From the Institute of Gastroenterology and
§ Department of Pathology, Tokyo Women's Medical
University, 8-1 Kawata-cho, Shinjuku-ku, Tokyo 162-8666, Japan,
¶ Center for Immunology, The University of Texas Southwestern
Medical Center, Dallas, Texas 75390-9093,
The Basel Institute
for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland,
and ** Fox-Chase Cancer Center, Philadelphia, Pennsylvania 19111
Received for publication, January 12, 2001, and in revised form, March 20, 2001
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ABSTRACT |
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A hallmark of many inflammatory diseases is the
destruction of tissue cells by infiltrating hematopoietic cells
including lymphocytes, neutrophils, and macrophages. The regulation of
apoptosis of both target tissue cells and the infiltrating cells is one of the key events that defines the initiation and the progression of
inflammation. However, the precise picture of the apoptosis regulation
of the cells at the inflammatory sites is still unclear. We recently
isolated a novel apoptosis inhibitory factor, termed AIM, which is
secreted exclusively by tissue macrophages. In this report, we present
unique characteristics of AIM associated with liver inflammation
(hepatitis), identified by introducing an experimental hepatitis in
both AIM-transgenic mice, which overexpress AIM in the body, and normal
mice. First, endogenous AIM expression in macrophages is rapidly
increased in response to inflammatory stimuli. Second, AIM appears to
inhibit the death of macrophages in the inflammatory regions, judging
by the remarkably increased number of macrophages observed in the liver
from transgenic mice. In addition, we show that AIM also enhances the
phagocytosis by macrophages, which emphasizes the multifunctional
character of AIM. All these findings strongly provoke an idea that AIM
may play an important role in hepatitis pathogenesis in a sequential
manner; first AIM expression is up-regulated by inflammatory stimuli,
and then in an autocrine fashion, AIM supports the survival of
infiltrating macrophages as well as enhances phagocytosis by
macrophages, which may result in an efficient clearance of dead cells
and infectious or toxic reagents.
Apoptosis is a form of cell death that is achieved by programmed
signal cascades triggered by differential stimuli depending on the
variety of physiological situations (1-4). Accumulating evidence has
revealed that apoptosis plays a key role in the pathology of
inflammation (5-13). The present consensus is emerging that both
positive (inducing) and negative (inhibiting) regulation of apoptosis
of tissue cells influence the initiation and the progression of tissue
damage (14-17). It has been indicated that apoptosis at the
inflammatory sites seems to be induced by: 1) inflammatory cytokines
produced by the infiltrating hematopoietic cells as well as the tissue
epithelium cells (18-20) and 2) interaction of CD95 (also called Fas)
on the tissue cells and CD95 ligand (CD95L) predominantly expressed on
infiltrating T-lymphocytes (21-27). In particular, the prevention of
endotoxin-induced hepatitis by the defect of CD95/CD95L ligation
strongly implies that CD95-mediated apoptosis of hepatocytes is the
initial event in the process of hepatitis (21). In addition to
apoptosis of tissue cells, apoptosis regulation of infiltrating cells
also seems to influence the progression of inflammation. This
indication was recently drawn by the observation of non-obese diabetic
mice, a mouse model of human autoimmune diabetes (type I diabetes),
under CD95-deficient conditions, which were free from destruction of
insulin-producing pancreatic However, we are essentially ignorant of the negative (inhibitory)
regulation of apoptosis at the inflammatory sites, although apoptosis must be regulated both positively and negatively, and the
balance of these two regulations may critically influence the
inflammation progression. This is mainly because the extracellular ligands produced at the inflammatory sites that mediate inhibitory signals for apoptosis have not been well defined so far despite the
recent identification of many intracellular apoptosis inhibitory elements (14-17).
We recently isolated a novel murine apoptosis inhibitory factor, termed
AIM, which is exclusively secreted by tissue macrophages including
Kupffer cells in the liver (30, 31). AIM inhibits apoptosis triggered
by multiple stimuli including irradiation, glucocorticoid, and
CD95-cross-linking (30). At the inflammatory sites of most tissues, the
macrophage is one of the cell types that is observed from the very
early stage of inflammation (32-36). Hence it is possible that AIM
might play a role in the negative regulation of apoptosis of cells at
the inflammatory sites.
