Download Catecholoestrogens: possible role in systemic lupus erythematosus

Rheumatology 2009;48:1345–1351
Advance Access publication 3 August 2009
doi:10.1093/rheumatology/kep168
Review
Catecholoestrogens: possible role in systemic lupus erythematosus
Wahid Ali Khan1, Moin Uddin2, Mohd. Wajid Ali Khan3 and Harvinder S. Chabbra4
It is well established that risk of developing SLE is higher among women compared with men but only very little is understood about the
underlying mechanisms. Oestrogen and their catechol metabolites seem to play an important role in SLE but the exact patho-aetiology
remains elusive. The evidences concerning the possibility of catecholoestrogens (CEs) in the development of SLE are very limited and
preliminary. The possible mechanism involves quinone–semiquinone redox cycling of CEs to generate the free radical that can cause DNA
damage. This would probably alter its immunogenicity leading to the induction and elevated levels of SLE autoantibodies cross-reacting with
native DNA. The data demonstrate the possible role of CE in presenting unique neo-epitopes that might form one of the factors in induction of
SLE autoantibodies. However, the role of oestrogen in immune modulation cannot be rule out as a mediator of various immune-related
diseases.
KEY
WORDS:
Catecholoestrogen, Systemic lupus erythematosus, Autoantibodies, Reactive oxygen species, Catecholoestrogen-modified DNA.
quinone [13]. In females, significantly higher concentration of
glutathione (GSH) conjugates resulting from reaction of GSH
with the 4-OHE2/E2-quinones were detected in the non-tumour
tissue from females with breast cancer as compared with controls
[14]. In addition, oestrogen 4-hydroxylase level had a higher
expression in the breast tissue of women with breast cancer as
compared with the expression of protective enzyme [15].
Previous study showed a link between genetic polymorphism in
oestrogen 4-hydroxylase and a risk for developing breast cancer
[16]. Microsomes obtained from tumour tissues predominantly
catalysed 4-hydroxylation, whereas those from normal tissues
comparable oestradiol 2- and 4-hydroxylase activities were
observed [17]. As previously described, oestrogen may be oxidized
by hepatic cytochrome P450 enzyme (mainly CYP 1A1 and CYP
1B1) to hydroxy CEs and further oxidized to the semiquinone and
quinone form [18]. The quinone formed from 4-hydroxyoestrogen
has half-life of 12 min as compared with the short life of
2-OHE2 (t1/2 ¼ 47 s) [19], whereas, the quinone formed from
4-hydroxyequilenin (4-OHEN) is much more stable (t1/2 ¼ 2.3 h)
than the endogenous CE [20]. It has been observed that adjacent
aromatic ring stabilizes 4-OHEN-quinone through extended
-conjugation. In view of this, it has been demonstrated that the
catechol metabolite of benzo[a]pyrene rapidly undergoes air
oxidation to yield a very stable quinone, benzo[a]pyrene-7,
8-dione [21].
A role for oestrogen in the pathogenesis of SLE has been
suspected for many years but the exact patho-aetiology remains
elusive. We herein review information pertaining to the possible
role of CE in the pathogenesis of SLE. The central hypothesis of
this review is that CEs formed in different tissue undergo oxidative
metabolism to produce reactive oxygen species (ROS), which
could cause damage in DNA. This would probably alter its
immunogenicity leading to the induction and elevated levels of
SLE autoantibodies cross-reacting with native DNA. In addition,
our data strongly suggest that CE appears to play an important
role in antigen-driven induction of SLE autoantibodies [22, 23].
Introduction
Sex hormones play an important role in the genesis of autoimmunity [1]. These hormones (oestrogens and their metabolites)
are presumed to contribute to sexual dimorphism in the immune
system. The presence or absence of oestrogen is implicated in the
aetiology and pathogenesis of multiple diseases including breast
and reproductive cancers, osteoporosis, coronary heart disease
and systemic lupus erythematosus (SLE). SLE is a complex,
chronic autoimmune disorder that is aetiologically multifactorial
with both genetic and environmental factors contributing to
disease initiation and progression [2].
