| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Department of Immunology, Kumamoto University School of Medicine, Kumamoto, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
/
-deficient
(IL-1-/-) mice and enhanced in IL-1R
antagonist-/- mice. The intrinsic functions of T, B, and
APCs were normal in IL-1-/- mice. However, we showed that
IL-1-/- APCs did not fully activate DO11.10 T cells,
while IL-1R antagonist -/- APCs enhanced the reaction,
indicating that IL-1 promotes T cell priming through T-APC interaction.
The function of IL-1 was CD28-CD80/CD86 independent. We found that CD40
ligand and OX40 expression on T cells was affected by the mutation, and
the reduced Ag-specific B cell response in IL-1-/- mice
was recovered by the treatment with agonistic anti-CD40 mAb both in
vitro and in vivo. These observations indicate that IL-1 enhances T
cell-dependent Ab production by augmenting CD40 ligand and OX40
expression on T cells. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-1, which exert similar, although not completely overlapping,
biological activities through IL-1R type I (IL-1RI; CD121a)
(4). Although an IL-1R type II (IL-1RII; CD121b) has also
been found, this receptor is not considered to be involved in the
signal transduction, but is believed to play more of a regulatory role
as a "decoy" (4). In addition, another member of the
IL-1 gene family, the IL-1R antagonist (IL-1ra), binds to IL-1Rs
without exerting agonistic activity (4). This molecule
together with IL-1RII and the secretory forms of IL-1RI and IL-1RII are
considered to be negative regulators of IL-1 signals, providing a
complex regulation of IL-1 activity. In the immune system, IL-1 is known to activate lymphocytes, monocytes, macrophages, and NK cells (3, 4). When mice were immunized with protein Ags together with IL-1, serum Ab production was enhanced, suggesting that IL-1 has an adjuvant effect (5, 6). Recently, we found that IL-1ra-/- mice developed chronic inflammatory arthropathy spontaneously, and production of autoantibodies against Igs, type II collagen, and dsDNA increased in these mice (7). These observations suggest an important role of IL-1 in the humoral immune responses. On the other hand, it was shown that humoral immune responses were normal in IL-1RI-/- mice (8, 9). Thus, the role of IL-1 in the humoral immune response is still controversial.
In this report we studied the roles of IL-1 in the humoral immune response using IL-1-/- and IL-1ra-/- mice that we had previously generated (10). Ab production to SRBC was reduced in IL-1-/- mice, while it was enhanced in IL-1ra-/- mice. We found that IL-1 was involved in T cell priming because IL-1-/- APCs could not fully activate Ag-specific T cells. In addition, this response was independent of CD28-CD80/CD86 cosignaling. Furthermore, we showed that IL-1 produced by APCs enhances the expression of CD40 ligand (CD40L; CD154) and OX40 (CD134) on T cells, which play an important role in CD4+ T cell priming as well as Ag-specific B cells (11, 12, 13, 14, 15). Since the defect in Ab production in IL-1-/- mice was rescued by the administration of agonistic anti-CD40 mAb, suggesting that IL-1 promotes humoral immune response by inducing these cosignaling molecules on T cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-1-/- and IL-1ra-/- mice were generated by homologous recombination as described previously and backcrossed to BALB/cA mice for seven or eight generations (10). DO11.10 transgenic (Tg) mice (BALB/c background) were provided by Dr. D. Y. Loh. All the mice were housed under specific pathogen-free conditions in an environmentally controlled clean room at the Center for Experimental Medicine, Institute of Medical Science, University of Tokyo (Tokyo, Japan). The experiments were conducted according to the institutional ethical guidelines for animal experiments and the safety guideline for gene manipulation experiments. Sex- and age-matched 8- to 12 wk-old adult mice were used for the experiments.