In this report, we applied a mouse hepatitis model to address potential
involvement of AIM in the progression of inflammation in
vivo. In addition, we present a new AIM function associated with
inflammation, enhancement of the phagocytic function of macrophages, and discuss the multifunctional character of AIM.
Mice--
Mice were bred and maintained in a specific
pathogen-free animal facility at the Basel Institute for Immunology
(Basel, Switzerland) and a semi-specific pathogen-free animal facility
at the Tokyo Women's Medical University (Tokyo Japan). All animal
experiments were approved by the research Ethics Committee of the Tokyo
Women's Medical University.
Generation of Transgenic Mice--
AIM cDNA was subcloned
into the pCAGGS expression vector (37). After the removal of the vector
sequence, a purified DNA fragment was microinjected into fertilized
eggs of (C57BL/6 × DBA/2)F1 mice. Embryos were transferred into
the oviducts of CD-1 foster mothers. Founders were screened for
transgene by PCR, and the resulting transgenic founders were bred with
C57BL/6 (B6) mice to generate progenies. Transgene-positive progenies
were back-crossed to B6 mice. After six back-crosses,
transgene-positive and -negative littermates were used for experiments.
Induction of Endotoxin-induced Fulminant Hepatitis--
Mice
were immunized by 1 mg/mouse of heat-inactivated
Propionibacterium acnes (Van Kampen Group, Inc., Utah) in
200 µl of phosphate-buffered saline by intravenous injection. 7 days
after the immunization, each mouse was challenged by intravenous
injection of 2.5 µg of lipopolysaccharide
(LPS)1 in 150 µl of
phosphate-buffered saline (38). At various time points after the LPS
injection, mice were sacrificed, and blood and liver specimens were
collected to evaluate liver damage.
In Situ mRNA Analysis and Histology--
The liver specimens
were fixed in 10% formalin and embedded in paraffin. 4-µm sections
were cut out and placed on silane-coated slides. These sections were
subjected to in situ hybridization using digoxigenin-labeled
(Roche Molecular Biochemicals) antisense-AIM cDNA probe (Ref. 30
and references therein). As a negative control, RNaseA (100 µg/ml)
pretreatment was carried out before hybridization. After hybridization,
sections were treated with antidigoxigenin-alkaline phosphatase, and
then signals were developed by 4-nitro blue tetrazolium chloride (NTB) treatment.
The fixed liver tissues were also used for histological analysis of
macrophage detection. Sections were stained with BM-8 antibody (BMA
Biochemicals), which recognizes pan-monocyte/macrophages including the Kupffer cells in the liver.
Phagocytosis Assay--
1.5 × 106 of either
RAW264 cells (a mouse macrophage cell line (39), provided by RIKEN Cell
Bank, Tsukuba, Japan) or mouse peritoneal macrophage cells derived from
thioglycolate-stimulated C57BL/6 mice (30) were cultured for 2 h
with appropriate numbers (cell:beads ratio was 25:1, according to the
Ref. 41) of fluorescein isothiocyanate-labeled polystyrene latex beads
(~1.95 µm in diameter; Sigma) in the presence or absence of
recombinant AIM (rAIM). Culture supernatant of the AIM-transfected
Chinese ovarian carcinoma cells was used as a source of rAIM (30, 31).
As a control, culture supernatant of nontransfected Chinese ovarian
carcinoma cells was used. After a 2-h incubation, cells were collected
by using a cell scraper followed by an extensive wash with
phosphate-buffered saline, then analyzed by fluorocytometry (FACScan;
Becton & Dickinson).
Binding Study--
Biotinylated rAIM protein and a control
protein (a transcription factor localized in the nucleus) generated by
recombinant baculovirus-infected Trichoplusia ni
egg cells were used for the binding study, as we described in Miyazaki
et al. (30) and Yusa et al. (31). After the binding
procedure of the proteins to either peritoneal macrophages or RAW264
cells, cells were analyzed using a FACScan cytometer (Becton Dickinson).