The principal oestrogens in women (oestradiol and oestrone)
undergo oxidative metabolism through hydroxylation at various
sites, including 2- and 4-hydroxylation, leading to the formation
of catecholoestrogen (CE, Fig. 1) [3, 4]. Studies have shown that
constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)inducible P450 isozymes (P450 1A1/1A2 and P450 1B1), selectively catalyse hydroxylation at the 2- and 4-positions of oestrone
and 17 -oestradiol (E2) [5, 6]. 2-Hydroxylation is the major
oxidative pathway, catalysed mainly by CYP 1A2 in the liver [7]
and by CYP 1A1 in endometrium [8]. 4-Hydroxyoestrone/
oestradiol was found to be carcinogenic in the male Syrian
golden hamster kidney tumour model, whereas 2-hydroxylated
metabolites were without activity [9]. Previous study has shown
that 4-hydroxyoestradiol (4-OHE2) induced uterine tumours in
66% of CD-1 mice, whereas mice treated with 2-hydroxyoestradiol or 17 -oestradiol had much lower uterine tumour
incidence [10]. The possible mechanism involves o-methylation
of 2-hydroxyoestradiol to 2-methoxyoestradiol, which is a
potent inhibitor of tumour cell proliferation and has antiangiogenic effects [11]. Animal model produced a contradictory
result with the ACI rat model for mammary carcinogenesis [12].
In contrast, DNA adducts of CE quinone have been detected in
the mammary gland of ACI rats treated with 4-OHE2 or its
1
Department of Clinical Biochemistry, College of Medicine and Medical Science,
King Khalid University, Abha, KSA, 2Department of Biochemistry, Faculty of
Medicine, J. N. Medical College, A. M. U. Aligarh, India, 3Department of
Biochemistry, Faculty of Medical Sciences, Al-Gomail, University of 7th of April,
Zawia, Libya and 4Indian Spinal Injuries Centre, Vasant Kunj, India.
CE and DNA damage
Studies of oestrogen metabolism, formation of DNA adducts,
carcinogenicity, cell transformation and mutagenicity have led
to the hypothesis that reaction of certain oestrogen metabolites,
predominantly CE-3,4-quinone, with DNA can generate the
critical mutations initiating different types of cancer [3, 13, 24].
They can undergo redox cycling with the semi-quinone
Submitted 22 January 2009; revised version accepted 21 May 2009.
Correspondence to: Wahid Ali Khan, Department of Clinical Biochemistry,
College of Medicine and Medical Science, King Khalid University, Abha, KSA.
E-mail: [email protected]
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ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
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Wahid Ali Khan et al.
FIG. 1. Oestrogen catabolism by different enzymes (CYP1A1, CYP1A2,
CYP1B1, COMT and GSTs) and CEs formation. E1, oestrone; E2, oestradiol;
2-OH E1 (E2), 2-hydroxyoestrone (oestradiol); 4-OH E1 (E2), 4-hydroxyoestrone
(oestradiol); 2-MeO E1 (E2), 2-methoxyoestrone (oestradiol); 4-MeO E1 (E2),
4-methoxyoestrone (oestradiol). Reprinted from [4] with permission from the
American Association for Cancer Research, Inc.
radical, generating superoxide radicals mediated through P450
reductase [3]. The oestrogens are biochemically interconvertable
in different form by enzyme 17 -oestradiol dehydrogenase. These
oestrogens are metabolized via two major pathways, i.e. formation of CEs and to a lesser extent, 16 -hydroxylation. The
catechols formed are the 2- and 4-hydroxylated oestrogens
(Fig. 2) [25]. Generally, these two catecholoestrogens can be inactivated by the enzyme catechol-o-methyltransferase (COMT)
through o-methylation [26]. Other possible mechanism of inactivation includes the conjugation of CE by glucouronidation and
sulphation. Excessive production of 4-hydroxylated metabolites
caused insufficient production of methyl, glucouronide or
sulphate conjugate which in turn results in CE toxicity in cell
and consequently competitive catalytic oxidation to semiquinone
(CE–SQ) and quinone (CE–Q). CE–SQ and CE–Q may conjugate
with GSH, catalyse by S-transferase. If this inactivating process is
incomplete, CE-Q may react with DNA to form stable and
de-purinating adduct [13].