Immunization of mice
Mice were immunized with 1 x 108 SRBC in PBS i.p. Secondary responses were examined after immunization with SRBC. For in vivo reconstitution analysis, agonistic rat anti-mouse CD40 mAb (200 µg; LB429) (16) or rat IgG (200 µg) was injected i.p. 1 day both after the primary and secondary immunizations with SRBC. Goat anti-mouse IgM F(ab')2 (200 µg; ICN Biomedical, Aurora, OH) or goat IgM F(ab')2 (200 µg) was administrated i.p. 1 day after the primary immunization with SRBC, then rabbit anti-mouse IgG F(ab')2 (200 µg; Rockland, Gilbertsville, PA) or rabbit IgG F(ab')2 (200 µg) was injected i.p. 1 day after the secondary immunization. Blood samples were collected from the tail vein before the immunization. At 15 days after the primary immunization, mice were given the secondary immunization, and blood samples were collected 2 wk later.
Measurement of Ab titers
Ig levels in sera or culture supernatants were measured by ELISA as described previously (17). Soluble SRBC Ag (2 µg/ml), prepared as described previously (18), was coated on Falcon 3912 Micro Test III Flexible Assay Plates (Becton Dickinson, Franklin Lakes, NJ). To measure OVA-specific Ab levels in culture supernatants, 96-well plates for ELISA were coated with OVA peptide (10 µg/ml), and 50 µl of the test sample was added to each well. After incubation for 1 h the well was washed with Tris-buffered saline and 0.05% Tween 20 three times, followed by addition of 50 µl of alkaline phosphatase-conjugated goat anti-mouse IgM, IgG, IgG1, IgG2a, IgG2b, IgG3 (Zymed, San Francisco, CA), or alkaline phosphatase-conjugated rat anti-mouse IgE (Southern Biotechnology Associates, Birmingham, AL). Alkaline phosphatase activity was measured using Substrate Phosphatase SIGMA104 (Sigma, St. Louis, MO) as the substrate, and the OD415 is shown.
Preparation of cells from lymphoid tissues
Cells were prepared from the spleen or lymph nodes (axillary, inguinal, and brachial) by grinding the tissues with the plunger of a 1-ml disposable syringe and were then suspended in RPMI 1640 (Life Technologies, Gaithersburg, MD) medium containing 50 µM 2-mercaptoethanol (Life Technologies), 50 µg/ml streptomycin (Meiji, Tokyo, Japan), 50 U/ml penicillin (Meiji), and 10% FCS (JRH Bioscience, Lenexa, KS). Spleen cells were treated with a hemolysis buffer (17 mM Tris-HCl and 140 mM NH4Cl, pH 7.2) to remove RBC. Adherent cells and nonadherent cells were separated after incubation for 1 h on a 10-cm dish. For APCs in the primary T cell response assay, B220+ and Thy1.2+ cells were removed from splenic adherent cells (SACs) using a MACS column (Miltenyi Biotec, Bergisch Gladbach, Germany). To prepare splenic and lymph node T cells, nonadherent cells were passed through a nylon wool column. CD4+ T cells were purified by treating the T cell preparation with anti-mouse CD8, anti-mouse B220, and anti-mouse Mac-1 magnetic beads (Miltenyi Biotec) and then passing them through a MACS column. B cells were prepared by treating splenic nonadherent cells with anti-Thy1.2 Ab (Serotec, Oxford, U.K.) and rabbit complement (Cedarlane Laboratories, Ontario, Canada). The purity of CD4+ cells and B220+ cells was monitored by FACScan and was usually approximately 90%.
T cell proliferative response
In the OVA-specific T cell proliferative response assay, splenic
and lymph node CD4+ T cells (5 x
104 cells/well) from DO11.10 Tg mice were
cocultured with irradiated APCs (5 x 103
cells/well) for 3 days in the absence as well the presence of
OVA323–339 peptide (0.1 µM; gift from Dr.
T. Saito) in a final volume of 200 µl RPMI 1640/10% FCS. The effects
of recombinant mouse IL-1 (125 pg/ml) and IL-1 (125 pg/ml;
PeproTech, London, U.K.), or CTLA-4 Ig (30 µg/ml; gifted by Dr. R.
