Abstract
There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in pro-inflammatory cytokines. On the other hand, oxidative stress has been implicated in the pathogenesis of several alterations due to menopause, and can arise through the increased production of lipid peroxides (LPO) and/or a deficiency of antioxidant defense. The aim of the present study was to investigate the effect of aging and ovariectomy on various physiological parameters related to inflammation and oxidative stress in livers obtained from old female rats and the influence of chronic exogenous administration of estrogens, phytoestrogens and growth hormone on these. Thirty-six female Wistar rats of 22 months of age were used in the present study. Twelve of them remained intact, and the other 24 had been ovariectomized at 12 months of age. Intact animals were divided into two groups and treated for 10 weeks with GH or saline, and ovariectomized animals were divided into four groups and treated for the same time with GH, estrogens, phytoestrogens or saline. A group of 2 month old intact female rats was used as young control. Protein expression of iNOS, HO-1, IL-6, TNFα, and IL-1β were determined by Western blot analysis. The levels of NO x , LPO, TNFα, IL-1β, IL-6 and IL-10 were determined in different fractions of the liver. Levels of LPO in the liver homogenates as well as iNOS protein expression and NO x levels were increased in old rats as compared to young animals; this effect was more evident in ovariectomized animals. Pro-inflammatory cytokines TNF-α, IL-1β and IL-6 were significantly increased and anti-inflammatory IL-10 decreased during ageing and after ovariectomy. Aging also significantly increased expression of HO-1 protein and ovariectomized rats showed an additional increase. Hormonal administration to the ovariectomized groups decreased NO x , LPO levels and pro-inflammatory cytokines as compared with untreated rats. Significant rise in IL-10 and reductions in the iNOS, IL-6, TNFα and IL-1β proteins expression were also found. Oxidative stress and inflammation induced during aging in the liver are more marked in castrated than in intact old females. Administration of the different hormonal replacement therapies was able to inhibit the induction of pro-inflammatory cytokines and iNOS, decreased the levels of oxidative stress markers and had therapeutic potential in the prevention of liver injury.
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Alm P, Ekstrom P, Henningsson R, Lundquist I (1999) Morphological evidence for the existence of nitric oxide and carbon monoxide pathways in the rat islets of Langerhans: an immunocytochemical and confocal microscopical study. Diabetologia 42:978–986
Arora A, Nair MG, Strasburg GM (1998) Structure–activity relationships for antioxidant activities of a series of flavonoids in a liposomal system. Free Radic Biol Med 24:1355–1363
Ayala A, Perrin MM, Ertel W, Chaudry IH (1992) Differential effects of haemorrhage on Kupffer cells: decreased antigen presentation despite increased inflammatory cytokine (IL- 1, IL-6 and TNF) release. Cytokine 4:66–75
Berg G, Ekerfelt C, Hammar M, Lindgren R, Matthisen L, Ernerudh C (2002) Cytokine changes in postmenopausal women treated with estrogen: a placebo-controlled study. Am J Reprod Immunol 48:63–69
Bresson JL, Jeay S, Gagnerault MC, Kayser C, Beressi N, Wu Z, Kinet S, Dardenne M, Postel-Vinay MC (1999) Growth hormone (GH) and prolactin receptors in human peripheral blood mononuclear cells: relation with age and GH-binding protein. Endocrinology 140:3203–3209
Carlson S, Peng N, Prasain JK, Wyss JM (2008) Effects of botanical dietary supplements on cardiovascular, cognitive, and metabolic function in males and females. Gend Med 5:76–90
Castillo C, Salazar V, Ariznavarreta C, Vara E, Tresguerres JA (2004) Effect of recombinant human growth hormone on age-related hepatocyte changes in old male and female Wistar rats. Endocr 25:33–39