Various free radical toxicities have been reported in
hamsters treated with E2 including DNA single-strand breaks
[27], 8-oxo-20 -deoxyguanosine (dG) formation [28] and chromosomal abnormalities [29]. Recently, it has also been shown that
4-hydroxyoestradiol also induces oxidative stress and apoptosis in
human mammary epithelial cells (MCF-10A) [30]. We have shown
FIG. 2. Oestrogen metabolism and DNA adducts formation. Reproduced from [112] by permission of Oxford University Press.
Role of catecholoestrogen in SLE
that 4-OHE2 is also capable of causing DNA single-strand breaks
and oxidative damage to DNA bases in vitro [31, 32]. Finally,
a recent study evaluated the potential of HRT to induce DNA
damage in peripheral blood leucocytes of post-menopausal
women using the comet assay [33]. Our results demonstrate
that CE leads to the production of patent ROS, capable of causing
DNA damage, thus playing an important role in carcinogenesis [31].
In order to see the genotoxic effect of CE-Q, they were
reacted with the nucleosides 20 -deoxyguanosine (dG) and
20 -deoxyguanosine (dA) and the nucleobase adenine [34]. The
major DNA adducts produced from 4-hydroxyoestradiol-oquinone are depurinating N 7-guanine and N 3-adenine adducts
resulting from 1,4-Michel addition both in vitro and in vivo
[35, 36]. It is interesting to note that N 3-adenine adduct
is likely to induce mutation since this adduct takes hours
to hydrolyse [37]. Considerably more rapid isomerization
of 2-hydroxyoestradiol-o-quinone to corresponding quinone
methides (QM) results in 1,6-Michael addition products with
exocyclic amino groups of adenine and guanine [38]. A depurinating N 3-adenine adduct of 2-hydroxyoestradiol QM has been
recently reported in reaction with adenine and guanine [36]. The
reaction of the CE 3,4-Q with dG at the N-7 position destabilizes
the glycosidic bond and results in loss of the deoxyribose moiety.
When the adduct is formed, it is released from the DNA by
spontaneous depurination. It has been observed that reaction
of E2-3-4-Q with dA produced no adducts, while reaction of
E2-3-4-Q with Ade resulted in the formation of 4-OHE2-1-N3
Ade [34]. This adduct was formed only with Ade because in dA
the adjacent deoxyribose bound to N-9 impedes the approach
of the electrophile E2-3-4-Q to N-3 [39]. This interference is not
present in DNA, as observed by formation of PAH-N3 Ade
adducts, which are rapidly lost from the DNA by depurination
[39, 40]. Oligonucleotides containing site-specific adducts
transfected in simian kidney cells has been used to see mutagenic
properties of 2-hydroxyoestrogen derived stable DNA adducts
where G!T and A!T mutations were observed [41]. It is
interesting to note that stable DNA adducts have been detected
by 32P-postlabelling in Syrian hamster embryo cells treated with
oestradiol and its catechol metabolites [42]. The order in which the
oestradiol and its catechol metabolites can be categorized according to the DNA adduct formation was 4-OHE2 > 2-OHE2 > E2.
Finally, mutagenic adducts of CE corresponding to alkylation of
guanine have been detected in human breast tumour tissue [43].