Abe) were examined by incubating the culture with those Abs for 72
h, followed by incorporation of [3H]thymidine
(0.25 µCi/ml; Amersham, Little Chalfont, U.K.) for 6 h. Then,
cells were harvested with a Micro 96 cell harvester (Skatron, Lier,
Norway), and [3H]thymidine radioactivity in the
acid-insoluble fraction was measured with Micro Beta (Pharmacia
Biotech, Piscataway, NJ).
B cell proliferative response
Splenic B cells (1 x 105 cells/well) and mitomycin C (Sigma)-treated DO11.10 T cells (1 x 105 cells/well) were cocultured for 3 days in the presence or the absence of OVA peptide (0.2 µM), and cells were labeled with [3H]thymidine for 6 h. To examine the effects of agonistic anti-mouse CD40 mAb (HM40–3; 1 µg/ml; PharMingen, San Diego, CA), cells were cultured for 3 days with this Ab, and proliferation and OVA-specific Ab levels were measured. Isotype IgG was used as a control.
Measurement of cytokine levels
IL-2 levels in the culture supernatant were determined by Titer Zyme enzyme immunoassay kit (PerSeptive Diagnostics, Cambridge, MA). As a standard recombinant cytokine, mouse IL-2 (Genzyme, Cambridge, MA) was used. TMB One-Step Substrate System was purchased from Dako (Carpinteria, CA).
Flow cytometric analysis
In the OVA-specific T cell and B cell proliferative response,
cells were harvested at the point when expression of each molecule
reached peak levels. Staining of I-Ad (72 h after
stimulation), CD80 (72 h), CD86 (72 h), and CD40 (72 h) on SACs; CD40L
(12 h), OX40 (72 h), and IL-2R (60 h) on CD4+
T cells; and OX40 ligand (OX40L; 72 h) on B cells was performed
according to the standard protocol. Detection of CD40L on
KJI-26+CD4+T cells was
conducted as described previously (19). Briefly, the
biotin-labeled anti-mouse CD40L mAb was added to OVA-specific T
cell proliferation culture, and at 12 h after stimulation cells
were harvested and stained with PE-anti-mouse CD4 mAb,
anti-mouse DO11.10 (KJI-26), and CyChrome-streptavidin
(PharMingen). After washing, cells were stained with second Ab,
FITC-anti-mouse Ig (PharMingen). To examine the effects of rIL-1 on
CD40L and OX40 expression on CD4+ T cells,
CD4+ T cells (1 x 106
cells/well) were cultured with rIL-1 only, with plate-coated
anti-CD3 (145-2C11; 0.1 µg/ml) in the presence or the absence of
rIL-1, or with plate-coated anti-CD3 (0.1 µg/ml). To detect IL-1RI
expression on CD4+ T cells, CD4+ T cells (1 x
106 cells/well) were cultured with plate-coated
anti-CD3 (0.1 µg/ml). Cells were incubated for 12 h for
analysis of CD40L and IL-1RI expression and for 72 h for analysis
of OX40 expression.
Anti-mouse CD16/CD32 (2.4G2), FITC- or PE-anti-mouse CD4
(GK1.5), PE-anti-mouse B220 (RA3-6B2), PE-anti-mouse CD25
(IL-2R; 3C7), biotinylated anti-mouse I-Ad
(AMS-32.1), biotinylated anti-mouse CD121a (IL-1RI; 12A6), and
FITC-streptavidin were purchased from PharMingen, and
FITC-anti-mouse CD80 (16-10A1) was obtained from BioSource
(Camarillo, CA). PE-anti-mouse CD40 (3.23) and PE-anti-mouse
OX40 (OX86) were purchased from Immunotech (Marseilles, France).
Anti-mouse CD86 (GL-1) mAb was provided by Dr. H. Nariuchi (Institute
of Medical Science, University of Tokyo, Tokyo, Japan). Biotinylated
anti-mouse OX40L, MGP34, was provided by Dr. K. Sugamura (Department of
Microbiology and Immunology, Tohoku University School of Medicine,
Sendai, Japan) and RM134L was purchased from PharMingen.
