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Animal Models |
§
From the Institute of Pathology,*
I. Department of
Medicine, Division of Pathophysiology,
and
Institute of Clinical Chemistry,¶
University of
Mainz, Germany; IRBM P. Angletti,
Pomezia,
Rome, Italy; and Boehringer Ingelheim Research
Group,§
Mainz, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-6 and the closely related cytokines IL-11, ciliary neurotrophic
factor, leukemia inhibitory factor, oncostatin M, and cardiotrophin-1
interact with a multisubunit receptor complex4,5
that
induces intracellular signaling via the Janus kinase-signal transducer
and activator of transcription and ras-mitogen-activated protein-kinase
pathway.6,7
This receptor complex contains the
transmembranous signal transducer gp130 as a common component. For
IL-6, IL-11, and ciliary neurotrophic factor, the existence of specific
soluble receptors (sRs) has been demonstrated.8
sRs are
generated from membrane-bound precursors by limited
proteolysis.9-11
Soluble IL-6 receptor (sIL-6R) binds to
IL-6 before interaction with gp130 and modifies IL-6-induced signal
transduction, a process called transsignaling.8
In contrast
to sRs for tumor necrosis factor-
(TNF), IL-1, and IL-4 that act
antagonistically, sIL-6R is an agonistic receptor that stimulates
signal transduction and sensitizes cells to IL-6
stimulation.8,12
sIL-6R is required to mediate the IL-6
stimulatory effects on neuronal and hematopoietic cells in cell culture
systems13,14
and is found in elevated concentrations during
inflammation in patients.15
The specific in vivo
effects of the IL-6/sIL-6R interaction have not been defined so far.
Transgenic mice constitutively overexpressing human IL-6 develop plasma
cell proliferation with progression to plasmacytomas.16,17
Transgenic mice expressing the human sIL-6R do not develop any specific
morphological changes, because murine IL-6 does not bind to the human
IL-6R.12,18
Upon injection of human IL-6, however, sIL-6R
transgenic mice are hypersensitized toward IL-6, and the plasma
half-life of IL-6 is drastically prolonged.12
Here we describe the phenotype of mice constitutively and simultaneously overexpressing human IL-6 and sIL-6R and show that these mice are different from IL-6 transgenic mice: 1) IL-6/sIL-6R coexpression leads to hepatocellular hyperplasia as well as to secondary liver pathology, including extensive necrosis and peliosis; 2) sIL-6R enhances the stimulatory effect of IL-6 on plasma cells and accelerates significantly plasmacytoma development; and 3) sIL-6R recruits extramedullary hematopoietic cells to the stimulatory effect of IL-6 and thus mediates excessive hematopoiesis in spleen and liver. Our results demonstrate that, in addition to the sensitizing effect of sIL-6R on plasma cells, cell populations that are not responsive to IL-6 alone become activated by the complex of IL-6/sIL-6R in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The generation of transgenic mice expressing human sIL-6R or human IL-6 has been described.12,19 The expression of the sIL-6R transgene was under control of the phosphoenolpyruvate carboxykinase promoter, which is active in liver and kidney.20,21 The promoter is known to be silent prenatally and is induced from day 3 after birth. The IL-6 transgene was under control of the murine metallothionein-1 promoter. Double-transgenic mice were generated by crossing homozygous sIL-6R and IL-6 transgenic mice. The transgene status was assayed by polymerase chain reaction as described previously.12,19 Overall, 86 transgenic mice between the ages of 3 and 16 weeks were investigated; 22 mice were transgenic for IL-6, 31 for sIL-6R, and 36 mice were double transgenic for both IL-6 and sIL-6R. The presence of the IL-6 transgene led to serum concentrations of IL-6 between 10 and 20 ng/ml in IL-6 single-transgenic and IL-6/sIL-6R double-transgenic mice; sIL-6R single-transgenic mice and IL-6/sIL-6R double-transgenic mice showed sIL-6R serum concentrations between 4 and 8 µg/ml.12,22
Peripheral Blood Cell Counts and Plasma Enzyme Activities
Peripheral blood was taken under general anesthesia by cardiac puncture. The cellular composition of 100 µl heparinized blood was analyzed in a Cell Dyn 3500 hemocounter (Abbott, Delkenheim, Germany). Plasma enzyme activities of alanine aminotransferase and aspartate aminotransferase (AST) were determined according to standard methods using an automated procedure.