As mentioned above, oestrogens are metabolized by cytochrome P450 enzymes and form hydroxylated products [3]. The
main metabolites of E2 include 2-, 4- and-16 -hydroxyoestradiol
[3, 44]. The 2- and 4-hydroxylated catechols contain the hydroxyl
groups, which predisposes them to further oxidation. Both can
be oxidized to semiquinones and quinones with formation of
superoxide anion radicals (O2) [45]. These O2 readily dismutated to H2O2 either spontaneously or even faster when catalysed
by superoxide dismutase. H2O2 is neutral but it may result in
the formation of hydroxyl radicals [46]. However, as a neutral
molecule, H2O2 can readily cross the cellular and nuclear
membrane and reach DNA where it can cause oxidation of
bases [47]. COMT prevent oxidation of CE to SQ by methylating
2- or 4-hydroxyl group. Moreover, 4-hydroxyl group of CE is not
as readily methylated as is the 2-hydroxyl group, which can
cause predominance of 4-OHE2 in redox cycling and inactivation
of 2-OHE2 by methylation [48].
CE and its immunology
Sex hormones are presumed to contribute to sexual dimorphism in
the immune system. These are implicated in immune response that
can mediate humoral response [49]. In fact, at physiological doses,
oestradiol induces IL-1, a cytokine that can initiate a cascade of
other cytokines, chemotactic and growth factors [50]. In addition,
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oestradiol also inhibits IL-1-induced IL-6 production, which
not only results in increased human epithelial cell proliferation
(a process important in tumour growth) but also inhibits the
activity of natural killer cells, thus allowing tumour growth [51].
Oestradiol also mediates macrophage proliferation and decreases
cell differentiation [50].
Despite a large number of reports that may explain the role
of oestrogen (or oestradiol) in modulation of immune response
[49–51], the role of CE in the immune response is lacking. In view
of this, we have in our earlier report showed that the CE-modified
DNA (CE-DNA) was highly immunogenic (>1:25 600) in experimental animals [31]. These antibodies were effectively used as
a probe for detecting oxidative lesions in human genomic DNA
as well as for the estimation of 8-hydroxy-20 -deoxyguanosine
(8-OHG) level in the urine of cancer patients [31]. In competition
ELISA, these antibodies showed strong preference for the
CE-DNA (immunogen) causing 92% inhibition in antibody
binding at 20 g/ml of the immunogen (competitor) concentration. Fifty percent inhibition was observed at 3.75 g/ml of
the immunogen. In addition, the antibodies also showed a high
degree of binding towards CE-modified forms of guanine,
thymine, human and calf thymus DNA, ROS-DNA, 8-OHG,
etc. It is important to note that CE-DNA was not only recognized
by cancer autoantibodies [31] but also by anti-DNA autoantibodies in SLE [22, 23]. Data from our laboratory suggest that
CE are likely to contribute to the generation of antibodies
which may directly or indirectly affect the immune system.
Oestrogen is metabolized into several different post-oestrogen
hormones, namely 2-hydoxy, 4-hydroxy and 16-hydroxyestrogens
[3]. Research has shown 4-hydroxy and 16-hydrxyestrogen to be
powerful growth and inflammation promoters, especially in
oestrogen-sensitive tissues such as the uterus, cervix and prostate
[52]. On the other hand, 2-hydroxyestrogens have shown to be
powerfully protective of those same tissues helping to prevent
cancer and elevated prostate specific antigen (PSA) from prostate
tissue [53].
Oestrogen causes macrophage proliferation and activation and
in turn, macrophages produce oestrogen, which may act on other
phagocytic cells. On stimulation, macrophages produce oxidants
(such as O2 and H2O2) by a reduced nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase catalysed reduction
of molecular oxygen. In addition, macrophages also synthesized
inducible nitric oxide synthase and mediate production of nitric
oxide (NO). O2 and NO may rapidly interact, with the generation of peroxynitrite, a much more potent oxidant [54]. Hence,
macrophage activation may lead to ROS and reactive nitrogen
species (RNS) production, which may cause DNA base hydroxylation, oxidation, nitration and deamination [55, 56]. Oestrogen
not only causes macrophage proliferation and activation but also
affects the function of PMNs (polymorphonuclear leucocytes,
neutrophils and granulocytes), which is also responsible for the
production of ROS on their stimulation. PMNs express myeloperoxidase, an enzyme that catalyses oxidation of chloride ions
by H2O2 to hypochlorite/hypochlorous acid (HOCl/OCl) [47].