Statistics
Student’s t test was used for statistical evaluation of the results.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although adjuvant effects of IL-1 on Ab production are well known,
it is not clear if IL-1 deficiency causes any defect in the humoral
immune response, because Ab production was normal in
IL-1RI-/- mice immunized trinitrophenyl
(TNP)-keyhole limpet hemocyanin (KLH) together with alum or CFA. Thus,
we examined whether IL-1 is involved in Ab production using
IL-1-/- and IL-1ra-/-
mice of the BALB/c background. After immunization with SRBC i.p.,
SRBC-specific serum Ab levels were measured by ELISA. SRBC-specific Ab
levels of IgM, IgG, and IgE classes in IL-1-/-
mice were significantly lower than those in wild-type mice after
secondary immunization (Fig. 1
A). In contrast,
SRBC-specific IgG and IgE levels in IL-1ra-/-
mice were increased compared with those in wild-type mice, although IgM
levels were comparable in both mice (Fig. 1B). The
suppression in IL-1-/- mice and the
augmentation in IL-1ra-/- mice were observed in
all IgG subclasses, showing no polarization to either Th1- or Th2-type
response.
|
We did not detect any difference in the number and composition of the
immune cells from the thymus, spleen, lymph nodes, and peritoneal
cavity between IL-1-/- and wild-type mice when
we examined various cell surface markers (CD4 and CD8 on thymocytes;
CD4, CD8, CD3
, B220, CD62L, and CD44 on lymph node cells; CD4, CD8,
CD3, B220, IgM, CD11b, CD11c, CD80, CD86,
I-Ad, CD54, CD40, CD16/CD32, CD21/CD35, CD62L,
and CD44 on splenocytes; B220, IgM, CD11b, F4/80, CD16/CD32, CD21/CD35,
and CD5 on peritoneal cells; data not shown). This indicates that IL-1
does not affect the development and maturation of T cells, B cells, and
APCs. Intrinsic B cell functions, such as proliferative response to LPS
or anti-IgM mAb and Ab production against T-independent Ag TNP-LPS,
were normal in IL-1-/- mice (data not shown).
Intrinsic T cell functions, such as proliferative response and cytokine
production to plate-coated anti-CD3 mAb or plate-coated
anti-CD3 mAb plus soluble anti-CD28 mAb, were also normal in
IL-1-/- mice (data not shown). Moreover, the
phagocytic activity of macrophage and DCs of
IL-1-/- mice was comparable with that of
wild-type mice using FITC-latex beads, FITC-dextran, and Lucifer
Yellow. The Ag-processing ability of these cells was also normal (data
not shown). These results indicate that intrinsic B cell, T cell, and
APC function was not affected by the deficiency of IL-1.
Role of IL-1 in T cell-APC interaction
Next we examined the roles of IL-1 in T cell-APC interaction. To
assess the role of IL-1 in T cell priming upon interaction with APCs,
the Ag-specific primary T cell proliferative response was assayed using
T cells from DO11.10 Tg mice, who express TCR specific for the
OVA323–339 peptide, and SACs from
IL-1-/- mice. The proliferative response of
DO11.10 T cells was reduced in IL-1-/- SACs
(Fig. 2A). On the other hand,
using IL-1ra-/- SACs, the response was slightly
increased (Fig. 2A; wild-type, 100%;
IL-1-/-, 41 ± 10%
(p < 0.01); IL-1ra-/-,
135 ± 12% (p < 0.05); average ±
SD from three independent experiments). When recombinant mouse IL-1
and IL-1 were added to this culture, the response of
IL-1-/- SACs was recovered, indicating that the
defect is not developmental (Fig. 2B). Similar
IL-1-dependent activation of T cells was observed when B cells were
used as APCs (data not shown). These results suggest that IL-1 from
SACs play an important role in T cell priming.
