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,§
*
William S. Rowe Division of Rheumatology, Children’s Hospital Medical Center, Cincinnati, OH 45229;
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45267;
University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
§
Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, but not IL-4, was markedly up-regulated in
response to IL-2. In mice treated with anti-IFN- Ab, both early
and late IL-2 administration exacerbated CIA. Thus, IL-2 can have two
opposite effects on autoimmune arthritis, a direct stimulatory effect
and an indirect suppressive effect that is mediated by
IFN-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, can be pro-inflammatory
(2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).
Support for this concept comes from a number of observations. The RA
synovium is infiltrated with CD4+ T cells of the
Th1 phenotype (13). In murine collagen-induced arthritis
(CIA), a model of RA, administration of IFN- can exacerbate disease
(14, 15), and administration of anti-IL-2R Abs can
inhibit disease onset (16). Thus, it is surprising that
most studies of cytokines in RA have failed to detect IL-2 protein in
RA synovial fluid (17). Recent studies from our laboratory
suggest that the failure to detect IL-2 may relate to the timing of
synovial sampling. Because of the difficulties in serially sampling the
synovium of patients with RA, our laboratory has used the murine
collagen-induced arthritis model to analyze mRNA cytokine patterns at
various stages of autoimmune arthritis. These studies demonstrated that
IL-2 mRNA levels are dramatically up-regulated in early CIA and that
the expression of IL-2 mRNA declines during the chronic stage of
disease (18). Further support for a possible role for IL-2
in early arthritis comes from the recent demonstration that IL-2
protein is significantly increased in peripheral blood mononuclear
cells from patients with early, but not late, RA (19).
IL-2 has been shown to regulate autoimmune processes in mice. IL-2-deficient mice develop autoimmune disorders, such as ulcerative colitis-like disease and generalized autoimmune hemolytic anemia (20, 21). Interestingly, these IL-2-deficient mice exhibit increased proliferation of both T and B cells, even though IL-2 has been characterized as a positive regulator of T cell proliferation. The development of autoimmune diseases in IL-2-deficient mice suggests a negative regulatory role for IL-2 in autoimmune diseases that may involve regulation of T and B cell proliferation.
These observations suggest that IL-2 might play a more important
role in autoimmune arthritis than has previously been appreciated. To
further define the role of IL-2 in CIA, the levels of IL-2 protein and
its receptor, as well as the effects of IL-2 administration, were
analyzed during the course of disease. These studies resulted in the
unexpected observation that, although IL-2 is pro-inflammatory in
established disease, it can play an anti-inflammatory role during
early stages of disease induction. Furthermore, our studies revealed
that IL-2-induced IFN- mediates this early suppression of CIA,
demonstrating the complex regulatory network of cytokine interactions
involved in autoimmune arthritis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male DBA/1 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were cared for according to American Association of Laboratory Animal Care guidelines. Mice were injected i.p. twice daily with 30,000 IU of recombinant human IL-2 (rhIL-2; Chiron, Emoryville, CA) in 0.5 ml of HBSS. All experimental procedures were approved by the Animal Care Committee of the Children’s Hospital Research Foundation of Cincinnati.
Type II collagen (CII) immunization
Bovine CII (Elastin Products, Owensville, MO) was dissolved in 0.1 M acetic acid at a concentration of 2 mg/ml and stored at -70°C until use. For immunization, 100 µg of CII was emulsified with an equal volume of CFA (2 mg/ml) and administered intradermally at the base of the tail of mice 6–8 wk of age. A booster, administered as above, was given 21 days after the primary injection. CII for footpad injections was prepared as above and consisted of one 100-µl injection into each footpad.
Clinical assessment of arthritis
Mouse paws were scored for arthritis, as previously described (22), using a macroscopic scoring system ranging from 0 to 4 (0, no swelling or redness; 1, swelling/redness of paw or one joint; 2, two joints involved; 3, more than two joints involved; and 4, severe arthritis of the entire paw and joints). The arthritic score for each mouse is the sum of the scores of all four paws.
RNase protection assay
Paws were quick frozen in liquid nitrogen and stored at -70°C. Frozen paws were homogenized with a polytron Tissue Tearor (Biospec Products, Bartlesville, OK) in appropriate volumes of RNA Stat 60 (Tel-Test, Friendswood, TX). RNA was extracted from the tissue homogenates according to the manufacturer’s instructions. RNA concentrations were determined by spectrophotometry.