This reaction is catalysed by myeloperoxidase released from
PMNs during activation process. Oestrogens and some of their
metabolites may induce myeloperoxidase release from the resting
(inactivated) cells and stimulate generation of oxidants in
the absence of pathogens [56]. It is interesting to note that
2-hydroxylated oestrogens act as powerful inhibitors of
PMNs activity, thereby one of the protective properties of the
2-hydroxylated CE. Therefore, oestrogens affect inflammatory
response and in turn, their activities are affected by the inflammation products.
SLE
Female hormones promote humoral autoimmunity. Sex hormone
expression is different in patients with SLE than in healthy
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Wahid Ali Khan et al.
controls [58]. High concentration of biologically potent oestrogens
cause SLE patients to circulate more self-reactive lymphocytes
that bypassed development deletion. SLE is a multisystem
autoimmune disease characterized by production of autoantibodies against many different autoantigens, typically including nucleic acid and associated protein [59]. Significant health
consequences include renal failure, vasculitis, thrombosis, seizures
and other neurological complications [60]. The disease activity
also considered as a major factor associated with menstrual
cycle disorders in the patients [61]. Almost all autoimmune
diseases are more common in women, but the female predominance in SLE is particularly strong. Of the patients 585% with
SLE are women [62]. The central immunological disturbance in
patients with SLE is autoantibody production. These are directed
at several self-molecules found in nucleus, cytoplasm and cell
surface [63]. In addition, autoantibodies are also directed against
platelets, lymphocytes, polysaccharides [64], phospholipids [65],
cell membrane structure [66] and nucleoproteins (DNA-histone,
nuclear ribonucleoproteins like Sm and Mo, and cytoplasmic ribonucleoproteins) [67]. The most remarkable feature of anti-DNA
antibodies is their association with glomerulonephritis. Anti-DNA
antibodies can be isolated in an enriched form from glomerular
eluates of patients with active lupus nephritis and these antibodies
can induce nephritis in normal and immunodeficient mice [68].
Anti-DNA antibodies differ in their properties, including isotype,
ability to fix complement and capacity to bind to the glomeruli
causing pathogenicity [69]. Only certain types of anti-DNA antibodies are pathogenic [70]. First, clinical observation in most
patients indicates that active nephritis is associated with raised
anti-DNA antibody titres and reduced total haemolytic complement values [71]. Secondly, anti-DNA antibodies show preferential deposition in the kidneys, suggesting that DNA–anti-DNA
antibody immune complexes are the main mediators of inflammation [72]. In addition, antibodies against CE-modified DNA
have been detected in SLE patients [22, 23]
SLE is characterized by a myriad of immune system aberrations
that involve B cells, T cells and cells of the monocytes lineage,
resulting in polyclonal B-cell activation, increased number of
antibody producing cells, hypergammaglobulinaemia, autoantibody production and immune complex formation [59]. The
activation of B- and T cells requires stimulation by specific
antigens. Chemicals such as pristine, bacterial DNA and cell
wall phospholipids and viral antigens can induce anti-DNA
antibody production in mice [70]. Moreover, self-antigens, such
as DNA–protein and RNA–protein complexes may induce autoantibody production [73]. B-cell activation is abnormal in patients
with SLE. The number of B cells at all stages of activation is
increased in the peripheral blood of patients with SLE [74].
These B-cell abnormalities can precede the development of SLE.