|
Because the above-mentioned results have suggested that T cell
activation through T cell-APC interaction is impaired in
IL-1-/- mice, we examined the molecules
involved in cell-cell interaction on APCs and T cells. The expression
levels of I-Ad on SACs from
IL-1-/- and IL-1ra-/-
mice were comparable with those from wild-type mice (Fig. 3A). The expression levels of
CD80 and CD86 on I-Ad+ APCs were also similar
among these mice (Fig. 3A). Moreover, despite the inhibitory
effect of CTLA-4 Ig, which inhibits CD28-CD80/CD86 cosignaling, T cell
responses were still reduced with IL-1-/- APCs
and enhanced with IL-1ra-/- APCs (Fig. 3B; wild-type, 100%; IL-1-/-,
29 ± 10% (p < 0.001);
IL-1ra-/-, 199 ± 29%
(p < 0.05); average ± SD from three
independent experiments). In these cultures IL-2 levels were
wellcorrelated to the proliferative response, consistent with the
impairment of T cell activation (Fig. 3B). These results
indicate that IL-1 acts on T cell priming independently of
CD28-CD80/CD86 costimulatory signals.
|
A). On the other hand, the expression levels of
CD40L and OX40 on CD4+ DO11.10 T cells stimulated
with IL-1-/- APCs were low compared with
wild-type APCs (Fig. 4; CD40L, wild-type,
100%; IL-1-/-, 68 ± 2%
(p < 0.01); OX40, 56 ± 16%
(p < 0.01); average ± SD from three
independent experiments). In contrast, the expression levels of these
molecules on T cells were enhanced when
IL-1ra-/- APCs were used (Fig. 4B;
CD40L, wild-type, 100%; IL-1ra-/-, 154 ±
10% (p < 0.01); OX40, 133 ± 7%
(p < 0.01); average ± SD from three
independent experiments). In support for the involvement of IL-1 in the
CD40L induction, we found that this reduced CD40L expression could be
rescued by the addition of recombinant mouse IL-1 and IL-1 in the
culture (Fig. 5A). In
addition, the expression level of IL-2R (CD25), an activation marker
of T cells, on CD4+ DO11.10 T cells upon
incubation with IL-1-/- APCs was reduced, and
that of IL-1ra-/- APCs was enhanced compared
with levels after incubation with wild-type APCs (Fig. 4B;
wild-type, 100%; IL-1-/-, 71 ± 4%
(p < 0.01); IL-1ra-/-,
123 ± 10% (p < 0.005); average ±
SD from three independent experiments). The expression levels of IL-1RI
on CD4+ DO11.10 T cells cultured with
IL-1-/- and IL-1ra-/-
APCs did not differ from that observed with wild-type APCs (data not
shown). These observations suggest that IL-1 produced by APCs plays a
crucial role in T cell priming by enhancing the expression of CD40L
and OX40.
|
|
B). This effect
of rIL-1 was not observed when high concentrations of anti-CD3 mAb
(1 and 10 µg/ml) were used (data not shown). High doses of rIL-1 (10
and 100 ng/ml) were, instead, inhibitory on the induction of CD40L and
OX40 expression (data not shown). We found that IL-1RI was not
expressed on naive CD4+ T cells, and it was
induced by the treatment with anti-CD3 mAb (Fig. 5C).
