ARTICLE
Auteur(s) : Elena Voronov1,
Molly Dayan*2, Heidy
Zinger2, Lubov Gayvoronsky1, Jian-Ping
Lin2, Yoichiro Iwakura3, Ron N Apte**1,*, Edna Mozes**2
1Department of Microbiology and Immunology, Faculty
of Health Sciences and The Cancer Research Center, Ben-Gurion
University of the Negev, Beer-Sheva 84105, Israel
2Department of Immunology, The Weizmann Institute of
Science, Rechovot 76100, Israel
3Center for Experimental Medicine, Institute of Medical
Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo
108-8639, Japan
accepté le 20 Mars 2006
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease
characterized by the increased production of autoantibodies and
defective T cell-mediated responses [1]. These are associated with
clinical manifestations of disease, such as immune complex
deposition in the kidneys and other organs [1].
Anti-double-stranded DNA (dsDNA) antibodies are characteristic of
SLE and are central to the diagnosis of the disease
[2-4].Experimental SLE can be induced in mice by immunization with
a monoclonal anti-DNA antibody bearing the common idiotype 16/6,
designated 16/6Id [5]. After immunization, the mice produce high
titers of antibodies to the 16/6 Id, and to DNA, and they develop
SLE-related clinical manifestations that include leukopenia,
proteinuria, and glomerulonephritis [5]. Cytokines are essential
for the control of the specific immune responses that characterize
SLE, as well as for the inflammatory response that induces the
pathogenic effects of the disease [6-8]. In young-adult mice,
experimental SLE is associated with a characteristic cytokine
response pattern, manifested by an initial burst of
pro-inflammatory cytokines, i.e., IL-1 and TNF-α, followed by a
wave of Th1 cytokines (IL-2 and IFN-γ), while the
Th2-type cytokines (IL-4 and IL-10) peak later, at the
time when the clinical manifestations are observed. At this stage,
there is a reduction in the levels of Th1-type
cytokines. However, pro-inflammatory cytokine levels (IL-1 and
TNF-α) remain high throughout the disease [6-8].IL-1 is a master
pro-inflammatory and immunostimulatory cytokine that acts mainly
through the induction of a network of cytokines, including itself,
chemokines and adhesion molecules in the microenvironment, and thus
it activates an array of stromal and immune/inflammatory cells;
this initiates and propagates immune and inflammatory responses
(reviewed in [9, 10]). The IL-1 family consists of two major
agonistic proteins, namely IL-1α and IL-1β, and one physiological
antagonistic protein, the IL-1 receptor antagonist (IL-1Ra) that
binds to the IL-1 receptor type I without transmitting an
activation signal (reviewed in [9, 10]). IL-1α and IL-1β bind to
the same receptors and there are no significant differences in the
spectrum of activities induced by recombinant IL-1α and IL-1β.
However, in the in vivo milieu, within the producing cells or their
microenvironment, IL-1α and IL-1β differ dramatically in the
sub-cellular compartments in which they are active. Thus, IL-1β is
active only as a secreted, mature product (17.5 kD) that is
secreted by macrophages, as well as by many other cells, whereas
its cytosolic precursor (31 kD) is inactive. On the other hand,
IL-1α is mainly active in cell-associated forms, i.e., the
unprocessed, cytosolic precursor form (31 kD) and the
membrane-associated form (23 kD). The mature, secreted form of
IL-1α (17.5 kD) is less abundant in the body, as it is secreted
only by activated macrophages, while other cells do not secrete
IL-1α, but rather express cell-associated IL-1α.In our previous
studies, we have demonstrated different tissue distribution of
IL-1α versus IL-1β, pointing to differential, in vivo functions of
the two IL-1 molecules. Indeed, we have demonstrated that IL-1α and
IL-1β exert differential effects on tumor invasiveness and
tumor-host interactions [9, 11, 12]. Thus, cell-associated IL-1α
expressed by tumor cells increases their immunogenicity and induces
efficient anti-tumor cell immune responses that lead to tumor
eradication, while secretable IL-1β increases tumor invasiveness
and metastasis and also induces tumor-mediated suppression [9,
11].The involvement of IL-1 in the pathogenesis of SLE has been
documented [7, 8, 13-15]. However, most studies have considered
both IL-1 molecules as synonymous, and have usually assessed only
one of the IL-1 molecules. Studies on the different roles of IL-1α
as compared to IL-1β in health and disease have only recently
started to appear, mainly following the generation of specific IL-1
KO mice in which one can assess the role of IL-1α and IL-1β in
vivo; IL-1β is mainly secreted and IL-1α is mainly cell-associated.