Castillo C, Salazar V, Ariznavarreta C, Vara E, Tresguerres JAF (2005) Effect of growth hormone and estrogen administration on hepatocyte alterations in old ovariectomized female Wistar rats. Endocr 26:11–18
Castillo C, Salazar V, Ariznavarreta C, Vara E, Tresguerres JAF (2006) Effect of isoflavone administration on age-related hepatocytes changes in old ovariectomized female Wistar rats. Phytomedicine 13:468–476
Cho JY, Kim PS, Park J, Yoo ES, Baik KU, Kim Y-K et al (2000) Inhibitor of tumor necrosis factor-α production in lipopolysaccharide-stimulated RAW 264.7 cells from Amorpha fruticosa. J Ethnopharmacol 70:127–133
Chung HY, Jung KJ, Yu BP (2005) Molecular inflammation as an underlying mechanism of aging: The anti-inflammatory action of calorie restriction. In: Surh YJ, Packer L (eds) Oxidative stress, inflammation and health. Marcel Dekker, NY, pp 387–419
Cioffi M, Esposito K, Vietri MT, Gazzerro P, D’Auria A, Ardovino I et al (2002) Cytokine pattern in postmenopause. Maturitas 41:187–192
Dhainaut JF, Marin N, Mignon A, Vinsonneau C (2001) Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 29:42–47
Ferrucci L, Ble A, Bandinelli S, Lauretani F, Suthers K, Guralnik JM (2004) A flame burning within. Aging Clin Exp Res 16:240–243
Franco C, Andersson B, Lonn L, Bengtsson BA, Svensson J, Johannsson G (2007) Growth hormone reduced inflammation in postmenopausal women with abdominal obesity: a 12 month, randomized, placebo-control trial. J Clin Endocrinol Metab 92:2644–2647
Gagliano N, Grizzi F, Annoni G (2007) Mechanisms of aging and liver function. Dig Dis 25(2):118–123
Haeffner N, Thieblemont N, Deas O, Marelli O, Charpentier B, Senik A, Wright SD, Cavaillon N, Hirsh F (1997) Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kB translocation in lipopolysaccharide-stimulated human monocytes. J Immunol 158:1310–1314
Hilmer SN, Cogger VC, Le Couteur DG (2007) Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 62:973–978
Ho KM, Ny L, Mcmurray G et al (1999) Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the human urethral sphincter. J Urol 161:1968–1972
Hori R, Kashiba M, Toma T, Yachie A, Goda N, Makino N, Soejima A, Nagasawa T, Nakabayashi K, Suematsu M (2002) Gene transfection of H25A mutant heme oxygenase-1 protects cells against hydroperoxide-induced cytotoxicity. J Biol Chem 277:10712–10718
Inaba K, Suzuki S, Ihara H, Sakaguchi T, Baba S, Urano T, Konno H, Nakamura S (2005) Sexual dimorphism in endotoxin susceptibility after partial hepatectomy in rats. J Hepatol 42:719–727
Jeay S, Sonenshein GE, Postel-Vinay MC, Baixeras E (2000) Growth hormone prevents apoptosis through activation of NF-kB in interleukin-3-dependent Ba/F3 cell line. Mol Endocrinol 14:650–661
Jeschke MG, Barrow RE, Herndon DN (2000) Recombinant human growth hormone treatment in pediatric burn patients and its role during the hepatic acute phase response. Crit Care Med 28:1578–1584
Kamada M, Irahara M, Maegawa M et al (2001) Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol 184:309–314
Kankofer M, Radzki RP, Bienko M, Albera E (2007) Anti-oxidative/oxidative status of rat liver after ovariectomy. J Vet Med A Physiol Pathol Clin Med 54:225–229
Karbownik-Lewinska M, Kokoszko A, Lewandowski KC, Shalet SM, Lewinski A (2008) GH replacement reduces increased lipid peroxidation in GH-deficient adults. Clin Endocrinol 68:957–964
Kireev RA, Tresguerres AF, Vara E, Ariznavarreta C, Tresguerres JA (2007) Effect of chronic treatments with GH, melatonin, estrogens, and phytoestrogens on oxidative stress parameters in liver from aged female rats. Biogerontology 8(5):469–482
Kooijman R, Hooghe-Peters EL, Hooghe R (1996) Prolactin, growth hormone, and insulin-like growth factor-I in the immune system. Adv Immunol 63:377–454