Thus, these results clearly show that IL-1 directly induces CD40L and
OX40 expression on CD4+ T cells, although
induction of IL-1RI through TCR signaling is necessary in advance. Dependency on CD40-CD40L signaling in IL-1-deficient mice
We, then, examined whether activation of CD40 can recover the
Ag-specific B cell response in IL-1-deficient mice. When splenic B
cells from wild-type and IL-1-/- mice were
cultured with mitomycin C-treated T cells from DO11.10 Tg mice in the
presence of the OVA peptide, the proliferative response of B cells from
IL-1-/- mice was reduced compared with those
from wild-type mice (Fig. 6A,
wild-type, 100%; IL-1-/-, 48 ± 12%
(p < 0.05); average ± SD from three
independent experiments). The OVA-specific Ig levels in the culture
supernatant of IL-1-/- B cells were also
reduced to 40% (Fig. 6A). Under this culture condition, the
CD40L-expressing T cell population was less in the culture with
IL-1-/- B cells than in the culture with
wild-type B cells (Fig. 6B). Moreover, OX40L expression of
IL-1-/- B cells was reduced compared with that
of wild-type B cells, indicating that IL-1-/- B
cells were activated only weakly (wild-type, 100%;
IL-1-/-, 69% ± 3% (p
< 0.01); average ± SD from three independent experiments; Fig. 6C). Since CD40 activation is necessary for the induction of
OX40L on B cells (20), this result is consistent with the
observation that CD40L expression was reduced on T cells activated with
IL-1-deficient APCs. Then, we tried to recover the immune response of
IL-1-/- B cells by treating cells with
agonistic anti-CD40 mAb. As shown in Fig. 6D, the
reduced proliferative response and Ab production of the mutant B cells
were recovered to normal levels when agonistic anti-CD40 mAb was
added to the culture.
|
A). On the other hand,
anti-IgM F(ab')2 plus anti-IgG
F(ab')2 administration was not effective to
recover SRBC-specific IgG production in IL-1-/-
mice to the wild-type levels, although SRBC-specific IgG levels were
increased in both IL-1-/- and wild-type mice
(Fig. 7B). Thus, it was shown that IL-1 can be substituted
by CD40 activation. These results suggest that IL-1 produced by APCs
plays an important role in T cell priming and Ab production by
enhancing the expression of CD40L and OX40 on T cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The importance of CD40-CD40L interaction in T cell priming and B cell activation has been amply documented (11, 12, 13, 21). It has also been shown that neither CD40-/- mice nor CD40L-/- mice are able to react with T-dependent (TD) Ags to produce IgG Ab efficiently (11, 22, 23). CD40L-/- mice also showed a profound reduction in the primary IgM Ab responses to SRBC (23), although the IgM anti-KLH response was not completely absent in CD40L-/- mice.
The OX40-OX40L signaling system has been suggested to play an important
role in the humoral immune response. OX40 ligation with OX40L activates
naive T cells to produce Th2 cytokines and differentiate into Th2 cells
(24, 25), and promotes Ab production against TD Ags
(26). Murata et al. (20) reported that Ab
production against KLH was impaired in OX40L-/-
mice. However, other investigators reported that serum Ag-specific Ig
levels were similar to those in wild-type mice when
OX40-/- or OX40L-/-
mice were immunized with various TD Ags, including vesicular stomatitis
virus, lymphocytic choriomeningitis virus, Theiler’s murine
encephalomyelitis virus, Leishmania major,
Nippostrongylus brasiliensis, nitrophenyl-conjugated chicken
globulin (NP-CGG), TNP-KLH, and TNP-OVA, indicating that the
OX40-OX40L system is not required under certain conditions of
immunization (27, 28, 29). These observations indicate that
the CD40L-CD40 and OX40-OX40L cosignaling systems play an important,
but not absolute, role in T cell-priming and Ab production. Thus, it is
suggested that the inefficiency of TD Ab production and T cell priming
in IL-1-/- mice is caused by the reduced
expression of CD40L and OX40 on T cells upon interaction with
IL-1-/- APCs. In support of this idea, we
showed that the defects in T cell-APC interaction could be rescued by
the addition of agonistic anti-CD40 Ab both in vivo and in
vitro.
The CD28-CD80/CD86 cosignaling system is known to be important for T cell proliferation and cytokine secretion in humoral immune responses (30). Both primary and secondary T cell responses and Th2 type cytokine secretion are impaired in CD80/CD86-/- mice (31). However, the expression levels of CD80 and CD86 on APCs were normal in IL-1-/- mice. Moreover, we showed that CTLA-4 Ig suppressed CD4+ DO11.10 T cell proliferation independently of the IL-1 deficiency. These results strongly suggest that IL-1 has a previously unknown T cell activation mechanism that differs from the CD28-CD80/CD86 system.