Induction of Hepatitis Strongly Up-regulated AIM Expression within
Macrophage/Kupffer Cells in the Liver--
Although AIM is exclusively
expressed by tissue macrophages, only part of the macrophages in the
tissue express AIM, suggesting the requirement of a specific
microenvironment surrounding the macrophages for AIM expression
induction (30). The precise mechanism for AIM expression regulation is,
however, entirely unknown. In the previous report, we demonstrated that
AIM was strongly expressed within infiltrating macrophages within
Bacillus Calmette Guérin-induced granulomas,
which may suggest potential up-regulation of AIM expression in response
to inflammatory stimuli (30). To test this possibility, we introduced
the endotoxin-induced hepatitis in C57BL/6 (B6) mice by immunizing mice
with P. acnes followed by LPS injection (38) and analyzed
AIM expression in both resident macrophages (Kupffer cells) and
infiltrating macrophages. Two hours after the LPS injection, although
there was no obvious increase of BM-8-positive cells (compare Fig.
1, a and c), most
of these cells revealed AIM expression when assessed by in
situ mRNA analysis (Fig. 1d). This was also
confirmed quantitatively by a Northern blot analysis for AIM expression
by using RNA from the liver of either before or 2 h-after hepatitis
induction (Fig. 1g). Thus, hepatitis induction rapidly
up-regulated AIM expression in Kupffer cells. A markedly increased
number of BM-8-positive cells was observed in the liver after 12 h, representing massive infiltration of macrophages into the liver
(Fig. 1e). Most of these cells also expressed AIM strongly (Fig. 1f). These results support the idea that inflammatory
stimuli rapidly induce AIM expression in macrophages.
Increased Number of Infiltrating Macrophages in Response to
Hepatitis Induction in AIM-transgenic Mice--
Rapid up-regulation of
AIM expression by hepatitis induction provokes a potential involvement
of AIM in hepatitis pathogenesis, either via inhibition of apoptosis or
another unknown function. In particular, since macrophages show a
remarkable binding capacity for AIM (Ref. 30, and see Fig.
5B this report), AIM may function on macrophages at
hepatitis regions in an autocrine fashion. To obtain a clue for the
possible role of AIM at inflammatory sites, we generated transgenic
mice overexpressing AIM under the control of chicken
Despite the high AIM level in the serum, spontaneous infiltration of
macrophages was not obvious, judging by the comparable numbers of
BM-8-positive cells in the liver of nonstimulated transgenic and
negative littermate mice (Fig. 3,
a and b). This was also the case in all other
tissues, as assessed by a histological analysis (data not shown). Thus
AIM doesn't appear to be involved in either chemotaxis or migration
induction of cells in vivo. However, in response to
hepatitis induction via endotoxin, transgenic mice apparently harbored
an increased number of infiltrating macrophages in the liver than did
control littermate mice (Fig. 3, c and d). In
addition, many focal accumulations of macrophages were observed in the
liver of transgenic mice. This accumulation was found at regions where
the destruction of the liver tissue was apparent, harboring marked
infiltration of lymphocytes and neutrophils (Fig. 3e).
Although these accumulations of inflammatory cells were also found in
control littermate mouse liver, the size and the number of them were
remarkably larger in transgenic mice.
At inflammatory sites, macrophages are exposed to many cytokines that
mediate apoptosis (18-20). Hence in AIM-transgenic mice, high doses of
AIM may support survival of macrophages at inflammatory sites by
inhibiting apoptosis triggered by these cytokines, resulting in
seemingly increased number of infiltrating macrophages.
It is well known that CD95 (Fas)-mediated apoptosis of hepatocytes
(liver cells) is an essential event of hepatitis (21). It is not
likely, however, that AIM also protects hepatocytes against apoptosis,
because the binding of AIM to primary hepatocytes is not obvious so far
as tested by a binding study using labeled recombinant AIM (data not
shown). In line with this, there was no apparent histological
difference in the destruction of hepatocytes, in hepatitis-induced
transgenic and negative littermate mice (data not shown). Thus AIM
appears to be associated with hepatitis by supporting macrophage
survival at inflammatory sites via apoptosis inhibitory effect, which
may contribute to efficient clearance of dead cells and infectious or
toxic reagents by macrophages. However, in certain tissues, AIM might
be involved in regulating inflammation progression not only by
supporting macrophage survival but also by preventing apoptosis of
tissue cells.
