How does bacterial endotoxin influence gonadoliberin/gonadotropins secretion and action?
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The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
D. Tomaszewska-Zaremba   

The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
Publication date: 2016-11-25
J. Anim. Feed Sci. 2016;25(4):283–291
This review summarizes data concerning the mechanisms by which bacterial endotoxin, lipopolysaccharide (LPS), inhibits gonadoliberin (GnRH)/ luteinizing hormone (LH) secretion in mammals. LPS is a major component of Gram-negative bacteria cell walls and is released from the surface of replicated and dying Gram-negative bacteria into circulation. LPS is commonly used to induce immune/inflammatory challenge in animals. In this article the site of endotoxin action as well as LPS induced mediators are discussed. Hypothalamus seems to be a place where majority of the immune-neuroendocrine interactions occur, however the results of many research suggest that LPS may interfere with reproductive system at the pituitary level as well. Endotoxin may affect GnRH/LH secretion directly via toll-like receptors (TLR)4/TLR2 located both in the hypothalamus and pituitary or indirectly through the intermediates such as cytokines, catecholamines, prostaglandins or opioids.
Banks W.A., Robinson S.M., 2010. Minimal penetration of lipopolysaccharide across the murine blood-brain barrier. Brain Behav. Immun. 24, 102–109,
Battaglia D.F., Krasa H.B., Padmanabhan V., Viguié C., Karsch F.J., 2000. Endocrine alterations that underlie endotoxin-induced disruption of the follicular phase in ewes. Biol. Reprod. 62, 45–53,
Bernton E.W., Beach J.E., Holaday J.W., Smallridge R.C., Fein H.G., 1987. Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science 238, 519–521,
Bilezikjian L.M., Leal A.M.O., Blount A.L., Corrigan A.Z., Turnbull A.V., Vale W.W., 2003. Rat anterior pituitary folliculostellate cells are targets of interleukin-1β and a major source of intrapituitary follistatin. Endocrinology 144, 732–740,
Braden T.D., Fry C., Sartin J.L., 1998. Effects of interleukins on secretion of luteinizing hormone from ovine pituitary cells. Am. J. Vet. Res. 59, 1488–1493
Breuel K.F., Kougias P., Rice P.J., Wei D., De Ponti K., Wang J., Laffan J.J., Li C., Kalbfleisch J., Williams D.L., 2004. Anterior pituitary cells express pattern recognition receptors for fungal glucans: implications for neuroendocrine immune involvement in response to fungal infections. Neuroimmunomodulation 11, 1–9,
Chakravarty S., Herkenham M., 2005. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J. Neurosci. 25, 1788–1796,
Chen G., McCuskey R.S., Reichlin S., 2000. Blood interleukin-6 and tumor necrosis factor-α elevation after intracerebroventricular injection of Escherichia coli endotoxin in the rat is determined by two opposing factors: peripheral induction by LPS transferred from brain to blood and inhibition of peripheral response by a brain-mediated mechanism. Neuroimmunomodulation 8, 59–69,
Dange R.B., Agarwal D., Teruyama R., Francis J., 2015. Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension. J. Neuroinflamm. 12, 31,
Dascombe M.J., Milton A.S., 1979. Study on the possible entry of bacterial endotoxin and prostaglandin E2 into the central nervous system from the blood. Brit. J. Pharmacol. 66, 565–572,
Dentener M.A., Vreugdenhil A.C.E., Hoet P.H.M., Vernooy J.H.J., Nieman F.H.M., Heumann D., Janssen Y.M.W., Buurman W.A., Wouters E.F.M., 2000. Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications for local defense to bacterial endotoxins. Am. J. Respir. Cell Mol. Biol. 23, 146–153,
Dziarski R., Wang Q., Miyake K., Kirschning C.J., Gupta D., 2001. MD-2 enables toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components. J. Immunol. 166, 1938–1944,
Ebisui O., Fukata J., Tominaga T., Murakami N., Kobayashi H., Segawa H., Muro S., Naito Y., Nakai Y. Masui Y., 1992. Roles of interleukin-1 alpha and -1 beta in endotoxin-induced suppression of plasma gonadotropin levels in rats. Endocrinology 130, 3307–3313,
