Estradiol Treatment Redirects the Isotype of the Autoantibody Response and Prevents the Development of Autoimmune Arthritis

Latham, Kary A.; Zamora, Alex; Drought, Heather; Subramanian, Sandhya; Matejuk, Agata; Offner, Halina; Rosloniec, Edward F.

doi:10.4049/jimmunol.171.11.5820

Cited by 98 publications

(51 citation statements)

References 52 publications

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“…Estrogen has known anti-inflammatory effects in models of arthritis (Badger et al, 1999;Latham et al, 2003), and those effects were also observed in this study with respect to paw swelling and circulating cytokine levels. In addition, weekly treatment with E also resulted in thymic involution and increased body weight loss compared with controls.…”

Section: Figsupporting

confidence: 66%

“…Estrogens, elevated during pregnancy, reduce inflammation in a mouse model of autoimmune arthritis (Latham et al, 2003) and in a rat model of adjuvant-induced arthritis (Badger et al, 1999). Relaxin (RLX), another hormone of pregnancy, remodels connective tissue (Unemori et al, 1993;Lenhart et al, 2001) and has been reported to play a role in wound healing (Unemori et al, 2000) and modulation of immune function (Piccinni et al, 1999).…”

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confidence: 99%

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Antiarthritic Effects of Relaxin, in Combination with Estrogen, in Rat Adjuvant-Induced Arthritis

Santora¹,

Rasa²,

Visco³

et al. 2007

J Pharmacol Exp Ther

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The incidence and severity of rheumatoid arthritis (RA) are reduced during pregnancy. Estradiol-17␤ and relaxin (RLX), hormones of pregnancy, are implicated in decreased immune responsiveness. The aim of this study was to determine the effects of estrogen and RLX, alone or in combination, on the development of adjuvant-induced arthritis (AIA) in ovariectomized (OVX) Lewis rats. Arthritis was induced on day 0 by adjuvant injection in the left hind paw. Rats were treated with estradiol valerate (E), porcine RLX, E ϩ RLX, or vehicle. Healthy OVX control animals were used for comparison. Treatment with RLX or E alone decreased adjuvant-induced inflammation in both the injected (primary) and noninjected (secondary) hind paws. Combined treatment with E and RLX was more effective than either hormone alone in blocking secondary paw inflammation. Furthermore, E plus RLX reduced changes to spleen and thymus weights induced by adjuvant injection. Both E and RLX alone decreased circulating tumor necrosis factor (TNF) ␣. The combination of E and RLX resulted in a greater decline in TNF␣ than treatment with either hormone alone. There was no effect of hormones on the proinflammatory cytokine, interleukin (IL)-1␤. The anti-inflammatory cytokine IL-10 increased in response to E and E plus RLX. In conclusion, combined therapy with E and RLX was more effective than either hormone alone in reducing chronic inflammation, joint changes, and high circulating TNF␣ associated with AIA in rats. Accordingly, these hormones could play a role in reducing RA-induced inflammation during pregnancy by an effect on the immune system.

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Section: Figsupporting

confidence: 66%

mentioning

confidence: 99%

Antiarthritic Effects of Relaxin, in Combination with Estrogen, in Rat Adjuvant-Induced Arthritis

Santora¹,

Rasa²,

Visco³

et al. 2007

J Pharmacol Exp Ther

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“…Most reports using IRA pellets sample for the levels of 17 β-E2 or P4 at the termination of the study [for example, see (49,(55)(56)(57)(58)], and only a few of these studies report levels of the ovarian hormones within or near physiologically relevant concentrations at that time (49,57). 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%

“…As such, the initial release of 17 β-E2 following implantation could have contributed to the observed uterine, vaginal and pituitary hyperplasia. Additionally, the few studies using mice that have measured 17 β-E2 concentrations as an end parameter have reported abnormal pharmacological responses (49) or strikingly high 17 β-E2 concentrations (53,54), even as long as 35 to 90 days after implantation of the pellets (55)(56)(57)(58).…”

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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“…1) In particular, endocrine-disrupting chemicals, which exert estrogenic activity, will be afraid to affect allergies because 17β-estradiol (E2) is considered to affect immune responses. [2][3][4] E2 has been reported to exert immunological effects in conditions such as menstrual asthma, 5) symptom changes in systemic lupus erythematosus, 6,7) and rheumatoid arthritis 8) during pregnancy. Human contact dermatitis, a type-I helper T cells (Th1)-type immune reaction, is severer in the ovulation phase than in the other menstrual cycle.…”

Section: Introductionmentioning

confidence: 99%

17.BETA.-Estradiol Enhances Interleukin-18 mRNA Expression after Sensitization of Mice with Contact Hypersensitivity

Sakazaki

Fujiyama

Ueno

et al. 2009

JOURNAL OF HEALTH SCIENCE

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To clarify the mechanism underlying the enhancing effect of 17β-estradiol (E2) on contact hypersensitivity (CHS) and the expression of interferon (IFN)-γ in mice, the mRNA expression levels of interleukin (IL)-18 were evaluated. Female BALB/c mice aged 3 weeks were ovariectomized, administered 3.2 µg of E2, and sensitized by 50 µl of 3% 4-ethoxymethylene-2-phenyl-2-oxazolin-one (OXA). Seven days later, CHS was elicited by the application of 7.5 µl of 1% OXA on the ear auricles. The auricles, cervical lymph nodes and spleens were excised, and gene expression was evaluated by reverse transcription-polymerase chain reaction. E2 enhanced the expression of IL-18 mRNA in the spleen on the following day and in the ear auricles on days 4 and 7 after sensitization with OXA. The preadministration of an antibody against IL-18 receptor suppressed the CHS and reduced IFN-γ mRNA expression in E2-administered mice. IL-18 was present in the dermis of the ear skin and absent in the epidermis. E2 also enhanced the expression of IFN-γ and IL-18 mRNAs in splenocytes cultured with lipopolysaccharide (LPS). IL-18 protein was detected by flow cytometry in CD4 + , CD8 + and NKG2 + lymphocytes among splenocytes cultured with LPS. These results suggest that E2 enhances lymphocyte activation in the sensitization phase of CHS, and that IFN-γ mRNA expression is enhanced in the elicitation phase of CHS.

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Estradiol Treatment Redirects the Isotype of the Autoantibody Response and Prevents the Development of Autoimmune Arthritis

Cited by 98 publications

References 52 publications

Antiarthritic Effects of Relaxin, in Combination with Estrogen, in Rat Adjuvant-Induced Arthritis

Antiarthritic Effects of Relaxin, in Combination with Estrogen, in Rat Adjuvant-Induced Arthritis

Estrogens and progesterone as neuroprotectants: what animal models teach us

17.BETA.-Estradiol Enhances Interleukin-18 mRNA Expression after Sensitization of Mice with Contact Hypersensitivity

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