Activated lupus B cells have higher intracytoplasmic calcium
responses than controls [75]. There is also evidence that B cells
in patients with SLE are more sensitive to the stimulatory effects
of cytokines such as IL-6 than non-SLE B cells [76]. Moreover, the
phenomenon of epitope spreading has been demonstrated in both
human and murine SLE [77]. Abnormalities in T-cell function are
also evident in patients with SLE. The total number of peripheral
blood T cells is usually reduced, probably because of the effects
of anti-lymphocyte antibodies [78]. There is a skewing of T-cell
function towards B cell help, leading to enhanced antibody
production [76]. Experiments have shown that the early events
of T-cell activation are defective in patients with SLE compared
with controls [79]. Down-regulation by excessive Th 2 cytokines,
defective interaction between APCs and T cells, the suppressive
effects of CD8þ T cells and natural killer (NK) cells, the presence
of IL-2 inhibitors and the down-regulation of IL-2 receptor are
possible mechanisms [80].
Many cytokines have been implicated in regulating disease
activity and in the involvement of different organs in patients
with SLE [81]. Lupus T cells are less responsive to IL-2 stimulation than normal T cells [82]. However, the expression of IL-2 in
freshly prepared SLE peripheral blood mononuclear cells
(PBMCs) was increased compared with control PBMCs [83].
Lupus T cells are capable of producing normal amount of IL-2
in response to optimal stimulation with phytohaemagglutin
combined with phorbol esters or with anti-CD28 antibodies [84].
IL-10 played an important role in the pathogenesis of SLE. Earlier
studies have shown that spontaneous production of IL-10
from SLE peripheral blood B cells and monocytes is significantly
higher than controls [85]. The expression of IL-10 transcripts was
significantly increased in the non-T-cell population of PBMCs
from patients with SLE compared with controls [86]. Moreover,
serum IL-10 concentration is higher in patients with SLE than in
controls and is correlated with clinical and serological disease
activity and anti-DNA antibody titres [87]. Similarly, IL-12
production was found to be impaired in stimulated PBMCs
from patients with SLE compared with match controls [88].
IL-12 promotes cell-mediated immune responses but exerts some
inhibitory activities on humoral responses [89]. The results from
these studies suggest that dysregulation of the IL-10/IL-12 balance
play a crucial role in the impaired cellular immune responses
seen in patients with SLE.
Defective immune regulatory mechanisms, such as the clearance of apoptotic cells and complexes, were important contributors to the development of SLE [59]. MRL/Ipr mice are
characterized by the presence of the Ipr gene, which is associated
with Fas (CD95) receptors on the surface of lymphocytes.
The interaction of Fas and Fas ligand (Fas L) transduces an
active signal for cellular apoptosis [90]. Defective Fas-mediated
apoptosis in MRL/Ipr mice results in massive lymphoproliferation
and the development of a severe lupus-like disease with immune
glomerulonephrities [91]. Gld/gld mice, characterized by a mutation in the Fas L gene leading to a non-functional Fas L molecule,
also develop lymphoproliferation, hypergammaglobulinaemia
and immunoglobulin deposits in the kidney [92]. Patients or
mice with homozygous C1q deficiency develop autoantibodies
and lupus-like syndrome apparently because of the inability to
eliminate apoptotic cells effectively, which leads to an increase
in the exposure of antigens to the immune system [93]. Mice
with a targeted deletion of C1q show glomerulonephritis with
deposits of immune complexes and apoptotic cells in the glomeruli.
In addition, environmental factors, such as chemicals and
drugs, UV light, dietary factors, viruses and oestrogen are
probably required to participate at the onset of the disease [94].
Role of CE in the aetiopathogenesis of SLE
Oestrogen (mainly 17-oestradiol, oestradiol) and their metabolites seem to play an important role in SLE and autoimmune
rheumatic disease [95]. A role for oestrogens in the pathogenesis
of SLE has been suspected for many years [96]. SLE is 9 times
more common in women than in men and 15-times more common
during the childbearing years. Patients with Klinefelter’s syndrome (i.e. males with 47 chromosomes and an XXY complement
by karyotype analysis) are hyperoestrogenic and have an increased
incidence of SLE [96]. Studies have revealed an abnormal pattern
of oestrogen metabolism among SLE patients whereby the
16-hydroxylation pathway is used as the major catabolic route
[95, 98–100]. This pathway generates metabolic intermediates
that function as reactive haptens capable of forming covalent
adducts with epsilon amino groups of lysine residues via a
Heyns-type rearrangement [101]. These conjugated products are
thought to elicit the production of anti-oestrogen antibodies.
