Estrogen Impact on Autoimmunity Onset and Progression: the ...

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INTERNATIONAL TRENDS IN IMMUNITY VOL.1 NO.2 APRIL 2013ISSN 2326-3121 (Print) ISSN 2326-313X (Online) http://www.researchpub.org/journal/iti/iti.htmlII. ESTROGEN RECEPTORS IN IMMUNE CELLSIntracellular ERs are expressed in all immune celltypes [14, 15]. Particularly, our group has recentlydemonstrated the intracellular expression of bothERα and ERβ in T, B lymphocyte subsets, andperipheral NK cells [16]. The ERα46 isoformappeared to be the most represented ER inlymphocytes without significant differences amonglymphocyte subsets. Although ERβ was expressed inall lymphocyte subsets, our data suggest a lowerexpression level of this receptor with respect toERα46.The typical physiological level of E2 is extremelylow, in the range of 10–900 pg/ml, and it varies basedon the age and physiological status of the individual(i.e., E2 levels are typically less than 100 pg/ml, butjust before ovulation they spike to 800 pg/ml, andduring the third trimester of pregnancy vary from 0.5to 140 ng/ml) [17]. E2 can produce different effectsdepending on its concentration but also on the type oftarget cell, the receptor subtype present on a givencell type, and the timing of administration. Table Isummarizes the most important effects of high andlow concentrations of E2 on different types ofimmune cells. In brief, at pregnancy levels, E2inhibits pro-inflammatory pathways such as TNFα,IL-1β, IL-6, and activity of natural killer (NK) cells,whereas E2 at the same concentration stimulatesanti-inflammatory pathways such as IL-4, IL-10, andTGFβ [2]. Additionally, it enhances the number andfunction of CD4+CD25+ regulatory T cells [18, 19].Surprisingly, no direct effect of E2 on Th17 cells orIL-17 production has been described in humans untilnow, whereas conflicting results have been reportedin animal models where E2, at high concentrations,either enhances [20] or decreases [21] IL-17production. At lower concentrations, E2 stimulatesTNFα, IFN-γ, IL-1β, and activity of NK cells [2].Differently, E2 stimulates antibody production by Bcells throughout the concentration range [2].Regarding cell surface expression of ERs on humanlymphocytes, previously reported data, obtainedusing E2 covalently bound to bovine serum albumin(BSA)-FITC, indicated that an estrogen bindingprotein exists on the plasma membrane of humanlymphoblastoid B cells [22]. More recently, by usingepitope-binding technologies, we demonstrated thecell surface expression of a functionally activeERα46 isoform, but not of ERβ, on lymphocytes,supporting the idea that E2 level fluctuations may beassociated with a prompt lymphocyte response [16].In particular, E2-BSA significantly increased CD4+and CD8+ T lymphocyte proliferation in response toanti-CD3 monoclonal antibody and IFN-γ productionby NK cells. Further studies are needed to a betterdefinition of mER expression and its signaltransduction pathway in different lymphocytesubpopulations. In this regard, the development of anovel transgenic mouse in which mER-signaling isblocked [23] may be helpful to elucidate how mERsignaling contributes to the transcriptional functionsof intracellular ERs and could lead to identify therapid ER signaling pathway as a potential target fornovel therapeutic agents.TABLE IESTROGEN EFFECTS ON IMMUNE CELLS↑, indicates stimulation by E2, ↓ indicates inhibition by E2III. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)Sex hormones, including estrogens, have beenproposed to play an important role in autoimmunity,[14, 24-26], although the precise mechanisms bywhich estrogens modulate the cellular and molecularprocesses that govern immune homeostasis are far tobe fully elucidated. A prototypic autoimmunedisease is SLE which is a multifactorial and highlypolymorphic systemic AD with a higher incidence inwomen than man [27]. Pre-menopausal women haveSLE incidence rates of 9:1 when compared toage-matched males [28]. These rates decline to 5:1after menopause. In the pre-adolescent population,where estrogen levels are more similar betweengenders, females have SLE with a frequency of 3:1when compared to males.25
