004) BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1β administration. J. Neuroimmunol. 155, 119–126.
Beattie E. C., Stellwagen D., Morishita W., et al. (2002) Control of synaptic strength by glial TNFα. Science 295, 2282–2285.
Boelen A., Kwakkel J., Thijssen-Timmer D. C., Alkemade A., Fliers E., and Wiersinga W. M. (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J. Endocrinol. 182, 315–323.
Bruhn T. O., Huang S. S., Vaslet C., and Nillni E. A. (1998) Glucocorticoids modulate the biosynthesis and processing of prethyrotropin releasing-hormone (pro TRH). Endocrine 9, 143–152.
Carvey P.M., Chang Q., Lipton J. W., and Ling Z. (2003) Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamineneurons in offspring: a potential, new model of Parkinson’s disease. Front. Biosci. 8, s826-s837.
Cearley C., Churchill L., and Krueger J. M. (2003) Time of day differences in IL1β and TNFα mRNA levels in specific regions of rat brain. Neurosci. Lett. 352, 61–63.
Collares E. F. (1997) Effect of bacterial lipopolysaccharide on gastric emptying of liquids in rats. Braz. J. Med. Biol. Res. 30, 207–211.
Dantzer R., Wollman E. E., and Yirmiya R., eds. (1999) Cytokines, Stress, and Depression. Kluwer Academic/Plenum: New York.
Dauphinee S. M. and Karsan A. (2006) Lipopolysaccharide signaling in endothelial cells. Lab. Invest. 86, 9–22.
David H. N., Ansseau M., and Abraini J. H. (2005) Dopamine-glutamate reciprocal modulation of release and motor responses in the rat caudate-putamen and nucleus accumbens of “intact” animals. Brain Res. Brain Res. Rev. 50, 336–360.
Fekete C., Gereben B., Doleschall M., et al. (2004) Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthy roidal illness syndrome. Endocrinology 145, 1649–1655.
Fekete C., Singru P. S., Sarkar S., Rand W. M., and Lechan R. M. (2005) Ascending brainstem pathways are not involved in lipopolysaccharide-induced suppression of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus. Endocrinology 146, 1357–1363.
Finck B. N., Kelley K. W., Dantzer R., and Johnson R. W. (1998) In vivo and in vitro evidence for the involvement of tumor necrosis factor-alpha in the induction of leptin by lipopolysaccharide. Endocrinology 139, 2278–2283.
Fortunato F., Deng X., Gates L. K., et al. (2006) Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? Am. J. Physiol. Gastrointest. Liver Physiol. 290, G232-G241.
Guan Z., Vgontzas A. N., Omori T., Peng X., Bixler E. O., and Fang J. (2005) Interleukin-6 levels fluctuate with the light-dark cycle in the brain and peripheral tissues in rats. Brain Behav. Immun. 19, 526–529.
Hayley S., Poulter M. O., Merali Z., and Anisman H. (2005) The pathogenesis of clinical depression: stressor-and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678.
Hermann G. E., Tovar C. A., and Rogers R. C. (2002) LPS-induced suppression of gastric motility relieved by TNFR:Fc construct in dorsal vagal complex. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G634-G639.
Hestad K. A., Tonseth S., Stoen C. D., Ueland T., and Aukrust P. (2003) Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J. ECT. 19, 183–188.
Heuer H., Schafer M. K., O’Donnell D., Walker P., and Bauer K. (2000) Expression of thyrotropin releasing hormone receptor 2 (TRH-R2) in the central nervous system of rats. J. Comp. Neurol. 428, 319–336.
Hinkle P. M., Pekary A. E., Senanayake S., and Sattin A. (2002) Role of TRH receptors as possible mediators of analeptic actions of TRH-like peptides. Brain Res. 935, 59–64.
Ichiyama T., Okada K., Lipton J. M., Matsubara T., Hayashi T., and Furukawa S. (2000) Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB. Brain Res. 857, 246–251.
Kapsimalis F., Richardson G., Opp M. R., and Kryger M. (2005) Cytokines and normal sleep. Curr. Oppin. Pulm. Med. 11, 481–484.