Numerous case reports may be found in the literature demonstrating an association between the administration of certain synthetic
oestrogens which are largely catabolized by the 16-hydroxylation
Role of catecholoestrogen in SLE
route, e.g. ethyl-oestradiol and the onset of a drug-induced
lupus-like syndrome [98, 102].
Metabolism of oestrone and oestradiol to hydroxylated end
product is also a modifiable process. The ratio of high to
low-potency oestrogen is 20-fold higher among patients with
SLE than among healthy controls. CYP1A1 hydroxylate oestrogens into biological effectors of low potency (2-hydroxyoestrone).
Greater CYP1A1 activity results in less available oestradiol for
metabolism into high potency forms (16 -hydroxyoestrone).
CYP1A1 is an inducible enzyme [103]. Enzyme induction occurs
in the presence of indole-3-carbinol, an organic compound
found in cruciferous vegetables and omega-3-fatty acids. These
two dietary factors have proved to be preventive in the development of ER-positive adenocarcinoma of breast, another condition
with SLE-like ratios of high to low potency oestrogen [103, 104].
Indole-3-carbinol is currently under investigation for its diseasemodifying potential of SLE. In addition, patients with SLE
metabolize oestrogen in patterns that are distinct from those
observed in unaffected controls. Cytochrome P450 isoenzymes
CYP1B1 and CYP1A1 convert oestradiol to the biologic effectors
16 -hydroxyoestrone and 2 -hydroxyoestrone, respectively.
16 -Hydroxyoestrone is among the most biologically active
serum oestrogens with immunomodulatory effect. It activates B
and T cells, induces transcription and promotes cell division.
In contrast, the 2-hydroxy product has little biologic effect
[103]. Patients with SLE have increased activity of CYP1B1,
with preferential hydroxylation of oestradiol to the more feminizing 16-hydroxy metabolite [58, 105]. The altered conversion
results in a 20-fold increase in the fraction of high- to low-potency
oestrogen in patients with SLE when compared with healthy
control [105].
16-Hydroxyoestrone is a mitogenic and proliferative endogenous hormone that covalently binds to the oestrogen receptor
leading to nuclear translocation [106]. Conversion products of
oestrone and oestradiol are the 2-hydroxylated oestrogens such
as 2-hydroxyoestrone and 2-hydroxyoestradiol. In contrast to
16-hydroxylated oestrogens, the 2-hydroxylated forms inhibit
growth-promoting effect of oestradiol [107]. The study shows
that urinary concentrations of the 2-hydroxylated oestrogens
were 10 times lower in patients with RA and SLE than in
healthy controls, whereas the ratio of 16-hydroxyoestrone/
2-hydroxyoestrogens was 20-times higher in RA and SLE than
in controls [95]. Inspite of that, Weidler et al. [94] showed that
disease activity in SLE was negatively correlated with urinary
concentration of 2-hydroxylated oestrogen. In a patient with
RA and SLE, the magnitude of conversion to the mitogenic
16-hydroxyoestrone is greatly up-regulated, which likely contributes to maintenance of the proliferative state in these diseases.
Elevated serum concentrations of 16-hydroxyoestrone have been
described in patients with SLE [98], suggesting that abnormal
patterns of oestradiol metabolism may lead to increased oestrogenic activity. Similarly, there was a significantly higher concentration of 16-hydroxyoestrone/4-hydroxyoestradiol in the synovial
fluids of patients with RA as compared with control fluids [108].