Fassbender K., Ries S., Schminke U., Schneider S., Hennerici M., 1996. Inflammatory cytokines in CSF in bacterial meningitis: association with altered blood flow velocities in basal cerebral arteries. J. Neurol. Neurosurg. Psychiatr. 61, 57–61,
Fitzgerald K.A., Rowe D.C., Golenbock D.T., 2004. Endotoxin recognition and signal transduction by the TLR4/MD-2 complex. Microbes Infect. 6, 1361–1367,
Givalois L., Dornand J., Mekaouche M., Solier M.D., Bristow A.F., Ixart G., Siaud P., Assenmacher I., Barbanel G., 1994. Temporal cascade of plasma level surges in ACTH, corticosterone, and cytokines in endotoxin-challenged rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 267, R164–R170
Good D.W., George T., Watts B.A. 3rd, 2012. Toll-like receptor 2 is required for LPS-induced toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J. Biol. Chem. 287, 20208–20220,
Harris T.G., Battaglia D.F., Brown M.E., Brown M.B., Carlson N.E., Viguié C., Williams C.Y., Karsch F.J., 2000. Prostaglandins mediate the endotoxin-induced suppression of pulsatile gonadotropin-releasing hormone and luteinizing hormone secretion in the ewe. Endocrinology 141, 1050–1058,
Haziak K., Herman A.P., Tomaszewska-Zaremba D., 2013. The effect of LPS on LH release and gene expression of LH-β, GnRHR and TLR4 in the anterior pituitary of follicular phase ewes – an in vitro study. J. Anim. Feed Sci. 22, 97–105 ,
Haziak K., Herman A.P., Tomaszewska-Zaremba D., 2014. Effects of central injection of anti-LPS antibody and blockade of TLR4 on GnRH/LH secretion during immunological stress in anestrous ewes. Mediat. Inflamm. 2014, 867170,
Heine H., Kirschning C.J., Lien E., Monks B.G., Rothe M., Golenbock D.T., 1999. Cutting edge: cells that carry a null allele for toll-like receptor 2 are capable of responding to endotoxin. J. Immunol. 162, 6971–6975
Herman A.P., Herman A., Haziak K., Tomaszewska-Zaremba D., 2013a. Immune stress up regulates TLR4 and Tollip gene expression in the hypothalamus of ewes. J. Anim. Feed Sci. 22, 13–18 ,
Herman A.P., Krawczyńska A., Bochenek J., Antushevich H., Herman A., Tomaszewska-Zaremba D., 2014. Peripheral injection of SB203580 inhibits the inflammatory-dependent synthesis of proinflammatory cytokines in the hypothalamus. BioMed Res. Int. 2014, 475152,
Herman A.P., Krawczyńska A., Bochenek J., Antushevich H., Herman A., Tomaszewska-Zaremba D., 2016. Involvement of prolactin in the meloxicam-dependent inflammatory response of the gonadotropic axis to prolonged lipopolisacharide treatment in anoestrous ewes. Reprod. Fert. Develop. 28, 914–923,
Herman A.P., Krawczyńska A., Bochenek J., Dobek E., Herman A., Tomaszewska-Zaremba D., 2013b. LPS-induced inflammation potentiates the IL-1β-mediated reduction of LH secretion from the anterior pituitary explants. Clin. Dev. Immunol. 2013, 926937,
Herman A.P., Misztal T., Herman A., Tomaszewska-Zaremba D., 2010. Expression of interleukin (IL)-1β and IL-1 receptors genes in the hypothalamus of anoestrous ewes after lipopolysaccharide treatment. Reprod. Domest. Anim. 45, e426–e433,
Herman A.P., Misztal T., Romanowicz K., Tomaszewska-Zaremba D., 2012. Central injection of exogenous IL-1b in the control activities of hypothalamic pituitary gonadal axis in anestrous ewes. Reprod. Domest. Anim. 47, 44–52,
Heumann D., Gallay P., Barras C., Albrecht H., de Flaugergues J.C., Steck A., Glauser M.P., 1995. Lipopolysaccharide binding protein (LBP) as a marker of protein leakage in cerebrospinal fluid. Innate Immun. 2, 1–7,
Inoue K., Couch E.F., Takano K., Ogawa S., 1999. The structure and function of folliculo-stellate cells in the anterior pituitary gland. Arch. Histol. Cytol. 62, 205–218,
Igaz P., Salvi R., Rey J.-P., Glauser M., Pralong F.P., Gaillard R.C., 2006. Effects of cytokines on gonadotropin-releasing hormone (GnRH) gene expression in primary hypothalamic neurons and in GnRH neurons immortalized conditionally. Endocrinology 147, 1037–1043,
Janeway C.A. Jr., Travers P., Walport M., Shlomchik M.J., 2001. Immunobiology. 5th Edition. Garland Publishing. New York (NY), USA