Organ Weight and Histomorphology
Upon sacrifice, total body weight and organ weights were recorded. Tissues were fixed in 4% formaldehyde/phosphate-buffered saline and embedded in paraffin; bone sections were decalcified in ethylenediaminetetraacetic acid. Sections 1 to 2 µm were stained with hematoxylin/eosin. Stained sections were viewed and photomicrographs were taken with a Diaplan microscope (Leica, Bensheim, Germany). When a significant focal or diffuse accumulation of plasma cells was detected only in a single location, eg, spleen, the lesion was termed plasma cell proliferation. When plasma cell proliferation exhibited a focal, mostly nodular pattern frequently showing significant nuclear atypia and involving two or more different organs, the lesions were judged to constitute a plasmacytoma. Extramedullary hematopoiesis was evaluated histologically and scored as follows: 0, absent; +, mild; ++, moderate; and +++, severe/maximal; in the spleen, where extramedullary hematopoiesis persists in normal mice, the presence of physiological hematopoiesis equaled a score of +. The extent of liver pathology, consisting of hepatocellular hyperplasia, areactive necrosis and peliosis, was scored as follows: 0, absent; +, mild; ++, moderate; and +++, severe.
Analysis of Hepatocellular Proliferation
Hepatocellular proliferation was analyzed by immunohistochemistry for proliferating cell nuclear antigen (PCNA) on sections from formalin-fixed and paraffin-embedded liver tissues. Immunodetection was performed using a monoclonal antibody that specifically reacts with the PCNA p36 protein expressed at high levels in proliferating cells (Santa Cruz Biotechnology, Santa Cruz, CA). Specific immunoreactivity was detected by the indirect avidin-biotin complex method using diaminobenzidine as the chromogen. The percentage of positive hepatocytes was determined by evaluating at least 500 hepatocytes per animal on different parts of the liver section. Only those hepatocytes showing distinct nuclear staining were judged as positive.
To exclude secondary effects induced by liver necrosis or activated hepatic hematopoiesis, only animals between 6 and 7 weeks of age were analyzed. In IL-6/sIL-6R double-transgenic mice, only those animals were studied that showed neither hepatocellular necrosis nor activated hepatic hematopoiesis by careful histological analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-6/sIL-6R mice displayed a significant phenotype. They were smaller than control or single-transgenic mice and had a reduced body weight. Moreover, they developed distended abdominal regions caused by two- to fourfold increases of liver and spleen weight relative to the total body weight. Livers appeared dark in color and had a rugged and humpy surface caused by round, whitish, and (with respect to the liver surface) elevated foci. The spleen was diffusely and symmetrically enlarged. Weight and macroscopic appearance of the other organs and behavior of the mice were in general not suspicious, with the exception of plasmacytoma development (see below).
sIL-6R Enhances the Proliferative Effect of IL-6 on Plasma Cells
IL-6 transgenic mice are known to frequently develop plasma cell
proliferations and plasmacytomas.16,17
In our study, plasma
cell proliferations were first observed in the spleen and further
progressed to multifocal plasmacytomas detectable in different organs,
such as liver, spleen, lung, kidney, and bone marrow (Table 1
; Figure 1
, C and D). None of 13 IL-6 transgenic
mice younger than 11 weeks of age developed plasmacytoma, whereas 7 of
9 mice that were 11 weeks or older developed plasmacytomas. None of 31
sIL-6R transgenic mice between 3 and 16 weeks of age showed plasma cell
proliferation or plasmacytoma (Table 1)
.