Kim W. K., Hwang S. Y., Oh E. S., Piao H. Z., Kim K. W., and Han I. O. (2004) TGF-betal represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity. J. Immunol. 172, 7015–7023.
Klir J. J., Roth J., Szelenyi Z., McClellan J. L., and Kluger M. J. (1993) Role of hypothalamic interleukin-6 and tumor necrosis factor-α in LPS fever in rat. Am. J. Physiol. 265, R512-R517.
Kondo K., Harbuz M. S., Levy A., and Lightman S. L. (1997) Inhibition of hypothalamic-pituitary-thyroid axis in response to lipopoly saccharide is independent of changes in circulating corticosteroids. Neuroimmunomodulation 4, 188–194.
Krueger J. M., Obal F. J., Fang J., Kubota T., and Taishi P. (2001) The role of cytokines in physiological sleep regulation. Ann. N.Y. Acad. Sci. 933, 211–221.
Kubera M., Kenis G., Bosmans E., et al. (2000) Suppressive effect of TRH and imipramine on human interferongamma and interleukin-10 production in vitro. Pol. J. Pharmacol. 52, 481–486.
Larson S. J., Collins S. M., and Weingarten H. P. (1996) Dissociation of temperature changes and anorexia after experimental colitis and LPS administration in rats. Am. J. Physiol. 271, R967-R972.
Li F. Q., Lu X. Z., Liang X. B., et al. (2004) Triptolide, a Chinese herbal extract, protects dopaminergic neurons from inflammation-mediated damage through inhibition of microglial activation. J. Neuroimmunol. 148, 24–31.
Li F. Q., Wang T., Pei Z., Liu B., and Hong J. S. (2005) Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neurons. J. Neural. Transm. 112, 331–347.
Lloyd R. L., Pekary A. E., Sattin A., and Amundson T. (2001) Antidepressant effects of thyrotropin-releasing hormone analogues using a rodent model of depression. Pharmacol. Biochem. Behav. 70, 15–22.
Luo L. and Stopa E. G. (2004) Thyrotropin releasing hormone inhibits tau phosphorylation by dual signaling pathways in hippocampal neurons. J. Alzheimers Dis. 6, 527–536.
Maes M., Song C., Lin A. H., et al. (1999) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20, 370–379.
Medina E. A., Erickson K. L., Stanhope K. L., and Haavel P. J. (2002) Evidence that tumor necrosis factor-alphainduced hyperinsulinemia prevents decreases of circulating leptin during fasting in rats. Metabolism 51, 1104–1110.
Minor T. R., Pekary A. E., Sattin A., Witt A. E., and Stevens S. (2005) pGlu-Glu-Pro-NH2 (EEP), a TRH analog, mitigates the fear response typical in learned helplessness. Program No. 889.18. Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.
Munford R. S. (2005) Detoxitying endotoxin: time, place and person. J. Endotoxin. Res. 11, 69–84.
Nguyen K. T., Deak T., Owens S. M., et al. (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. J. Neurosci. 18, 2239–2246.
Pariante C. M., Thomas S. A., Lovestone S., Makoff A., and Kerwin R. W. (2004) Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29, 423–447.
Pekary A. E. (2006a) Thyrotropin-releasing hormone: new functions for an ancient peptide, in The Handbook of Biologically Active Peptides, Elsevier, NY: pp. 649–654.
Pekary A. E., Davidson J. M., and Zondek B. (1967) Failure to demonstrate a role of midbrain-hypothalamic afferents in reproductive processes. Endocrinology 80, 365–368.
Pekary A. E., Faull K. F., Paulson M., Lloyd R. L., and Sattin A. (2005) TRH-like antidepressant peptide, pyroglutamyltyrosylprolineamide, occurs in rat brain. J. Mass Spectr. 40, 1232–1236.
Pekary A. E. and Hershman J. M. (2001) Hormone assays, in Endocrinology and Metabolism, 4th Edition, McGraw-Hill: pp. 91–107.
Pekary A. E., Meyer N. V., Vaillant C., and Hershman J. M. (1980) Thyrotropin-releasing hormone and a homologous peptide in the male rat reproductive system. Biochem. Biophys. Res. Commun. 95, 993–1000.