The alterations in oestrogen metabolism have been reported in
both male and female patients [109, 110]. Peripheral oestrogen
hydroxylation found to be increased in both men and women
with SLE and oestrogenic metabolites were reported to increase
B-cell differentiation and activate T cells [111].
Oestradiol was found to increase IgG and IgM production by
PBMCs from patients with SLE which led to elevated levels of
polyclonal IgG, including IgG anti-double strand DNA, by
enhancing B-cell activity via IL-10 [112]. To have a better insight
into the possible role of CE in the aetiopathogenesis, we have
demonstrated that CE-modified DNA was highly recognized
by SLE IgG [22, 23], indicating the possible participation of
modified DNA in SLE pathogenesis as it has been reported that
CE-modified DNA bases cause DNA strand breakage and adduct
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formation in vivo and in vitro [113]. Hydroxylated metabolites of
oestrogen have been detected in tissue, blood, bile and urine
in humans [3]. The spontaneous production of anti-DNA autoantibodies in SLE might arise as a consequence of antigenic
changes in DNA. Therefore, it could be possible that CE-modified
bases of DNA might be one of the contributing factors towards
the production of autoantibodies. In addition, oestrogen not only
induces ROS production, but also modulates immune response
and immune-mediated disease [50]. It might be possible that
oestrogen causes T- and B-cell differentiation and increases
immunoglobulin production. These autoantibodies could be
more strongly bound with modified DNA than native polymer.
These studies show that hydroxylated oestrogen might have a
role in the aetiopathogenesis of SLE and other autoimmune
diseases.
Conclusion
It is well appreciated that oestrogen has profound influence on
numerous tissues and in the development of various autoimmune
diseases. It has become increasingly accepted that we must not
only consider the parent oestrogens, oestradiol and oestrone,
when we evaluate disease risk (autoimmune disease) but also the
oestrogen metabolites (2- and 4-hydroxylated metabolites) should
be taken in consideration. The CE metabolites, when oxidized to
the electrophilic CE-Q, may react with DNA to form stable
and depurinating adducts. The 4-CE that form predominantly
depurinating adducts are carcinogenic, whereas the noncarcinogenic 2-CE exclusively form stable DNA adducts.
Oxidation of CE also leads to overwhelming amount of ROS
that generate extensive DNA damage, alter its immunogenicity,
thus leading to the induction and elevated levels of SLE
autoantibodies. Therefore, it could be possible that CE-modified
bases of DNA might be one of the contributing factors towards
the production of SLE autoantibodies.
The risk of developing SLE is higher among women compared
with men. The role of oestrogen may provide a partial explanation
for the aetiology of SLE but many questions remain. Females
exhibit higher levels of serum IgG than males and mount
a more vigorous humoral immune response [114]. PBMCs derived
from patients with SLE, when treated with oestrogen undergo
polyclonal activation, secrete anti-DNA IgG and display diminished apoptosis [115]. In addition, oestrogen not only induces
ROS production but also modulates immune response and
immune-mediated diseases. It might be possible that oestrogen
causes T- and B-cell differentiation and increases IgG production.
These autoantibodies could be strongly bound with DNA and
serve as an immunochemical marker for the diagnosis of this
disease.
The preliminary data presented in this review lead to the conclusion that CE (including other metabolites of oestrogen) might
have a role in the pathogenesis of SLE. The results might also be
replicated in the presence of 16-hydroxyoestrone as well as other
hydroxylated metabolites to know the exact aetiopathology. SLE
is a potential model for autoimmune disease in general and a
model for complex diseases affected by numerous factors including hormonal interaction. Only by understanding the complexity
of these interactions will we ultimately understand the aetiology
of SLE.
Rheumatology key messages
This review describes the possible role of CE in the aetiopathogenesis of SLE.
The review describes the mechanism behind the generation of
autoantibodies in SLE including the role of CE.
This review is considered as the preliminary search of literature
that may unfold various aspects of SLE.
1350
Wahid Ali Khan et al.
Disclosure statement: The authors have declared no conflicts of
interest.
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