Krakauer T, Li BQ, Young HA (2001) The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines. FEBS Lett 500:52–55
Kroncke KD, Fehsel K, Kolb-Bachofen V (1998) Inducible nitric oxide synthase in human diseases. Clin Exp Immunol 113:147–156
Kumru S, Godekmerdan A, Yilmaz B (2004) Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J Reprod Immunol 63:31–38
Leclercq IA, Farell GC, Sempoux C, De la Pena A, Horsmans Y (2004) Curcumin inhibits NF-kB activation and reduces the severity of experimental steatohepatitis in mice. J Hepatol 41:926–934
Lee YM, Cheng PY, Hong SF et al (2005) Oxidative stress induces vascular heme oxygenase-1 expression in ovariectomized rats. Free Radic Biol Med 39:108–117
Liu Y, Shimizu I, Omoya T, Ito S, Gu XS, Zuo J (2002) Protective effect of estradiol on hepatocytic oxidative damage. World J Gastroenterol 8:363–366
Luedde T, Trautwein C (2006) Intracellular survival pathways in the liver. Liver Int 26:1163–1174
Luedde T, Liedtke C, Manns MP, Trautwein C (2002) Losing balance: cytokine signalling and cell death in the context of hepatocyte injury and hepatic failure. Eur Cytokine Netw 13:377–383
Martínez-Flórez S, Gutiérrez MB, Sánchez-Campos S, González-Gallego J, Tuñón MJ (2005) Quercetin prevents nitric oxide production and nuclear factor kappa B activation in interleukin-1β-activated rat hepatocytes. J Nutr 135:1359–1365
Mester M, Carter EA, Tompkins RG et al (1994) Thermal injury induces very early production of interleukin-1 alpha in the rat by mechanisms other than endotoxemia. Surgery 115:588–596
Morales AI, Vicente-Sánchez C, Jerkic M, Santiago JM, Sánchez-González PD, Pérez-Barriocanal F, López Novoa JM (2006) Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats. Toxicol Appl Pharmacol 210:128–135
Moutsatsou P (2007) The spectrum of phytoestrogens in nature: our knowledge is expanding. Hormones (Athens) 6(3):173–193
Nagai H, Matsumaru K, Feng G, Kaplowitz N (2002) Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes. Hepatology 36:55–64
Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Thomas P, Dannenberg AJ (2003) Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kB-dependent genes. Am J Physiol Gastrointest Liver Physiol 284:321–327
Nesibe A, Nursen Y (2007) TNF-α levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. Growth Hormon IGF Res 17:149–153
Pang JL, Ricupero DA, Huang S, Fatma N, Sing DP, Romero JS, Chattopadhyay N (2006) Differential activity of kaempferol and quercetin in attenuating tumor necrosis factor receptor family signaling in bone cells. Biochem Pharmacol 71:818–886
Polan ML, Loukides J, Nelson P, Carding S, Diamond M, Walsh A, Bottomly K (1989) Progesterone and estradiol modulate interleukin 1-beta messenger ribonucleic acid levels in cultured human peripheral monocytes. J Clin Endocrinol Metab 69:1200–1206
Rachon D, Mysliwska J, Suchecka-Rachon K, Wieckiewicz J, Mysliwski A (2002) Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. J Endocrinol 172:387–395
Ray A, Prefontaine KE, Ray P (1994) Down-modulation of interleukin-6 gene expression by 17b-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem 269:12940–12946
Sabharwal P, Varma S (1996) Growth hormone synthesized and secreted by human thymocytes acts via insulin-like growth factor I as an autocrine and paracrine growth factor. J Clin Endocrinol Metab 81:2663–2669
Saucedo R, Rico G, Basutro L, Ochoa R, Zarafe A (2002) Transdermal estradiol in menopausal women depresses interleukin-6 without effecting other markers of immune response. Gynecol Obstet Invest 53:114–117
Scacchi M, Valassi E, Pincelli AI, Fatti LM, Pecori Giraldi F, Ascoli P, Viarengo R, Cestaro B, Cavagnini F, Cazzola R (2006) Increased lipid peroxidation in adult GH-deficient patients: effects of short-term GH administration. J Endocrinol Invest 29:899–904