Pekary A. E., Sattin A., and Stevens S. A. (2006b) Rapid modulation of TRH-like peptides in rat brain by thyroid hormones. Peptides 27, 1577–1588.
Pekary A. E., Sattin A., and Stevens S. A. (2006c) Valproate and copper accelerate TRH-like peptide synthesis in rat pancreas and reproductive tissues. Peptides 27, 2901–2911.
Pekary A. E., Stevens S. A., and Sattin A. (2006d) Rapid modulation of TRH and TRH-like peptide levels in rat brain and peripheral tissues by corticosterone. Neurochem. Int. 48, 208–217.
Pekary A. E., Stevens S. A., and Sattin A. (2006e) Circadian rhythms of TRH-like peptides in rat brain. Brain Res. 1125, 67–76.
Raison C. L., Gumnick J. F., and Miller A. H. (2002) Neuroendocrine-immune interactions: implications for health and behavior, in Hormones, Brain and Behavior. Academic, San Diego: pp. 209–261.
Reynolds J. L., Ignatowski T. A., Gallant S., and Spengler R. N. (2004) Amitriptyline administration transforms tumornecrosis factor-alpha regulation of norepinephrine release in the brain. Brain Res. 1023, 112–120.
Reynolds J. L., Ignatowski T. A., Sud R., and Spengler R. N. (2004b) Brain-derived tumornecrosis factor-alpha and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant. J. Pharmacol. Exp. Ther. 310, 1216–1225.
Saitoh N., Awaya A., Sakudo A., et al. (2004) Serum thymic factor prevents LPS-induced pancreatic cell damage in mice via up-regulation of Bcl-2 expression in pancreas. Microbiol. Immunol. 48, 629–638.
Schiepers O. J. G., Wichers M. C., and Maes M. (2005) Cytokines and major depression Prog. Neuro-Psychoparmacol Biol. Psychiatry 29, 201–271.
Schwarz R. I. (1985) Procollagen secretion meets the minimum requirements for the rate-controlling step in the ascorbate induction of procollagen synthesis. J. Biol. Chem. 260, 3045–3049.
Seydel U., Scheel O., Muller M., Brandenburg K., and Blunck R. (2001) A K+ channel is involved in LPS signaling. J. Endotoxin Res. 7, 243–247.
Sharp T. (2006) A new molecule to brighten the mood. Science 311, 45–46.
Stellwagen D. and Malenka R. C. (2006) Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059.
Svenningsson P., Chergui K., Rachleff I., et al. (2006) Alterations in 5-HTlb receptorfunction by p11 in depressionlike states. Science 311, 77–80.
Tobin B. W., Leeper-Woodford S. K., Hashemi B. B., Smith S. M., and Sams C. F. (2001) Altered TNF-alpha, glucose, insulin, and amino acids in islets of Langerhans cultured in a microgravity model system. Am. J. Physiol. Endocrinol. Metab. 280, E92-E102.
Wichers M. C., Koek G. H., Robaeys G., Verkerk R., Scharpe S., and Maes M. (2005) IDO and interferonalpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol. Psychiatry 10, 538–544.
Wichers M. and Maes M. (2002) The psychoneuroimmunopathophysiology of cytokine-induced depression in humans. Int. J. Neuropsychopharmacol. 5, 375–388.
Wideman R. F., Chapman M. E., Wang W., and Erf G. F. (2004) Immune modulation of the pulmonary hypertensive response to bacterial lipopolysaccharide (endotoxin) in broilers. Poult. Sci. 83, 624–637.
Yarbrough G. G. (2003) Fundamental molecular mechanism of the CNS effect of TRH. Trends Pharmacol. Sci. 24, 617–618.
Zacharowski K., Zacharowski P. A., Koch A., et al. (2006) Toll-like receptor 4 plays a crucial role in the immuneadrenal response to systemic inflammatory response syndrome. Proc. Natl. Acad. Sci. U. S. A. 103, 6392–6397.
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Pekary, A.E., Stevens, S.A. & Sattin, A. Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs. J Mol Neurosci 31, 245–259 (2007). https://doi.org/10.1385/JMN:31:03:245
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DOI: https://doi.org/10.1385/JMN:31:03:245