Quantitation of IL-2 mRNA was performed on 5 µg of total RNA
utilizing the Riboquant Multiprobe RNase Protection Assay System
(PharMingen, San Diego, CA) following manufacturer’s instructions.
[
-32P]UTP-labeled anti-sense RNA probes
were synthesized by in vitro transcription of cDNA templates for IL-2
and GAPDH. DNA templates were degraded by DNase I digestion, and probes
were purified by phenol/chloroform extraction and ethanol
precipitation, with subsequent hybridization to total RNA at 56°C
overnight. Samples were treated with RNase A+T1, and double-stranded
RNA was purified by phenol/chloroform extraction and precipitated with
ethanol and salt. Samples were resuspended in loading dye and
electrophoresed on a 5% denaturing polyacrylamide gel. The gel was
dried and subjected to PhosphorImage analysis using a Storm 860 and
ImageQuant software (Molecular Dynamics, Sunnyvale, CA). The mRNA level
of IL-2 is expressed as the ratio of the PhosphorImager units of IL-2
to those of GAPDH from the same RNA sample.
Protein extraction from paws
Mice were sacrificed and paws minced in 1 ml of ice-cold PBS containing 2 mM PMSF and 1% Triton X-100. Tissues were placed on ice and homogenized. Homogenates were centrifuged at 2000 rpm and 4°C for 5 min to pellet cellular debris, and the supernatant was frozen in aliquots at -70°C until assayed. Protein concentrations were determined with bicinchoninic acid solution (Sigma, St. Louis, MO) using BSA as a standard.
IL-2 ELISA
IL-2 levels in paw homogenates were determined by ELISA as follows: a 96-well flat-bottom plate was coated with anti-IL-2 mAb (JES6-1A12; PharMingen) at a concentration of 5 µg/ml in PBS and incubated at 4°C overnight. Plates were washed with PBS-Tween 20 and blocked for 40 min with PBS containing 1% BSA. After washing, 40-µl aliquots of thawed paw homogenate were added to duplicate wells and incubated for 40 min. Plates were washed again, and biotin-labeled anti-IL-2 (JES6-5H4; PharMingen) at a concentration of 5 µg/ml in PBS was added and incubated for 40 min. After washing, streptavidin-peroxidase (Kirkegaard & Perry Laboratories, Gaithersburg, MD) was added. Plates were developed with Peroxidase Substrate System 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (Kirkegaard & Perry Laboratories). The plates were read at 405 nm in a microtiter plate reader (Dynex, Chantilly, VA). OD readings for the duplicate wells were averaged. Units of IL-2 in experimental samples were calculated by using a standard curve generated with dilutions of purified recombinant mouse IL-2 (PharMingen).
Immunohistochemistry
Staining for IL-2R was performed on 8-micron frozen sections
of paws using a Techmate 500 automatic immunostainer (Ventana, Tucson,
AZ). All steps were performed at room temperature, and all rinses were
with 1x PBS. Sections were blocked with CAS block (Zymed, San
Francisco, CA) for 8 min. A biotin-conjugated rat anti-mouse CD25
mAb was used as the primary Ab at 2 µg/ml (PharMingen). The slides
were exposed to the primary Ab for 1 h and then to
streptavidin-peroxidase for 15 min. Aminoethyl carbazole (Zymed; four
incubations at 5 min each) was used as the substrate. Sections were
counterstained with Mayer’s hematoxylin.
Anti-CII Ab titers
Titers of anti-CII Abs in the serum samples were determined by ELISA, as previously described (22). All samples were measured in duplicate. Peroxidase-labeled goat anti-mouse IgG (Kirkegaard & Perry Laboratories) was used to measure CII-specific total IgG. IgG1 and IgG2a were measured using biotinylated rat anti-mouse IgG1 or IgG2a (PharMingen) and then streptavidin-peroxidase. Plates were developed with Peroxidase Substrate System 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid). The plates were read at 405 nm, as described above. OD readings for the duplicate wells were averaged. A serum sample consisting of pooled serum from control mice was tested at various dilutions and used as a standard to generate a curve from which relative titers of the other serum samples were calculated.