In the present study, we have assessed the different in vivo
involvement of the IL-1 molecules in experimental SLE, by using
knockout (KO) mice that selectively lack IL-1 molecules as follows:
IL-1α-/-, IL-1β-/- and IL-1α/β-/-
(double KO) mice. The results point to a key role of IL-1β in the
induction and propagation of experimental SLE.
Materials and methods
Mice
Female BALB/c mice were purchased from Harlan (Jerusalem, Israel).
The generation of IL-1 KO mice, i.e., IL-1α-/-,
IL-1β-/- and IL-1α/β-/- (double KO mice) were
previously described by us [16]. These mice were extensively
backcrossed to BALB/c mice for more than eight generations. These
strains of mice are homozygous for the relevant mutation. The
IL-1-/- mice were bred and kept at the Animal Facilities
of the Faculty of Health Sciences, Ben-Gurion University, under
aseptic conditions. Mice were treated according to the Animal Care
NIH guidelines adapted by our Animal Committee.
Monoclonal antibody
The human monoclonal anti-DNA antibody that bears the common
idiotype 16/6Id (IgG1/k) has been characterized previously [17].
This antibody will be designated here as 16/6Id. The mAb were
secreted by hybridoma cells in culture, and were purified using a
protein G-Sepharose column (Pharmacia, Fine Chemicals, Uppsala,
Sweden).
Induction of experimental SLE
In order to induce experimental SLE, mice were immunized with
1 μg of the human mAb 16/6Id. The primary injection was
administered in Freund’s complete adjuvant (CFA, Difco, MI, USA),
intradermally into the hind footpads. Three weeks later, the mice
received a booster injection of the same amount of the 16/6Id in
PBS.
ELISA for determination of anti-mouse dsDNA and anti-16/6Id
antibodies
For measuring anti-mouse dsDNA antibodies, 96 well Maxisorb
microtiter plates (Nunc, Denmark) were coated with poly-L-lysine
(Sigma). The plates were then washed and coated with lambda phage
dsDNA (Worthington Biochemical Corporation, New Jersey, USA). After
incubation with different dilutions of sera, goat antimouse IgG
(γ-chain-specific) conjugated to horseradish peroxidase (Jackson
Immuno Research, West Grove, PA, USA) was added to the plates.
Plates were then incubated with the substrate, ABTS [2,2’-azino-bis
(3-ethylbenzthiazoline-6-sulfonic acid); Sigma, Israel] and read at
405 nm using an ELISA reader [18]. For the determination of
16/6Id-specific Abs, plates were coated with 2 μg/mL of the
monoclonal human 16/6Id. The assay was carried out as above [5,
19].
Detection of proteinuria
Proteinuria was measured by a standard, semi-quantitative test,
using a Combur 10 Test kit (Roche Diagnostics GmbH, Mannheim,
Germany). Results were graded according to the manufacturer as:
negative, + = 0.3g/L, ++ = 1g/L, +++ = 3g/L, ++++ = ≥ 20g/L.
Immunohistology for detection of immune complex deposits in
kidneys
Mice were sacrificed six to seven months following disease
induction and kidneys were removed and immediately frozen in liquid
nitrogen. Frozen cryostat sections of 5 μm were air-dried and
fixed in acetone. For the detection of Ig deposits, sections were
incubated with FITC-conjugated goat antimouse IgG
(γ-chain-specific) (Jackson Immuno Research, West Grove, PA, USA).
Staining was visualized using a fluorescence microscope. The immune
complex deposits were scored using semi-quantitative grading as
follows: 0, no complexes; 1, minimal deposition of complexes; 2,
moderate complexes; 3, intense complexes.
Cytokine production and secretion
Assays of cytokine production by spleen cells were performed in
mice with overt SLE, at sacrifice. Pooled cells of five mice from
each experimental group were examined.
Splenocytes (5 x 106/mL) from mice in each
experimental group were incubated with 16/6Id 25 μg/mL in enriched
culture medium consisting of RPMI-1640 supplemented with 10 %
heat-inactivated FCS, 2 mM L-glutamine, penicillin G
(100 u/mL), streptomycin (100 u/mL) 2-mercaptoethanol (5
x 10-6M) for 48 h. Supernatants were tested
for the presence of IFN-γ, IL-10, and TNF-α. Cytokine levels were
determined by commercial ELISA kits, using the relevant standards,
capture and detecting antibodies (Pharmingen, San Diego, CA, USA),
according to the manufacturer’s instructions. The results were
measured using an ELISA reader at 405nm wavelength.