The precise mechanism of AIM-mediated apoptosis inhibition is not clear
yet. As we described in the previous reports, there was no significant
difference in the expression levels of various apoptosis-inducing or
-inhibiting elements, including c-FLIP, in thymocytes of
AIM AIM Enhances Phagocytotic Function of Macrophages--
When
analyzed histologically in a higher magnification, macrophages harbored
small nuclei within the cells that probably represent nuclei from
phagocytized cells. Interestingly, a significantly larger number of
macrophages harbored these small nuclei in AIM-transgenic mice than in
negative littermate mice. In addition, the number of these small nuclei
per macrophage was apparently larger in transgenic mice (Fig.
4). Thus AIM may activate the
phagocytotic function of macrophages.
To test this hypothesis, we determined whether AIM enhances
phagocytosis by macrophages in vitro by using rAIM produced
by AIM-transfected Chinese ovarian carcinoma cells (30). Either peritoneal macrophages or a macrophage-derived cell line, RAW264, both
of which have binding capacity of AIM (see Fig.
5b), were incubated with
fluorescein isothiocyanate-labeled polystyrene latex beads in the
presence or absence of rAIM and then the number of phagocytosed beads
in each cell was analyzed by a fluorocytometry (40). Fig. 5A
shows the histogram of fluorescein isothiocyanate intensity from
peritoneal macrophages that were incubated either in the presence
(solid line) or absence (dotted
line) of rAIM. There are several peaks, which represent the
number of phagocytized beads in each cell. The first peak (P0)
corresponds to the macrophages that had no bead. This population was
far smaller in size when macrophages were incubated in the presence of
rAIM (2.9% in rAIM (+) versus 13.3% in rAIM (
All together AIM apparently enhances the phagocytotic function of
macrophages. However, rAIM revealed more efficient enhancement in
peritoneal macrophages than in RAW264 cells. This is, perhaps, due to
the difference of the binding capacity for AIM between the two cell
types as shown in Fig. 5B, which clearly shows the significantly higher binding capacity of peritoneal macrophages.
Inflammatory Stimuli Up-regulate AIM Expression in
Macrophages--
As we previously reported (30), AIM expression
regulation harbors several unique characteristics. 1) AIM expression is
restricted in tissue macrophages, 2) in a tissue, AIM expression is
observed in only a part of the macrophages, (3) when ex vivo
macrophages are cultured on a plastic dish, AIM expression entirely
disappears, (4) AIM expression in macrophages is unable to be induced
in vitro by any reagents that are known to activate
macrophages, including phorbol 12-myristate 13-acetate, LPS, and
various cytokines. These previous observations implied that a specific
microenvironment is required for AIM expression induction in
macrophages (30).
In the present study, we found that inflammatory stimuli appear to
induce AIM expression in vivo. Soon after hepatitis
induction, most of resident macrophages (Kupffer cells) and
infiltrating macrophages in the liver revealed strong expression of
AIM. Since AIM expression had already been up-regulated in Kupffer
cells before infiltration of leukocytes was apparent, inflammatory
cytokines produced by the liver tissue cells as well as by Kupffer
cells themselves might predominantly induce AIM expression at the early stage of inflammation. At the later stage of inflammation, cytokines produced by infiltrating lymphocytes may also contribute to the up-regulation of AIM expression. Nevertheless, since AIM expression in
ex vivo macrophages is not induced on a plastic dish
in vitro even by various inflammatory cytokines (30),
inflammatory stimuli may synergies the basic mechanism of AIM
expression induction, which may depend on microenvironment,
e.g. cell-cell interaction between specific type of cells
and macrophages. Further study will precisely clarify the elements
required for AIM expression induction.
AIM Enhances Phagocytosis of Macrophages; Multifunctional Character
of AIM--
We recently reported that AIM induces strong and sustained
growth inhibition of B-lymphocytes in combination with TGF-
So far, a variety of reagents is known to activate phagocytotic
function of macrophages, including cytokines also secreted from
macrophages, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-4 and
-10 (42, 43). One might argue that enhancement of phagocytosis may be
an indirect effect; AIM might induce production of such cytokines in
macrophages, resulting in enhanced phagocytosis. It is, however,
unlikely because we could not detect any up-regulation of expression of
these cytokines in macrophages by AIM in
vitro,3 although
we cannot mutually exclude a possibility that AIM may induce an unknown
factor(s) that may enhance phagocytosis.