IL-1 function in the humoral immune response has been recently examined using IL-1RI-/- mice (8, 9). These reports showed that specific serum Ab levels were normal in IL-1RI-/- mice when these mice were immunized with TNP-KLH/alum or TNP-KLH/CFA either i.p. or s.c. Furthermore, they showed that KLH-specific secondary T cell proliferative responses were normal in these mice. These results apparently contradict our findings. This discrepancy is probably not due to a difference in the mouse strains used in the experiments, because we obtained the same results using IL-1-/- mice on the C57BL/6 background as those obtained using the BALB/c background mice. Another possibility could be that there were differences in the immunization method.
Many studies indicate that Ag dosage, adjuvant, and the route of
immunization (e.g., i.p., i.v., or s.c.) affect the efficiency of the
immune response and the Ig subclasses of the Abs. Different immune
responses depending on the immunization program employed among
investigators have been reported using
CD80/CD86-/- mice (32),
IL-6-/- mice (33, 34, 35, 36),
TNF--/- mice (17), and
OX40-/- and OX40L-/-
mice as described previously (20, 27, 28, 29). Regarding this,
it has been reported that the s.c. route of immunization may cause
local inflammation (37, 38). Adjuvants also cause
inflammation at the site of injection, which could potentially induce
the production of various inflammatory cytokines, including IL-1. Since
the functions of these inflammatory cytokines overlap partially, it is
conceivable that the adjuvant effect of IL-1 could be substituted by
some other cytokines, such as TNF- or IL-6. In a recent study it was
reported that using alum as an adjuvant could induce Th2 responses
independently from IL-4- and IL-13-mediated signals (39).
It is conceivable that the effects of IL-1 deficiency might not be
observed when mice were immunized with adjuvant or soluble Ags, as in
the reports by Glaccum et al. (8) and Satoskar et al.
(9).
Another possibility is that the discrepancy is caused by a difference
between protein Ags and particle Ags. With regard to this, it was
reported that SRBC-specific IgG production was impaired in
LT-/- mice, which show deficiencies in LNs
formation, splenic microarchitecture, germinal center formation, and
follicular dendritic cell network. Whereas IgG production against high
dose NP-OVA was observed normally in this mutant mouse, suggesting that
Ab production against SRBC depends on the follicular dendritic cell
clustering, while that against NP-OVA does not
(40, 41, 42).
This discrepancy is not caused by the difference in the mutant mice we used. We examined SRBC-specific Ab production in IL-1RI-/- mice without using any adjuvant and found that the immune response was reduced in both IL-1RI-/- and IL-1-/- mice of the C57BL/6J background and accelerated in IL-1ra-/- mice of the same background (data not shown).
In conclusion, these observations indicate that IL-1 is a potent activator of the humoral immune response, and that IL-1ra has important regulatory functions in the immune system. Immune-modulating activity via IL-1 is clearly of benefit for host defenses, as IL-1 produced upon infection with bacteria or viruses would enhance the immune response against these pathogens. Any deficiency of the IL-1/IL-1ra system, then, will probably cause serious problems in immunologic response. Our recent finding that IL-1ra-/- mice develop autoimmune arthritis supports this idea (7). This suggests that the balance between IL-1 and IL-1ra is of great importance in maintaining the homeostasis of the immune system. Involvement of IL-1/IL-1ra in various autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, psoriasis, lichen sclerosis, alopecia areata, and Sjogren’s syndrome has also been suggested (1, 43). Further elucidation of the control mechanisms of the IL-1/IL-1ra system should provide us with important cues in the quest to develop therapeutics for these diseases.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Current address: Institute for Experimental Animals, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
3 Address correspondence and reprint requests to Dr. Yoichiro Iwakura, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address: iwakura{at}ims.utokyo.ac.jp
4 Abbreviations used in this paper: DC, dendritic cells; IL-1RI and IL-1RII, IL-1R types I and II; IL-1ra, IL-1R antagonist; CD40L, CD40 ligand; OX40L, OX40 ligand; TD Ag, T-dependent Ag; TI Ag, T-independent Ag; SAC, splenic adherent cells; TNP, trinitrophenyl; KLH, keyhole limpet hemocyanin; Tg, transgenic; NP-CGG, nitrophenyl-conjugated chicken globulin.