T cell IFN- production
Draining lymph nodes were removed from mice and pooled to prepare single cell suspensions. Cells were plated in triplicate at a concentration of 5 x 105 cells/well in the presence of 300 µg/ml heat-denatured CII (10 min, 56°C) or 50 µl of 2C11 containing culture supernatant (anti-CD3). Supernatants were harvested at 48 h and analyzed by ELISA as described (22).
In vivo cytokine production
Serum levels of IL-4 and IFN- were measured using the
Cincinnati Cytokine Capture Assay (23). Mice were treated
twice daily with rhIL-2 (30,000 U) for 2 days and once on the third
day. Two hours after the last IL-2 administration, 10 µg of
biotin-labeled anti-IL-4 (BVD4-1D11) or 50 µg of anti-IFN-
(R4-6A2) was administered i.v. via the lateral tail vein. Mice were
bled 3 h later, and serum was collected and analyzed for IL-4 and
IFN- levels by ELISA as described (23).
Statistical analysis
Intergroup differences were assessed for statistical
significance by the Mann-Whitney U test for qualitative
data. The generalized Wilcoxon (Gehan) test was used to compare the two
"survival curves." To test frequency data for statistical
significance, 
2 was used. To compare baseline
characteristics of the two groups, we used the independent two-tailed
for parametric data t test. Comparisons of more than two
means were done using the one-way ANOVA. Tukey’s honest significant
difference multiple comparison test was used for pair-wise comparisons
if significance was found by ANOVA. The p values less than
0.05 were considered statistically significant, and all p
values shown are unadjusted for multiple comparison. All calculations
were performed by means of the software package SPSS-PC (version 8.0
for Windows, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After immunization of DBA/1 mice with CII on days 0 and 21,
arthritis is first observed between days 26 and 35. We have previously
demonstrated that IL-2 mRNA levels are markedly increased in early CIA
(18). The increase in IL-2 mRNA expression levels is first
observed on day 28 and correlates with disease severity (Fig. 1
A). To determine whether the
presence of mRNA for IL-2 correlated with protein levels, paw
homogenates from arthritic mice were analyzed for IL-2 at various times
during disease evolution (Fig. 1B). IL-2 protein was
detected during both acute disease (day 35) and chronic disease
(day 49).
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subunit of the IL-2R can be caused by IL-2
gene activation and the presence of IL-2 protein (24, 25).
To determine whether IL-2R is expressed in synovium of arthritic
mice, joints from mice with acute (day 35) and chronic (day 49) CIA
were analyzed by immunohistochemistry (Fig. 2). High levels of IL-2R were detected
on day 35 in paws with severe arthritis (score of 4; Fig. 2A). This IL-2R expression required the presence of
active synovitis because nonarthritic, day-35 paws (score of 0; Fig. 2B) and pre-arthritic, day-21 paws (data not shown)
expressed little IL-2R. In contrast to early CIA, little IL-2R
was observed in chronic disease (day 49), regardless of the severity of
arthritis (Fig. 2, C and D). These observations
suggest a functional role for IL-2 during the early stages of
established CIA.
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To further define the role of IL-2 in established CIA, rhIL-2
(30,000 U i.p. twice daily) was administered for 7 days to
CII-immunized mice starting one day after the first
clinical manifestation of CIA (average day of onset, day 28). Mice were
scored for arthritis daily. IL-2 significantly exacerbated established
disease (Fig. 3), demonstrating that IL-2
is pro-inflammatory in established CIA.
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).
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The above studies demonstrate that IL-2 is pro-inflammatory when
administered during established CIA or just before development of
clinical disease. These findings are not unexpected, given that the
onset of CIA is dependent on T cell and B cell responses to CII
(26, 27, 28, 29, 30), which are well-established by the time of the
booster administration on day 21 (31). Because IL-2 can
enhance T cell responses to Ag (32), we hypothesized that
a similar exacerbation of CIA would be observed if IL-2 was
administered between the first and second CII immunization.
Surprisingly, when rhIL-2 was administered from day 14 to 21, a
significant decrease in both the incidence and severity of arthritis
was observed (Fig. 5).