Perspective--
It may be worth emphasizing that the unique
characteristics of AIM that we presented in this report strongly imply
the association of AIM with hepatitis in a sequential manner. First,
AIM expression is up-regulated in response to inflammatory stimuli, and
then, in an autocrine fashion, AIM supports the survival of
infiltrating macrophages as well as activates phagocytosis by
macrophages, which may result in an efficient clearance of dead cells
and infectious or toxic reagents.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
cells by the infiltrating
T-lymphocytes. In these mice, a defect of CD95 appeared to decrease
apoptotic death of T-lymphocytes infiltrating into the pancreatic
Langerhans islets, resulting in the prevention of tissue damage
(28, 29). Thus, the regulation of both target tissue cells and
infiltrating cells influence the progression of inflammatory diseases.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Fig. 1.
Rapid up-regulation of AIM expression
by hepatitis induction. Shown is in situ
hybridization analysis of AIM expression (violet/dark
blue signals in b, d, and f) and
its comparison with immunolocalization of pan-macrophage (including
Kupfer cells) antigen, BM-8 (dark yellow/brown
signals in a, c, and e) in the
liver from mouse before (a and b), 2 h after
(c and d), and 12 h after (e and
f) inducing fulminant hepatitis. a and
b, AIM is expressed in few Kupffer cells. c and
d, 2 h after hepatitis induction, a far increased
number of Kupffer cells expressed AIM. e and f,
12 h after hepatitis induction, a large number of macrophages
infiltrated in the liver (e), and they expressed AIM
(f). Magnifications: a, c,
e, ×100; b, d, f, ×150.
g, Northern blot analysis for AIM expression. Total liver
RNA was obtained from either pre- or 2-h-after-hepatitis induction. 10 µg of RNA was separated on an agarose gel, blotted, and hybridized
with a 32P-labeled AIM or mouse -actin cDNA
probe.
-actin promoter
and cytomegalovirus enhancer (37) (Fig.
2a). These mice overexpress
AIM ubiquitously, resulting in a strikingly increased level of AIM
concentration in the serum (Fig. 2b).
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Fig. 2.
AIM transgenic mice. a,
transgene construct. A 1.0-kilobase (Kb) fragment of the
coding sequence (cds) of AIM cDNA was subcloned into the
pCAGGS expression vector, which contained cytomegalovirus
(CMV) enhancer, chicken -actin promoter, and rabbit
globin exon and intron (37). b, Western blot analysis of
serum from AIM-transgenic mouse or negative littermate mouse for AIM. 5 µl of serum from each type of mouse as well as 500 ng of recombinant
AIM protein produced by recombinant baculovirus-infected T. ni egg cells were size-fractionated on 10% SDS-polyacrylamide
electrophoresis gels, blotted on a membrane, and stained by anti-AIM
monoclonal antibody (clone 3G14; Ref. 20). Signals were developed by
the ECL system (Amersham Pharmacia Biotech).
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Fig. 3.
Potentially longer survival of inflammatory
macrophages in AIM-transgenic mouse liver. Liver sections from
AIM-transgenic mouse (a and c) and negative
littermate mouse (b and d) either before or
8 h after hepatitis induction were stained by BM-8 (dark
yellow/brown signals) for pan-macrophage (including
Kupffer cells) antigens. There is no increase of BM-8-positive cells in
transgenic mouse liver before hepatitis induction (a and
b). 8 h after hepatitis induction, a markedly larger
number of BM-8-positive cells were observed in transgenic mouse liver
than in negative littermate mouse liver (c and
d). In transgenic mouse liver, a number of accumulation of
BM-8-positive cells and leukocytes were detected (e).
Magnifications: a-d, ×100; e, ×200.
/
and AIM+/+ mice, as well as in a
macrophage-cell line, J774.A1, in the presence or absence of
recombinant AIM (30),2
suggesting that AIM appears to inhibit apoptosis of cells not simply by
modulating the expression of these known apoptosis-related molecules
but by mediating an independent signaling cascade.