Kaiser U.B., Sabbagh E., Katzenellenbogen R.A., Conn P.M., Chin W.W., 1995. a mechanism for the differential regulation of gonadotropin subunit gene expression by gonadotropinreleasing factor. Proc. Natl. Acad. Sci. USA 92, 12280–12284,
Kalra P.S., Edwards T.G., Xu B., Jain M., Kalra S.P., 1998. The antigonadotropic effects of cytokines: the role of neuropeptides. Domest. Anim. Endocrinol. 15, 321–332,
Kalra P.S., Fuentes M., Sahu A., Kalra S.P., 1990. Endogenous opioid peptides mediate the interleukin-1-induced inhibition of the release of luteinizing hormone (LH)-releasing hormone and LH. Endocrinology 127, 2381–2386,
Kang S.S., Kim S.R., Leonhardt S., Jarry H., Wuttke W., Kim K., 2000. Effect of interleukin-1β on gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in castrated male rats. J. Neuroendocrinol. 12, 421–429,
Kitchens R.L., Thompson P.A., 2005. Modulatory effects of sCD14 and LBP on LPS-host cell interactions. J. Endotoxin Res. 11, 225–229,
Knapp S., Florquin S., Golenbock D.T., van der Poll T., 2006. Pulmonary lipopolysaccharide (LPS)-binding protein inhibits the LPS-induced lung inflammation in vivo. J. Immunol. 176, 3189–3195,
Kumar H., Kawai T., Akira S., 2009. Toll-like receptors and innate immunity. Biochem. Biophys. Res. Commun. 388, 621–615,
Kochman K., Przekop F., Okrasa S., 2007. Neural regulation of the reproductive processes at the central level (in Polish) In: T. Krzymowski (Editor). Physiological Regulation of Reproduction in Female. UWM, Olsztyn (Poland)
Laflamme N., Rivest S., 2001. Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J. 15, 155–163,
Lagaraine C., Skipor J., Szczepkowska A., Dufourny L., Thiery J.-C., 2011. Tight junction proteins vary in the choroid plexus of ewes according to photoperiod. Brain Res. 1393, 44–51,
Lee H.-K., Dunzendorfer S., Tobias P.S., 2004. Cytoplasmic domainmediated dimerizations of toll-like receptor 4 observed by β-lactamase enzyme fragment complementation. J. Biol. Chem. 279, 10564–10574, M311564200
Lohrer P., Gloddek J., Nagashima A.C., Korali Z., Hopfner U., Pereda M.P., Arzt E., Stalla G.K., Renner U., 2000. Lipopolysaccharide directly stimulates the intrapituitary interleukin-6 production by folliculostellate cells via specific receptors and the p38α mitogen-activated protein kinase/nuclear factor-κB pathway. Endocrinology 141, 4457–4465,
Magata F., Horiuchi M., Echizenya R., Miura R., Chiba S., Matsui M., Miyamoto A., Kobayashi Y., Shimizu T., 2014. Lipopolysaccharide in ovarian follicular fluid influences the steroid production in large follicles of dairy cows. Anim. Reprod. Sci. 144, 6–13,
Majewska M., Szczepanik M., 2006. The role of toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation (in Polish). Postep. Hig. Med. Dosw. 60, 52–63
Mallard C., 2012. Innate immune regulation by toll-like receptors in the brain. ISRN Neurol. 2012, 701950. doi:10.5402/2012/701950,
Marques F., Sousa J.C., Coppola G., Falcao A.M., Rodrigues A.J., Geschwind D.H., Sousa N., Correia-Neves M., Palha J.A., 2009a. Kinetic profile of the transcriptome changes induced in the choroid plexus by peripheral inflammation. J. Cereb. Blood Flow Metab. 29, 921–932,
Marques F., Sousa J.C., Coppola G., Geschwind D.H., Sousa N., Palha J.A., Correia-Neves M., 2009b. The choroid plexus response to a repeated peripheral inflammatory stimulus. BMC Neurosci. 10, 135,
Martin T.R., Rubenfeld G.D., Ruzinski J.T., Goodman R.B., Steinberg K.P., Leturcq D.J., Moriarty A.M., Raghu G., Baughman R.P., Hudson L.D., 1997. Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory response in patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 155, 937–944,
Meilleur M.-A., Akpovi C.D., Pelletier R.-M., Vitale M.L., 2007. Tumor necrosis factor-α-induced anterior pituitary folliculostellate TtT/GF cell uncoupling is mediated by connexion 43 dephosphorylation. Endocrinology 148, 5913–5924,
Mishra B.B., Mishra P.K., Teale J.M., 2006. Expression and distribution of toll like receptors in the brain during murine neurocysticercosis. J. Neuroimmunol. 181, 46–56,
Murata T., Ying S.-Y., 1991. Effects of interleukin-1β on secretion of follicle- stimulating hormone (FSH) and luteinizing hormone (LH) by cultured rat anterior pituitary cells. Life Sci. 49, 447–453,