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; Table 1
). Between
5 and 11 weeks of age, 7 of 13 animals showed plasma cell
proliferations (5 animals) or plasmacytomas (2 animals). All 15 animals
beyond the age of 11 weeks had plasmacytomas. These data demonstrate
that the presence of the sIL-6R significantly accelerates the
development of IL-6-induced plasmacytomas. Also, in IL-6/sIL-6R
double-transgenic mice, plasmacytoma development was seen more
frequently as compared with IL-6 single-transgenic mice (Figure 1
, A
and B). Extramedullary Hematopoiesis in IL-6/sIL-6R Double-Transgenic Mice
The development of extramedullary hematopoiesis in transgenic and
nontransgenic mice is demonstrated in Table 2
. In nontransgenic mice or
single-transgenic mice, mild extramedullary hematopoiesis was present
in the spleen but absent in the liver (not shown).
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. Bone marrow
hematopoiesis examined in femoral sections was not significantly
different between single- and double-transgenic mice (data not shown).
In IL-6/sIL-6R double-transgenic mice, however, extramedullary
hematopoiesis was extensively activated (Table 2)
. Proliferating
hematopoietic foci that increased in size with the age of the mice were
observed in spleens and livers from the age of 4 weeks on. In mice
between 3 and 4 weeks of age, 6 of 7 animals had developed moderate or
severe hematopoiesis as compared with 0 of 9 in sIL-6R mice; 3 of 6
IL-6 mice had moderate hematopoiesis. Fifteen of 15 mice 11 weeks or
older displayed severe hematopoiesis compared with 0 of 5 sIL-6R mice
and 8 of 9 IL-6 mice, in which hematopoiesis was only moderate and only
present in the spleen.
Interestingly, no significant extramedullary hematopoiesis was observed
in organs other than spleen and liver. Histology showed that splenic
and hepatic hematopoiesis were different. In the spleen, the number of
erythro- and granulopoietic cells as well as megakaryocytes appeared to
be elevated to an equal extent (Figure 2
,
A and C). However, hepatic hematopoiesis was predominantly
granulopoietic (Figure 2D)
. Splenic hematopoiesis generally preceded
hepatic hematopoiesis and was more severe within the same animal
(Figure 2
, A and B). Furthermore, splenic hematopoiesis diffusely
involved the whole organ and dissolved the definition of the red and
white pulp (Figure 2
, A and C). In the liver, the number and size of
hematopoietic foci increased with time but remained localized (Figure 2D)
. Frequently, hepatic hematopoietic foci were accompanied by
significant fibrosis (see below).
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) matched
well to the time course of the cellular blood components. A significant
rise of white blood cells (Figure 3A)
consisting mainly of neutrophilic granulocytes (Figure 3B)
occurred in
IL-6/sIL-6R double-transgenic mice from the age of 8 weeks on but not
in the IL-6 or sIL-6R single-transgenic mice, nor in control mice. In
double-transgenic mice, erythrocyte counts (Figure 3C)
and thrombocyte
counts (Figure 3E)
already increased between the ages of 2 and 4 weeks
and remained high throughout the study period.
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IL-6/sIL-6R double-transgenic mice developed significant liver
pathology that was not observed in IL-6 or sIL-6R single-transgenic
mice, except plasmacytoma infiltrates in IL-6 transgenic animals (Table 3)
. Normal liver morphology was seen in
all single-transgenic mice or control animals (Figure 4A)
. In IL-6/sIL-6R double-transgenic
mice, the development of multifocal hepatocellular hyperplasia,
frequently surrounded by areactive necrosis and peliosis was observed
from the age of 4 weeks on (Figure 4
, B and C). Necrosis and peliosis
were predominantly found in the perivenular (zone III) parenchyma,
whereas hepatocellular hyperplasia extended multifocally from the
periportal parenchyma (Figure 4B)
. In a few animals that showed
extensive necrosis and peliosis, focal coagulation was infrequently
found within the distended sinusoids. Liver pathology, especially the
extent of necrosis and peliosis, was quite variable although
demonstrable in the majority of IL-6/sIL-6R double-transgenic mice. In
5 to 10-week-old double-transgenic mice, four animals showed mild or
moderate hepatocellular hyperplasia, respectively. Two animals showed
severe hyperplasia. In mice 11 weeks old or older, three animals showed
mild, five animals moderate, and three animals severe hyperplasia
(Table 3)
. The severity of necroses as demonstrated by the histological
score (see Materials and Methods) was reflected by the elevation of
liver transaminases (Figure 5)
. Whereas
single-transgenic mice and nontransgenic littermates had normal serum
transaminases (data not shown), in double-transgenic mice there was an
elevation of transaminases in strict correlation with the histological
score. In mice with mild necrosis, the mean AST level was 124 ±
13 U/ml; in those with moderate necrosis, the mean AST level was
273 ± 30 U/ml; and in mice with severe necroses, AST levels were
746 ± 105 U/ml (Figure 5)
. One IL-6/sIL-6R double-transgenic and
one IL-6 single-transgenic mouse, both with multiorgan involvement of
plasmacytoma, exhibited plasmacytoma kidneys with significant hyaline
deposition.