Detection of intracellular cytokines
Single spleen cell suspensions were permeabilized using the
Cytoperm kit (Pharmingen, San Diego, CA, USA) according to the
manufacturer’s instructions. Size-gated splenic leukocytes were
analyzed. Thereafter, cells were incubated with appropriate
anti-cytokine-FITC conjugated antibodies and analyzed by a FACScan
flow cytometer. The data were analyzed using Lysis software. The
percentage staining shown is after substructing levels obtained
with isotype controls.
Statistical analysis
Two experiments to induce experimental SLE in control and
IL-1-/- mice were performed. Each group consisted of
8-10 mice. Similar patterns of antibody production and disease
manifestations were observed in the two experiments. Results shown
are from one representative experiment. To evaluate the
significance of the difference between control and IL-1 KO groups,
the Student’s t-test and the non-parametric Mann-Whitney test were
used. Values of p ≤ 0.05 were considered significant.
Results
Effects of endogenous IL-1 on antibody levels in experimental
SLE
In this study, we attempted to assess the role of endogenous IL-1
on the induction and development of experimental SLE. We used
different strains of IL-1 KO mice as follows: IL-1β-/-,
IL-1α-/-, IL-1α/β-/- (double knockout) mice
and BALB/c mice as a control. To induce experimental SLE,
two-month-old mice were immunized and boosted (3 weeks later) with
the16/6 Id, as described [5]. Levels of anti-16/6Id antibodies were
assessed, two months after the primary immunization. As can be seen
in ( figure 1 ), all types
of mice, regardless of the patterns of IL-1 expression, generated
similar high levels of anti-16/6 Id antibodies. The mice were bled
periodically and levels of anti-dsDNA antibodies, which are
characteristic of experimental SLE, were assessed. As can be seen
in ( figure 2 ), similar
levels of anti-dsDNA antibodies were detected in control BALB/c and
IL-1α-/-, while lower levels were observed in mice
deficient in IL-1β, i.e., IL-1β-/- and
IL-1α/β-/- (double knockout) mice. These differences
were observed at all time intervals after immunization until the
sacrifice of mice with overt disease.
Clinical manifestations of experimental SLE in
IL-1-/- and control mice
Clinical manifestations of experimental SLE were evaluated by
assessing proteinuria and immune complex deposits in the kidneys,
seven months following immunization with the 16/Id antibody. (
Figure 3 )
shows similar levels of protein in the urine of control and
IL-1α-/- mice, while in IL-1β-/- and IL-1α/
β-/- mice, significantly lower levels of proteinuria
were detected (p = 0.004 and 0.025, respectively). In
IL-1β-/- and IL-1α/β-/- mice, no immune
complex deposits or minimal deposits, were observed in kidney
sections. Although the intensity of immune complex deposits in
kidneys of 16/6Id immunized-IL-1α-/- mice was
significantly lower than in kidneys of control BALB/c mice (( figure 4 )), the
frequency and intensity of the immune deposits in the kidneys of
the IL-1α-/- mice were much more prominent than in
IL-1β-/- and IL-1α/β-/- mice. Similar
patterns were observed when leucopenia was assessed (data not
shown). These results indicate the dominant involvement of IL-1β in
determining the susceptibility of mice to SLE induction and
severity of disease.
Cytokine generation in 16/6 Id-immunized control and
IL-1-/- mice
As cytokines were shown to play a major role in the pathogenesis of
experimental SLE [6-8, 18, 20-23], it was of interest to find out
whether endogenous IL-1 affects the cytokine profile of overt SLE,
seven months post-immunization with the 16/6Id antibody. We
assessed the expression of IL-2, IFN-γ and TNF-α, representatives
of Th1-type cells and IL-4 and IL-10, representatives of
Th2-type cells. IL-10, TNF-α and IFN-γ are also
generated and secreted by macrophages and other innate cells.
Intracellular cytokines were detected by immunofluorescence and
FACS analyses, in freshly isolated spleen cells from immunized
mice, as described in Materials and Methods. Secreted cytokines
were assessed in supernatants of spleen cells from immunized mice
that were challenged in culture with the 16/6Id. As can be seen, in
figures 5 and 6, representing the expression of
intracellular and secreted cytokines, respectively, cytokine levels
were generally lower in IL-1β-/- and
IL-1α/β-/- mice, as compared to control and
IL-1α-/- mice. Thus, cytokine levels in the spleen
correspond to the clinical manifestations of overt experimental
SLE.