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Fig. 4.
Enhanced phagocytosis by macrophages in
AIM-transgenic mouse liver. Liver sections from AIM transgenic
mouse (a) and negative littermate mouse (b and
c) 8 h after hepatitis induction were stained for BM-8
and analyzed in a high magnification (×400). A number of BM-8-positive
cells, which contained more than two small nuclei derived from dead
cells, were detected in transgenic mouse liver (a). In
contrast, BM-8-positive cells in negative littermate mouse contained 0 or 1 small nucleus derived from dead cells (b and
c).
)),
indicating most of macrophages incubated with rAIM phagocytized beads
in 2 h. In the absence of rAIM, 27.1% of macrophages phagocytized
a single bead (P1), 26.1% phagocytized two beads (P2), and 14.9%
phagocytized three beads (P3), respectively. There seemed to be a few
macrophages that had more than four beads (P4), although they did not
generate obvious peaks. In contrast, the major peak was P4, when cells were incubated in the presence of rAIM; 69% of cells had more than
four beads (P4 in Fig. 5A). Similar results were obtained when assessed by using a macrophage-derived cell line, RAW264. Almost
twice the number of cells achieved phagocytosis of beads in 2 h
when incubated with rAIM (60% of incubated cells in rAIM (+)
versus 34% of incubated cells in rAIM (
)). Furthermore,
the average of the intensity of FL-1-positive population was
significantly higher in the rAIM+ population (rAIM(+):rAIM(
) = 42:29), indicating each cell phagocytized larger number of beads in the
presence of rAIM.
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Fig. 5.
AIM accelerates phagocytotic function of
macrophages in vitro. A, peritoneal macrophages were
incubated with fluorescein isothiocyanate (FITC)-labeled
polystyrene latex beads for 2 h in the presence or absence of
rAIM. Cells were then analyzed for their uptake of the beads by FACScan
(Becton-Dickinson). P0-P3 correspond to the number of phagocytized
beads (e.g. P3 = 3-bead uptake), and cells that have
more than 4 beads together are represented as P4. In the presence of
rAIM (solid line) macrophages apparently showed enhanced
phagocytosis of beads as compared with cells in the absence of rAIM
(dotted line). B, AIM binding capacity of
peritoneal macrophages and a macrophage cell line, RAW264, are
presented as log fluorescence by black histograms. The
control protein bindings, which are regarded as backgrounds, are
represented by white histograms. Peritoneal macrophages
showed higher capacity of AIM binding than RAW264 cells.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
1 (31). Thus, other than apoptosis inhibitory effect, AIM has different functions depending on the target cell type and the combination with
other cytokine(s). In line with this, we identified that AIM enhances
phagocytotic function of macrophages. Contrary to the case of
B-lymphocytes (31), AIM revealed two different functions on
macrophages, apoptosis inhibition and enhancement of phagocytosis, without specific conditions. This multifunctional character of AIM is
reminiscent of various cytokines such as interleukin-4, which activates
B-lymphocyte proliferation in combination of IgM cross-linking as well
as induces immunoglobulin class switching toward IgE (41).
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ACKNOWLEDGEMENTS |
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We thank Dr. Sumiko Yamakawa and Itoe Okamoto Foundation for financial support, Dr. Shin Ohnishi (Tokyo, Japan) for discussions. The Basel Institute for Immunology was founded and supported by Hoffmann-La Roche Ltd, Basel Switzerland.
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FOOTNOTES |
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* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Center for
Immunology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., NA7200, Dallas, TX 75390-9093. Tel.:
1-214-648-7322; Fax: 1-214-648-7331; E-mail:
toru.miyazaki@UTSouthwestern.edu.
Published, JBC Papers in Press, April 9, 2001, DOI 10.1074/jbc.M100324200
2 I. Haruta, C. Minjares, and T. Miyazaki, unpublished results.
3 C. Minjares, S-i. Yusa, and T. Miyazaki, manuscript in preparation.
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ABBREVIATIONS |
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The abbreviations used are: LPS, lipopolysaccharide; rAIM, recombinant AIM.
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REFERENCES |
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