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Abstract
We investigated effects of IL-4, dexamethasone DXM., and the combination of IL-4 and DXM, low- or high-dose, on
collagen-induced arthritis CIA. in DBAr1 mice and correlated severity of arthritis with changes in IL-10 and IFN-g.
Compared with control mice, mice treated with IL-4 had increased IL-10 with the same degree of arthritis, whereas mice
treated with high-dose DXM had decreased IL-10 and increased IFN-g production with less severe arthritis. Mice treated
with low-dose DXM showed the absence of IL-10 and increased IFN-g production with a trend toward the resolution of
arthritis. Mice treated with IL-4 and low-dose DXM had neither IL-10 nor IFN-g production but revealed less severe
arthritis, compared with mice treated with low-dose DXM alone. These results suggest that the beneficial effects of
high-dose DXM and the combination of IL-4 and DXM on CIA are independent of IL-10 and IFN-g. q 2000 Elsevier
Science B.V. All rights reserved.
Keywords: CIA; Steroid; IL-4
1. Introduction
Rheumatoid arthritis RA. is an autoimmune disease characterized by chronic inflammation in multiAbbreiations: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; CFA, complete Freunds adjuvant; DXM, dexamethasone; IL, interleukin; IFN, interferon; TNF, tumor necrosis
factor; Th, T heler; SC, spleen cell; IFA, incomplete Freunds
adjuvant; PBS, phosphate-buffered saline; ELISA, enzyme-linked
immunoabsorbent assay
)
Corresponding author. 609 LCI Section of Rheumatology,
Department of Internal Medicine, Yale University School of
Medicine, 333 Cedar St., New Haven, CT 06520, USA. Tel.:
q1-7203-785-2454; fax: q1-7203-785-7053.
E-mail address: insoo.kang@yale.edu I. Kang..
0162-3109r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 2 - 3 1 0 9 0 0 . 0 0 2 4 8 - 4
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Wilckens and De Rijk, 1997.. In fact, glucocorticoids can suppress or enhance IL-4 and IL-10 productions depending on the stage of T-cell development Brinkmann and Kristofic, 1995..
In this study, we investigate the synergistic effect
of glucocorticoids and IL-4 on the resolution of CIA
by measuring the macroscopic and microscopic
severity of arthritis. Changes in the Th1rTh2 cytokine balance were also studied by measuring IL-10
and IFN-g productions in spleen cells SCs. of these
mice, and correlating them with the severity of
arthritis. We report that the systemic administration
of dexamethasone DXM. and IL-4 synergistically
accelerates the resolution of CIA, which may be due
to blocking of DXM-induced IFN-g production by
IL-4.
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3. Results
3.1. Deelopment of CIA
In our experiments, about 20% of mice had developed CIA before the injection of LPS at day 28 after
the first immunization with bovine type II collagen.
The subsequent LPS injection to mice without CIA
at day 28 increased the incidence of CIA to 95% in
mice.
3.2. Effects of high-dose DXM and IL-4 on CIA
On macroscopic examination, mice treated with
IL-4 had the same degree of arthritic index as mice
treated with PBS throughout the period of treatment
p ) 0.05, Fig. 1a., whereas mice treated with highdose DXM showed a significant reduction in arthritic
index mean " S.D.. at days 2 0.563 " 0.727., 3
0.500 " 0.730. and 4 0.375 " 0.500. of treatment,
compared with mice treated with PBS at the same
time points p - 0.05, Fig. 1a.. Also, mice treated
with both IL-4 and high-dose DXM had less severe
arthritis at days 3 0.438 " 0.629. and 4 0.375 "
0.619. than did mice treated with PBS and mice
treated with IL-4 alone p - 0.05, Fig. 1a.. No
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4. Discussion
In this study, we investigated effects of IL-4,
DXM, and the combination of IL-4 and DXM on
CIA in DBAr1 mice and correlated the macroscopic
and microscopic severity of arthritis with changes in
the Th1 and Th2 immune responses by measuring
IL-10 and IFN-g productions from SCs. During the
active phase of CIA, mice treated with PBS had a
Th2 predominant immune response characterized by
high level of IL-10 and low level or absence of
IFN-g in spite of active inflammation in joints. This
is consistent with the finding by Doncarli et al.
1997., who showed that CD4 q T cells in type II
collagen-immunized DBAr1 mice converted from a
dominant Th0rTh1 immune response to a Th2 immune response during the development of CIA. The
significance of this Th2 immune response in the
pathogenesis of CIA is not completely understood,
but some reports claimed that injections of IL-4
accelerated the resolution of arthritis and that a
neutralization of IL-4 or IL-10 with monoclonal
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Acknowledgements
This work was supported by the Hallym University Medical Center Research Grant.
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