Discussion
The present study emphasizes the role of secretable IL-1β in the
initiation and propagation of experimental SLE. In mice deficient
in IL-1β, i.e., IL-1β-/-and IL-1α/β-/-
(double KO) mice, the immunological and clinical manifestations of
disease, i.e., production of dsDNA specific antibodies, immune
complex (IC) deposition in the kidneys and proteinuria, are
diminished compared to control BALB/c or IL-1α-/- mice.
The effects of the IL-1 molecules on SLE may encompass regulatory
effects on the immune response, leading to the development of
pathogenic antibodies and T cells, as well as subsequent effects on
the inflammatory response that mediate tissue-damage in the
kidneys, small blood vessels and other target organs that are
afflicted in experimental disease [5, 6, 8, 22].
The involvement of IL-1 in in vivo inflammatory responses in SLE
and other autoimmune inflammatory diseases has been described. Its
involvement is possibly due to its adjuvant-like effects on immune
phenomena and its pro-inflammatory characteristics [10]. In mice
with active SLE, manifesting kidney involvement, local and systemic
low levels of the IL-1Ra were demonstrated, indicating the
contribution of unattenuated levels of IL-1 to the pathogenesis of
disease [13, 14, 24], which paved the way to some trials using the
IL-1Ra in SLE patients [25]. In addition, intrarenal production of
IL-1 was shown in MRL/lpr and in (NZBxNZW) F1 mice [26, 27].
Finally, an increase in IL-1β expression has been reported in
different tissues of SLE-prone mice and in PBL of patients with
active lupus [7, 8, 15]. Inhibition of IL-1 production or
neutralization of preformed IL-1 were shown to alleviate disease
symptoms in various experimental models of SLE, such as the NZB/NZW
model or 16/6Id-induced SLE [21, 28].
We have previously shown that treatment of 16/6Id-induced SLE
with Methotrexate [21], tamoxifen (an estrogen antagonist) [20],
anti-TNF-α antibodies or pentoxiphylline (that downregulates TNF-α)
[29] and a peptide based on the complementarity-determining region
(CDR) 1 of the 16/6Id [23], all resulted in beneficial effects on
the progression and severity of the experimental disease,
highlighted by a significant decrease in expression and secretion
of IL-1β.
Clinical symptoms of SLE are observed starting four months after
disease induction, and full-blown disease appears in all immunized
control mice after seven months; at this time mice were sacrificed.
Disease symptoms are persistent for the whole life span of the
mice, as they only seldom die from the disease. No signs of either
antibodies or other clinical manifestations were seen in the
IL-1β−deficient mice, excluding the possibility that disease is
delayed rather than prevented.
The crucial role of IL-1 as a master cytokine in autoimmune
diseases has been demonstrated in mice that are devoid of both IL-1
molecules (IL-1α/β-/-) and that are resistant to the
development of collagen type II-induced arthritis [30-32]. In
IL-1Ra-/-mice, all females of BALB/c origin
spontaneously develop RA, due to unattenuated levels of IL-1
[32-34]. Also, in IL-1 receptor type-1 (IL-R1-/-) and
interleukin-1-associated kinase 1 (IRAK1-/-) mice, in
which IL-1 signaling is impaired, the development of experimental
autoimmune encephalomyelitis (EAE) [35] and autoimmune myocarditis
[36], respectively, is decreased. It was also shown, that signaling
through the IL-1R plays a necessary and non-redundant role in
experimental autoimmune uveitis (EAU) and can, by itself, account
for the lack of EAU development in MyD88 mice [37]. In all these
autoimmune diseases, IL-1 contributes to the inflammatory response
that is involved in tissue damage. We have shown here that in mice
deficient in IL-1β, the disease is less severe than in mice
deficient in IL-1α. Secretable IL-1β diffuses into the local
microenvironment and activates diverse stromal and inflammatory
cells to produce a broad pro-inflammatory cascade, which amplifies
the inflammatory response, while the effects of IL-1α, which is
mainly cell-associated are more restrained. This is in agreement
with our previous results on the different contributions of IL-1α
as compared to IL-1β, to tumor invasiveness [9, 11, 12].
In our experiments, all types of mice (control and the various
IL-1-/- mice) produced equal levels of specific
antibodies following immunization with the 16/6Id. This probably
results from the supra-optimal immunization conditions that were
used, applying CFA as an adjuvant that activates macrophages and
other APCs to produce multiple pro-inflammatory/co-stimulatory
cytokines and to express cell surface co-stimulatory molecules,
such as B7. These conditions possibly override the homeostatic need
for endogenous IL-1β in the production of anti-16/6 antibodies.