INTERNATIONAL TRENDS IN IMMUNITY VOL.1 NO.2 APRIL 2013ISSN 2326-3121 (Print) ISSN 2326-313X (Online) http://www.researchpub.org/journal/iti/iti.htmlSLE affects multiple organs, including skin, muscle,joints, and vital internal organs, such as kidneys andheart. Despite the number of studies reported so far,the etiology of SLE remains unknown. However, it islikely that the complex interaction between genetic,environmental (e.g., infectious agents, UV light,drugs), and hormonal factors promotes the immunedysfunction underlying the pathogenesis of thedisease [29, 30]. SLE is characterized byautoantibody production by dysregulated B cells,target organ infiltration by inflammatory T cells, andaberrant immune cell activation due to abnormalantigen presenting cell function. Theautoantigen-autoantibody interaction triggers theformation of immune complexes that, once deposited,cause tissue injury. In particular, immune complexes,containing autoantibodies against DNA andribonucleoproteins, activate Toll like receptors(TLR)7 and TLR9 on dendritic cells and B cells, andthis event leads to enhanced autoantibody productionand IFN-α secretion, which is suggested to be keymodulator in the pathogenesis of SLE [31].As stated above, the incidence of SLE increases afterpuberty and flares are more common during thepre-menstrual period and pregnancy, time frameswith increased estrogen levels. Additionally, thedisease is more prevalent in some ethnic groups, suchas Afro-Americans and Asians. Interestingly,estrogen levels were shown to be higher in Asian(Japanese) and African (Bantu) women than inCaucasian women [32]. This evidence implies animportant role of estrogens in SLE pathogenesis butthe mechanisms involved have not been fullyelucidated [33, 34].IV. ESTROGENS AND ERs IN SLEIn vitro studies revealed that lymphocytes from SLEpatients exhibit an increased sensitivity to E2 [33]. Asummary of in vitro effects of E2 on lymphocytesfrom SLE patients is reported in Table II. It isimportant to underline that all the studies describedbelow were performed with physiological E2concentrations. E2 in vitro enhanced total IgGproduction as well as anti-dsDNA autoantibodyproduction in SLE patients by promoting B cellactivity and by increasing IL-10 production inmonocytes [35]. Autoantibodies were not secreted byB lymphocytes from healthy donors treated in thesame way [35]. Additionally, mRNA expression ofthe T cell activation markers calcineurin and CD154were up-regulated by E2 in SLE but not in normal Tcells through both ERα and ERβ [36-39]. Calcineurinand CD154 mRNA expression was alsodown-regulated in SLE patients treated with the ERantagonist Fulvestrant (Faslodex) in associationwhich a reduction of disease activity [40].Interestingly, although E2 induced ERKphosphorylation in a wide variety of cell types, itsuppressed ERK activation in activated T cells frompatients with inactive or mild disease but not frompatients with active disease [41]. WhetherE2-dependent dampening of ERK signalling isimportant for maintaining inactive disease remains tobe elucidated. E2 was also found to inhibits apoptosisin activated T cells, this favouring the persistence ofautoreactive clones [42]. On the other hand, Rastin etal. [43] showed that E2 increased the mRNAexpression level of FasL and caspase-8 in resting Tlymphocytes.More recently, E2 has been found to alter differentsignaling pathways in SLE T cells, that areassociated with disease onset and progression,including IFN-α signaling [44]. A further potentialmechanism of action of E2 in SLE pathogenesis hasbeen suggested by Young et al. [45] who found thatthe signaling and transcription molecule ZAS3,which is involved in regulating inflammatoryresponses, was overexpressed in peripheral bloodmononuclear cells (PBMC) from SLE patients and itwas up-regulated by E2. E2 induction of ZAS3requires ERα. Intriguingly, ZAS3 and E2 both targetNFκB and lead to its functional repression, just asobserved in SLE [46]. The expression of ER has beeninvestigated in T cells from SLE patients todetermine whether the hyper responsiveness of SLElymphocytes to E2 could be ascribed to differences inER levels. No alterations in the expression of ERα orERβ (both at mRNA and protein levels) weredetected in SLE [39, 47, 48], although ERα proteinwas found to exhibit a greater degree of variationthan that in control T cells [39].The contributions of microRNA (miRNA) topathogenesis of SLE are beginning to be uncovered[49]. miRNAs are short (19–24 nucleotides in length)non-coding RNAs that regulate messenger RNA(mRNA) or protein levels either by promotingmRNA degradation or by attenuating proteintranslation. Evidence suggests that estrogens may26
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