Seiva FRF, Ebaid GMX, Castro AVB et al (2008) Growth hormone and heart failure: oxidative stress and energetic metabolism in rats. Growth Hormon IGF Res 18:275–283
Sener G, Arbak S, Kurtaran P, Gedik N, Yegen BC (2005) Estrogen protects the liver and intestines against sepsis-induced injury in rats. J Surg Res 128(1):70–78
Shimizu I (2003) Impact of oestrogens on the progression of liver disease. Liver Int 23:63–69
Shiraishi T, Shimizu I, Itagaki T, Urata M, Tamaki K et al (2006) Inhibitory effects of estrogen on chemokine and proinflammatory cytokine production in mononuclear cells and macrophages [abstract]. Gastroenterology 150:A-793
Stachlewitz RF, Seabra V, Bradford B et al (1999) Glycine and uridine prevent d-galactosamine hepatotoxicity in the rat: role of Kupffer cells. Hepatology 29:737–745
Sugihara N, Arakawa T, Ohnishi M, Furuno K (1999) Anti-and prooxidative effects of flavonoids on metal-induced lipid hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with alpha-linoleic acid. Free Radic Biol Med 27:1313–1323
Suschek CV, Schnorr O, Kolb-Bachofen V (2004) The role of iNOS in chronic inflammatory processes in vivo: is it damage-promoting, protective, or active at all? Curr. Mol. Med. 4:763–775
Suzuki S, Toledo-Pereyra LH (1994) Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res 57:253–258
US Preventive Services Task Force (2002) Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 137:834–839
Verstraeten SV, Keen CL, Schmitz HH, Fraga CG, Oteiza PI (2003) Flavan-3-ols and procyanidins protect liposomes against lipid oxidation and disruption of the bilayer structure. Free Radic Biol Med 34:84–92
Vom Saal FS, Finch CE, Nelson JF (1994) Natural history and mechanisms of reproductive aging in humans, laboratory rodents and other selected vertebrates. In: Knobil E, Neill JD (eds) The physiology of reproduction, 2nd edn. Raven Press, NY, pp 1213–1314
Vural P, Akgul C, Canbaz M (2005) Effects of menopause and tibolone on antioxidants in postmenopausal women. Ann Clin Biochem 42:220–223
Wadsworth TL, Koop DR (2001) Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide. Chem Biol Interact 137:43–58
Wadsworth TL, McDonald TL, Koop DR (2001) Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide induced signaling pathways involved in the release of tumor necrosis factor-α. Biochem Pharmacol 62:963–974
Wagener FA, van Beurden HE, von den Hoff JW, Adema G, Figdor CG (2003) The heme–heme oxygenase system: a molecular switch in wound healing. Blood 102:521–528
Wang S, DeGroff VL, Clinton SK (2003) Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J Nutr 133:2367–2376
Wong MCY, Portmann B, Sherwood R, Niemela O, Koivisto H, Parkkila S et al (2007) The cytoprotective effect of α-tocopherol and daidzein against d-galactosamine–induced oxidative damage in the rat liver. Metab Clin Exp 56:865–875
Yagi K (1997) Female hormones act as natural antioxidants a survey of our research. Acta Biochim Pol 44:701–709
Yasuda M, Shimizu I, Shiba M, Ito S (1999) Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis in the liver in rats. Hepatology 29:719–727
Yasui T, Maegawa M, Tomita J, Miyatani Y, Yamada M et al (2007) Changes in serum cytokine concentrations during the menopausal transition. Maturitas 56:396–403
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This work was supported by grants: RETICEF RD 06/0013 (FIS) Instituto Carlos III and SAF 2007, 66878-C02-01. Dr. Kireev Roman was supported by Nutricia Research Foundation, International Training Fellowship (2007-T4).
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Kireev, R.A., Tresguerres, A.C.F., Garcia, C. et al. Hormonal regulation of pro-inflammatory and lipid peroxidation processes in liver of old ovariectomized female rats. Biogerontology 11, 229–243 (2010). https://doi.org/10.1007/s10522-009-9242-2
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DOI: https://doi.org/10.1007/s10522-009-9242-2