However, significantly reduced anti-DNA antibodies were observed in
IL-1β-/- mice and also in IL-1α/β-/- mice, as
compared to the high levels of anti-dsDNA antibodies that were
generated in control BALB/c and in IL-1α-/- mice. Using
the same series of IL-1-/- mice, it was shown that
homeostatic IL-1β, rather than IL-1α, is required for T
cell-dependent antibody production [38]. It was demonstrated that
endogenous IL-1β promotes antigen-specific TH cell
function through efficient interactions between APCs and the T
cells that result from IL-1β-mediated enhanced expression of CD40L
and OX40 on T cells [39]. On the other hand, IL-1α is more
essential for the development of contact sensitivity, a form of
cell-mediated immunity [40]. Effects of IL-1β on the function of
various cellular components that are involved in antibody
production, such as B cells, Th cells and
antigen-presenting cells have been described [9, 10]. Further
studies will be aimed at assessing the mechanisms of involvement of
endogenous IL-1β in the control of pathogenic antibodies in
experimental SLE.
Many types of cells have the potential to produce IL-1,
especially professional APCs. In the context of experimental SLE,
in B cells from old MRL/lpr mice, elevated levels of IL-1β
transcripts were observed, possibly reflecting post-transcriptional
stabilization of IL-1β mRNA controlled by the lpr mutation [41].
IL-1β production by B cells may be one of the mechanisms that lead
to the overproduction of autoantibodies in MRL/lpr mice.
SLE is characterized by high levels of Th1 and
Th2, and pro-inflammatory cytokines [6, 8]. This
manifests as high levels of intracellular (( figure 5 )) as well as
secreted (( figure 6 )) IFN-γ,
IL-10 and TNF-α in 16/6Id-stimulated spleen cell cultures of
SLE-afflicted control BALB/c mice. In IL-1α-/- mice,
levels of secreted cytokines were lower when compared to control
mice, and significantly lower levels of cytokines were observed in
spleen cell cultures from IL-1β-/- and
IL-1α/β-/- mice that manifested a very mild disease or
were disease-free. Assessment of secreted cytokines represents in
vitro activation of memory T cells from immunized mice, while
intracellular cytokine staining enumerates the pool of cells that
express the cytokine under chronic stimulation in vivo.
Significantly lower levels of all cytokines that are considered
pathogenic in SLE (i.e. INF-γ, TNF-α and IL-10) could be observed
in IL-1β-/- and IL-1α/β-/- mice.
Our results demonstrate a dominant involvement of IL-1β in the
initiation and propagation of experimental SLE, indicating a role
of microenvironment-secreted IL-1 in this process. However, the
results do not exclude some contribution of IL-1α to the disease,
as observed by the lower rate of IC in the kidney in
IL-1α-/- compared to control mice. The mutual in vivo
interactions between IL-1α and IL-1β are complex, and synergism
between them has been shown in different experimental systems [9,
10].
In conclusion, our study has emphasized the role of IL-1β as an
important factor in the induction and pathogenesis of experimental
SLE. Its major roles include the induction of the pathogenic
autoantibodies and T cells, as well as the control of inflammatory
responses that lead mainly to kidney disease in the experimental
models. Thus, IL-1β seems to be an essential factor in the “mosaic”
of genetic, environmental, microbial and immune/inflammatory
factors that are involved in the pathogenesis of SLE. Therefore,
approaches that efficiently neutralize IL-1β should be considered
for the treatment of lupus.
Acknowledgements
The authors would like to thank Mrs Rosalyn M. White for her
devoted help
Elena Voronov was supported by the Israel Cancer Association,
the Israel Ministry of Health Chief Scientist’s Office and the
Concern Foundation.
Ron N. Apte was supported by the Israel Ministry of Science
(MOS) jointly with the Deutsches Krebsforschungscentrum (DKFZ),
Heidelberg, Germany, the United States-Israel Bi-national
Foundation (BSF), the Israel Science Foundation founded by the
Israel Academy of Sciences and Humanities, the Israel Ministry of
Health Chief Scientist’s Office, and Association for International
Cancer Research (AICR) and the German-Israeli DIP collaborative
program.
Edna Mozes was supported in part by Teva Pharmaceutical
Industries Limited, Israel.
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** Ron N. Apte and Edna Mozes are equal
contributors.* Elena Voronov and Molly
Dayan are equal contributors.
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