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To determine the mechanism by which early administration of IL-2
inhibited CIA, T and B cell responses to CII were measured in mice
treated with IL-2. Mice were immunized with CII on day 0 in the
footpad. IL-2 was administered from day 7 to 14, at which time mice
were sacrificed, and draining popliteal and inguinal lymph nodes were
harvested. Lymph node cells were stimulated in vitro with CII or
anti-CD3 (2C11). Administration of IL-2 significantly suppressed
secretion of IFN- in response to CII and 2C11 in lymph node cell
cultures (Fig. 6).
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). The Th1-dependent IgG2a Ab
response was also inhibited. This inhibition did not reflect a
generalized B cell suppression, in that anti-CII IgG1 levels
measured from day 28 sera were not inhibited.
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Because both inhibitory and pro-inflammatory effects of IL-2 on
CIA were observed, we wanted to determine whether administration of
rhIL-2 affected cytokine production, and, if so, whether it stimulated
a predominantly IFN- (type 1) or IL-4 (type 2) cytokine response. To
address this issue, we compared in vivo serum levels of IFN- and
IL-4 in IL-2-treated or naive mice. Upon rhIL-2 treatment, a marked
increase in the serum levels of IFN-, but not IL-4, were observed
(Fig. 8).
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mediates the inhibition of acute CIA, but not the
exacerbation of chronic CIA, after rhIL-2 administration
To determine whether the observed effects of rhIL-2 administration
on CIA were mediated by IFN-, anti-IFN- Abs were administered
simultaneously with rhIL-2, both before and after disease onset. For
treatment before disease onset, anti-IFN- Ab (XMG.6) or a
control isotype Ab (GL113) was administered on days 13 and 20. rhIL-2
was administered from day 14 to 21, as previously described.
Administration of anti-IFN- Ab blocked the inhibitory effect of
IL-2 on acute disease (Fig. 9).
Interestingly, administration of Abs to IFN- alone results in
exacerbation of CIA (p 
0.05; days 25–34),
suggesting that IFN- suppresses acute CIA; however, administration
of IL-2 in the presence of Abs to IFN- exacerbated disease more than
anti-IFN- alone, suggesting that IL-2 has an IFN--independent
stimulatory effect on disease development.
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produced in response to rhIL-2
administration during chronic disease was responsible for the observed
exacerbation of established CIA. Anti-IFN- Ab was administered at
days 27 and 34 after primary CII immunization. rhIL-2 was administered
from day 28 to 35. Administration of anti-IFN- Ab had no
significant effect on the exacerbation of established disease by rhIL-2
administration (Fig. 10). Median
arthritic scores from both IL-2-treated groups were significantly
higher than from the PBS/HBSS group (day 35; p <
0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although recent studies using recombination-activating gene-1-deficient mice raise questions regarding the requirement for mature T and B cells in the induction of CIA (33), there is much evidence that T cells are normally involved in disease induction. CIA can be prevented by administration of Abs to CD4 (28, 30) or CD3 (22). Administration of anti-CD40 ligand prevents joint inflammation, infiltration of inflammatory cells into the subsynovial tissue, joint erosion, and anti-CII Ab production (29). Both cellular and humoral immunity against CII are dependent on the T cell costimulatory molecule CD28, because mice lacking CD28 show a minimal T cell response to CII and produce very low levels of anti-CII IgG or IgM Abs (26).
Because IL-2 administration results in a general suppression of T cell
responses to either CII or anti-TCR (2C11), the data presented here
support the hypothesis that T cells are necessary to induce CIA but
that they may not play a major role in established CIA. Lymph node
cells from CIA mice have been defined as more Th1-like during the early
response to CII, with IFN--secreting cells maximal around day 15
after primary immunization (34), whereas IL-4-producing
cells are predominant at day 30 right before disease onset. Therefore,
the observed suppressive effects that administration of IL-2 has on T
cell responses in CIA may be more critical early in disease when
Th1-type cells are dominant. The failure of IL-2 to suppress
established disease suggests that these T cell responses are not
critical in established CIA. Once the T cell response has been
established or after the second CII injection, IL-2 may stimulate the
production of IL-2R-bearing inflammatory cells in the synovium, such as
macrophages that may increase the inflammatory response to CII and
result in the observed exacerbation of disease.
