Modulatory effects of estrogen in two murine models  of experimental colitis

Verdú, Elena F.; Deng, Yikang; Berčík, Přemysl; Collins, Stephen M.

doi:10.1152/ajpgi.00460.2001

Cited by 89 publications

(67 citation statements)

References 61 publications

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“…The profound reduction of highmultiplicity ACFs in E 2 -treated mice is of significant interest because these lesions are most predictive of eventual tumor formation (33). These data support other findings showing E 2 to be protective against tumor formation (34)(35)(36). However, our studies were focused on examining premalignant tissue and show a chemoprotective role for E 2 therapy before tumor formation.…”

Section: Discussionsupporting

confidence: 85%

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Weige

Allred

2009

Cancer Research

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Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E 2 ) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E 2 in noncancerous colonocytes. E 2 treatments (0-10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E 2 in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E 2 on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectomized wild-type (WT) and ERβ knockout (ERβKO) mice treated with either vehicle or E 2 . WT E 2 -treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ERβKO animals receiving either treatment. For the first time, we showed that E 2 alters the growth of nontransformed colonocytes in vitro and that, through an ERβ-mediated mechanism, E 2 influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E 2 occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent. [Cancer Res 2009;69(23):9118-24]

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Section: Discussionsupporting

confidence: 85%

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Weige

Allred

2009

Cancer Research

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“…However, the in vivo severity of EAE was the same in WT females and males, possibly implicating other regulatory factors. The unexpected finding by Verdu et al (12) that IL-13 mRNA expression was decreased in mice treated with 17␤-estradiol finds relevance to this issue. This would lead us to speculate that IL-13 and estrogen have opposing effects on macrophage activation and MHC II expression.…”

Section: Discussionmentioning

confidence: 83%

“…This gender difference is also reflected in SJL/J mice with EAE, an animal model for MS. In these mice, females have stronger humoral and cell-mediated immune responses than males and a higher incidence and severity of EAE (12). However, the mechanisms underlying enhanced autoimmune disease susceptibility in females are poorly understood.…”

Section: Resultsmentioning

confidence: 99%

IL-13-Mediated Gender Difference in Susceptibility to Autoimmune Encephalomyelitis

Sinha

Kaler

Proctor³

et al. 2008

The Journal of Immunology

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Females tend to have stronger Th1-mediated immune responses and are more prone to develop autoimmune diseases, including multiple sclerosis. Macrophages are major effector cells capable of mediating or modulating immune responses in experimental autoimmune encephalomyelitis (EAE). IL-13 and estrogen have opposing roles on macrophages (the former enhancing and the latter inhibiting) in terms of MHC class II (MHC II) up-regulation and, thus, these factors might influence susceptibility to EAE differently in females vs males. In accordance with this hypothesis, females lacking IL-13 displayed lower incidence and milder EAE disease severity than males after immunization with myelin oligodendrocyte glycoprotein (MOG)-35–55 peptide/CFA/pertussis toxin. Female IL-13 knockout (KO) mice with EAE consistently had reduced infiltration of CD11b+ macrophages in the CNS along with significantly reduced expression of MHC II on these cells. Impaired MHC II expression was further corroborated upon LPS stimulation of female but not male bone marrow-derived CD11b+ macrophages from IL-13KO mice, with restored expression after IL-13 pretreatment of female but not male macrophages. APCs from IL-13KO females induced less proliferation by MOG-35–55-reactive T cells, and splenocytes from MOG peptide-immunized females had lower expression of IL-12, IFN-γ, MIP-2, and IFN-γ-inducible protein 10 than males. In contrast, these splenocytes had higher expression of anti-inflammatory factors, IL-10, TGF-β1, and FoxP3, a cytokine pattern typical of regulatory type II monocytes. These data suggest that the difference in EAE susceptibility in females is strongly influenced by gender-specific proinflammatory effects of IL-13, mediated in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b+ macrophages.

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“…Regrettably, many reports state their pellets produce physiological levels of 17 β-E2 based upon technical information provided by IRA [for example see (59,60)]. …”

Section: The Delivery Of Estrogens and Progesteronementioning

confidence: 99%

Estrogens and progesterone as neuroprotectants: what animal models teach us

Singh

Sumien²,

Kyser

et al. 2008

Front Biosci

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Estradiol and progesterone are two steroid hormones that target a variety of organ systems, including the heart, the bone and the brain. With respect to the latter, a large volume of basic science studies support the neuroprotective role of estradiol and/or progesterone. In fact, the results of such studies prompted the assessment of these hormones as protective agents against such disorders as Alzheimer's disease, stroke and traumatic brain injury. Interestingly, results from the Women's Health Initiative (WHI) yielded results that appeared to be inconsistent with the data derived from in vitro and in vivo models. However, we argue that the results from the basic science studies were not inconsistent with the clinical trials, but rather, are consistent with, and may even have predicted, the results from the WHI. To illustrate this point, we review here certain in vivo paradigms that have been used to assess the protective effects of estrogens and progesterone, and describe how the results from these animal models point to the importance of the type of hormone, the age of the subjects and the method of hormone administration, in determining whether or not hormones are neuroprotective. KeywordsEstrogens; Progestins; Neuroprotection; Alzheimer's disease; Animal Models; Review INTRODUCTIONThe U.S. Census Bureau estimates that by 2010, the population of women between 45 and 64 years old will reach approximately 42 million, a marked increase from the value reported for 2000 (approx. 32 million) (U.S. Census Bureau. Projected population of the United States, by Age and Sex: 200 to 2050. www.census.gov/ipc/www/usinterimproj/Internet release date: March 18, 2004). This increasing number of women will consequently need to make decisions about the use of hormone therapy to treat not only menopausal symptoms, but potentially, to maintain a healthy brain. And though numerous basic science studies, epidemiological studies and some clinical trials have supported the potential benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction (including reducing the risk for Alzheimer's disease), recent results from the Women's Health Initiative (WHI) have suggested the contrary and left the field unsettled as to the future of hormone therapy. For example, caveats of the WHI (particularly the WHI memory study, WHIMS) include the possibility that both the age of the subjects and the duration of post-menopausal hormone deprivation diminish the protective brain response to steroid hormones. Additionally, the type of hormone (for example, While it is clear that a better understanding of the neurobiology of gonadal steroid hormones and their receptors is needed, it is equally important that we interpret the basic science studies appropriately, and understand their limitations if we are to apply the results from these studies towards the design of the next large-scale clinical trial or in fact, implement safer and more effective ways of treating the menopause and the post-menopausal period. To this end,...

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Modulatory effects of estrogen in two murine models of experimental colitis

Cited by 89 publications

References 61 publications

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

IL-13-Mediated Gender Difference in Susceptibility to Autoimmune Encephalomyelitis

Estrogens and progesterone as neuroprotectants: what animal models teach us

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