Received for publication November 29, 2000. Accepted for publication April 16, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. J. Immunol. 142:3129.[Abstract]
, IL- 1, IL-1/, and IL-1 receptor antagonist shows that IL-1 is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187:1463.-deficient mice: a critical requirement for TNF in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184:1397.-deficient mice. Nature 382:462.[Medline]
(LT) supports development of splenic follicular structure that is required for IgG responses. J. Exp. Med. 185:2111.This article has been cited by other articles:
|
|
 |
|
  L. H. Ho, T. Ohno, K. Oboki, N. Kajiwara, H. Suto, M. Iikura, Y. Okayama, S. Akira, H. Saito, S. J. Galli, et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-Fc{epsilon}RI signals J. Leukoc. Biol., December 1, 2007; 82(6): 1481 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nakae, Y. Iwakura, H. Suto, and S. J. Galli Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17 J. Leukoc. Biol., May 1, 2007; 81(5): 1258 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Guay, T. A. Andreyeva, R. L. Garcea, R. M. Welsh, and E. Szomolanyi-Tsuda MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection J. Immunol., April 15, 2007; 178(8): 5124 - 5131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Chen, G. Sen, and C. M. Snapper Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine J. Immunol., November 1, 2006; 177(9): 6044 - 6051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M I Koenders, L A B Joosten, and W B van den Berg Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii29 - iii33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. O'Sullivan, H. E. Thomas, S. Pai, P. Santamaria, Y. Iwakura, R. J. Steptoe, T. W. H. Kay, and R. Thomas IL-1beta Breaks Tolerance through Expansion of CD25+ Effector T Cells. J. Immunol., June 15, 2006; 176(12): 7278 - 7287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nambu, S. Nakae, and Y. Iwakura IL-1{beta}, but not IL-1{alpha}, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses Int. Immunol., May 1, 2006; 18(5): 701 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nakae, H. Suto, M. Iikura, M. Kakurai, J. D. Sedgwick, M. Tsai, and S. J. Galli Mast Cells Enhance T Cell Activation: Importance of Mast Cell Costimulatory Molecules and Secreted TNF J. Immunol., February 15, 2006; 176(4): 2238 - 2248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsuki, S. Nakae, K. Sudo, R. Horai, and Y. Iwakura Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis Int. Immunol., February 1, 2006; 18(2): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsuki, K. Isoda, R. Horai, A. Nakajima, Y. Aizawa, K. Suzuki, F. Ohsuzu, and Y. Iwakura Involvement of Tumor Necrosis Factor-{alpha} in the Development of T Cell-Dependent Aortitis in Interleukin-1 Receptor Antagonist-Deficient Mice Circulation, August 30, 2005; 112(9): 1323 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Schmitz, M. Kurrer, M. F. Bachmann, and M. Kopf Interleukin-1 Is Responsible for Acute Lung Immunopathology but Increases Survival of Respiratory Influenza Virus Infection J. Virol., May 15, 2005; 79(10): 6441 - 6448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Haynes, S. M. Eaton, E. M. Burns, M. Rincon, and S. L. Swain Inflammatory Cytokines Overcome Age-Related Defects in CD4 T Cell Responses In Vivo J. Immunol., May 1, 2004; 172(9): 5194 - 5199. |
, Wild-type
APCs; •, IL-1-/- APCs. The results were confirmed in
another experiment. B, Expression levels of CD40L, OX40,
and IL-2R