The ability of IL-2 to suppress immune cell functions has also been observed in other settings. For example, IL-2-deficient mice have increased T and B cell proliferation and develop autoimmune disorders such as ulcerative colitis-like disease and autoimmune hemolytic anemia (20, 21, 35), which can be prevented by treatment with rhIL-2 before postnatal day 10 (36). IL-2 has also been shown to suppress the immune response to corneal implants by prolonging allograft survival in mice (37).
A number of recent studies suggest potential mechanisms for the
observed inhibitory effects of IL-2 on CIA. For example, in vitro
culture with IL-2 leads to apoptosis of activated T cells (38, 39). Other studies have implicated IFN-, which enhances Fas
and Fas ligand expression, in lymphocyte apoptosis
(40, 41, 42). Because the inhibitory effect of IL-2 on CIA
development is IFN--dependent and IL-2 treatment induces a large
increase in IFN- production, it seems likely that IL-2 indirectly
inhibits CIA by inducing production of IFN-, which enhances
apoptosis of lymphoid cells that would otherwise contribute to CIA
development. Although IL-2 might also suppress CIA by activating a
subpopulation of CD4+
IL-2R+ T cells that can induce peripheral T cell
tolerance to autoantigens (43, 44), this mechanism is not
known to be IFN- dependent. Consequently, it is less likely to be
mediating suppression of CIA in our system. Additional experiments to
investigate the mechanisms of IL-2 suppression of T and B cell
responses are in progress.
Analysis of the role of IFN- in animal models of arthritis have
suggested both protective and exacerbating effects of IFN- on
disease (14, 15, 45, 46, 47, 48). Interestingly, administration of
IFN- has been shown to protect or exacerbate disease in rat adjuvant
arthritis, depending on the time of administration (49).
These results are similar to our observations with rhIL-2
administration. However, even though the inhibition of onset of disease
was mediated by IFN- in response to IL-2 administration, IL-2 itself
mediated a pro-inflammatory effect on CIA, as evidenced by the increase
in arthritic scores in mice treated with both IL-2 and anti-IFN-
Abs. Additionally, the observed exacerbation of disease by IL-2
administration was not mediated by IFN-. Other studies have
demonstrated that treatment of mice with IL-2 can induce IFN-
production and subsequent in vitro killer cell activity (50, 51). Studies are currently underway to further characterize this
in vivo IFN- response to rhIL-2 treatment.
The observation that IL-2 mRNA levels paralleled the up-regulation of
IL-2R expression is consistent with the dependence of IL-2R
expression on the presence of IL-2 protein (24, 25). The
observed increase in IL-2 mRNA contrasts with results from previous
studies that were unable to detect IL-2 protein in RA synovial fluid or
CIA joints (17, 52). However, failure to detect IL-2 in
the RA synovium may reflect the tendency of investigators to biopsy
later in the disease course. Recently, IL-2 mRNA has been detected in
RA synovial cells (53), and IL-2 protein has been found to
be significantly increased in PBMCs from RA patients with early onset,
but not late onset, synovitis (19).
Results from other recent studies also support a possible role for IL-2 in the autoimmune disease process. Weak linkage of certain cytokine genes, including IL-2, to RA (54) suggests that IL-2 may play a role in the disease process but that it is probably one of several factors involved in disease manifestation. Additionally, mouse models of diabetes and experimental autoimmune encephalomyelitis have linked a region of mouse chromosome 3, including the IL-2 gene locus, to the manifestation of these autoimmune diseases in mice (55).
In summary, the results presented here demonstrate a role for IL-2
during the early stages of CIA. IL-2 can inhibit disease through
effects that are mediated by IFN-, and IL-2 can exacerbate disease,
possibly by direct effects on IL-2R-bearing cells. IL-2 may be integral
to many autoimmune processes. Further investigation of the mechanisms
of action of IL-2 in autoimmunity and the IFN- dependence of these
mechanisms may lead to a better understanding of the pathogenesis of
autoimmune arthritis and other autoimmune disorders.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Raphael Hirsch, Division of Rheumatology, Children’s Hospital Medical Center, Pavilion Building 2-129, 3333 Burnet Avenue, Cincinnati, OH 45229.
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; rhIL-2, recombinant human IL-2; CII, type II collagen.
Received for publication March 8, 2000. Accepted for publication May 17, 2000.
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References |
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