Pålsson-McDermott E.M., O’Neill L.A., 2004. Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4. Immunology 113, 153–162, 2567.2004.01976.x
Parnet P., Brunke D.L., Goujon E., Mainard J.D., Biragyn A., Arkins S., Dantzer R., Kelley K.W., 1993. Molecular identification of two types of interleukin-1 receptors in the murine pituitary gland. J. Neuroendocrinol. 5, 213–219,
Peter A.T., Bosu W.T.K., DeDecker R.J., 1989. Suppression of preovulatory luteinizing hormone surges in heifers after intrauterine infusions of Escherichia coli endotoxin. Am. J. Vet. Res. 50, 368–373
Rettori V., Gimeno M.F., Karara A., Gonzalez M.C., McCann S.M., 1991 Interleukin 1α inhibits prostaglandin E2 release to suppress pulsatile release of luteinizing hormone but not follicle-stimulating hormone. Proc. Natl. Acad. Sci. USA 88, 2763–2767,
Rietschel E.T., Kirikae T., Schade F.U., Mamat U., Schmidt G., Loppnow H., Ulmer A.J., Zähringer U., Seydel U., Di Padova F., 1994. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J. 8, 217–225
Schlafer D.H., Yuh B., Foley G.L., Elssaser T.H., Sadowsky D., Nathanielsz P.W., 1994. Effect of Salmonella endotoxin to the pregnant sheep at 133-142 days gestation on fetal oxygenation, maternal and fetal adsrenocorticotropic hormone and cortisol, and maternal plasma tumor necrosis factor a concentrations. Biol. Reprod. 50, 1297–1302,
Schumann R.R., Kirschning C.J., Unbehaun A., Aberle H., Knope H.-P., Lamping N., Ulevitch R.J., Herrmann F., 1996. The lipopolysaccharide-binding protein is a secretory class 1 acutephase protein whose gene is transcriptionally activated by APRF/ STAT-3 and other cytokine-inducible nuclear proteins. Mol. Cell. Biol. 16, 3490–3503,
Schwerk C., Rybarczyk K., Essmann F., Seibt A., Mölleken M.-L., Zeni P., Schroten H., Tenenbaum T., 2010. TNFα induces choroid plexus epithelial cell barrier alterations by apoptotic and nonapoptotic mechanisms. J. Biomed. Biotech. 2010, 307231,
Singh A.K., Jiang Y., 2004. How does peripheral lipopolysaccharide induce gene expression in the brain of rats? Toxicology 201, 197–207,
Sirivelu M.P., Burnett R., Shin A.C., Kim C., MohanKumar P.S., MohanKumar S.M.J., 2009. Interaction between GABA and norepinephrine in interleukin-1β-induced suppression of the luteinizing hormone surge. Brain Res. 1248, 107–114,
Skipor J., Szczepkowska A., Kowalewska M., Herman A.P., Lisiewski P., 2015. Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes. Acta Vet. Hung. 63, 69–78,
Skipor J., Thiery J.-C., 2008. The choroid plexus - cerebrospinal fluid system: undervaluated pathway of neuroendocrine signaling into the brain. Acta Neurobiol. Exp. 68, 414–428
Tichomirowa M., Theodoropoulou M., Lohrer P., Schaaf L., Losa M., Uhl E., Lange M., Arzt E., Stalla G.K., Renner U., 2005. Bacterial endotoxin (lipopolysaccharide) stimulates interleukin-6 production and inhibits growth of pituitary tumour cells expressing the toll-like receptor 4. J. Neuroendocrinol. 17, 152–160,
Tomaszewska-Zaremba D., Herman A., 2009. The role of immunological system in the regulation of gonadoliberin and gonadotropin secretion. Reprod. Biol. 9, 11–23,
Tomaszewska-Zaremba D., Herman A.P., Misztal T., 2013. Does central IL-1β affect GnRH secretion in the hypothalamus of anoestrous ewes via different regulatory pathways? J. Anim. Feed Sci. 22, 5–12,
Waage A., Halstensen A., Shalaby R., Brandtzaeg P., Kierulf P., Espevik T., 1989. Local production of tumor necrosis factor α, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J. Exp. Med. 170, 1859–1867,
Wolburg H., Lippoldt A., 2002. Tight junctions of the blood-brain barrier: development, composition and regulation. Vasc. Pharmacol. 38, 323–337,
Yang R.-B., Mark M.R., Gray A., Huang A., Xie M.H., Zhang M., Goddard A., Wood W.I., Gurney A.L., Godowski P.J., 1998. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395, 284–288,
Yu L., Wang L., Chen S., 2010. Endogenous toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 14, 2592–2603,
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