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To determine whether hepatocellular proliferation was reactive to
hepatic necrosis or to activated hepatic hematopoiesis,
double-transgenic mice, as well as IL-6 and sIL-6R single-transgenic
mice, all without hepatocellular necrosis or hepatic hematopoiesis,
were selected for proliferation analysis. We used a monoclonal antibody
recognizing the PCNA p36 protein, also known as cyclin or polymerase
D-associated protein, which is synthesized in early G1 and S phases of
the cell cycle and serves as an excellent marker for proliferating
cells. Semiquantitative evaluation of PCNA immunohistology demonstrated
that hepatocellular proliferation in IL-6/sIL-6R double-transgenic mice
(Figure 6C)
is highly increased compared
with IL-6 (Figure 6A)
and sIL-6R (Figure 6B)
single-transgenic animals.
It turned out that in the double-transgenic animals, 92% of the
hepatocytes stained positive for PCNA, whereas in IL-6 and sIL-6R
single-transgenic mice, only 5% and 7%, respectively, of the
hepatocytes were PCNA positive (Figure 6D)
. These results demonstrate
that hepatocellular proliferation is activated in hepatocytes
independently of hepatic necrosis and hematopoiesis (Figure 7)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The severe extramedullary hematopoiesis observed in IL-6/sIL-6R double-transgenic mice was not a compensatory event secondary to altered medullary hematopoiesis, given that analysis of femoral bone marrow sections in IL-6/sIL-6R mice showed neither a reduction nor altered composition of cellular components nor significant fibrosis.22 Plasmacytoma infiltrates in the bone marrow were only found in a few mice and much later in life compared with the onset of extramedullary hematopoiesis. Thus, activated extramedullary hematopoiesis appears to be a direct consequence of combined IL-6/sIL-6R overexpression. This notion is supported by recent observations obtained in vitro that the expansion of human hematopoietic progenitor cells is enhanced by IL-6/sIL-6R but not by IL-6 alone.14,23 The extramedullary hematopoiesis observed in IL-6/sIL-6R transgenic mice indicates that IL-6/sIL-6R complexes are potent stimulators of hematopoietic progenitor cells in vivo and that these cells do not express IL-6R and therefore are not responsive to IL-6 alone.
Interestingly, significant extramedullary hematopoiesis was only detectable in the primary hematopoietic organs, spleen and liver, but not elsewhere in the body. Thus, it can be hypothesized that activated hematopoiesis may arise from persisting hematopoietic progenitor cells in these organs. In keeping with that, activation of splenic hematopoiesis preceded and predominated hepatic hematopoiesis, reflecting significant pre-existing splenic hematopoiesis and the absence or rarity of hematopoietic progenitor cells in normal adult liver. Furthermore, activated and pre-existing hematopoiesis reflected the differential composition of hepatic and splenic hematopoiesis in that splenic hematopoiesis showed a balanced composition of all three lines (granulopoiesis, erythropoiesis, megakaryocytes), whereas hepatic hematopoiesis was predominantly granulopoietic. Nevertheless, it cannot be excluded that IL-6/sIL-6R signaling acts preferentially on circulating hematopoietic stem cells and that specific homing factors recruit these cells either to the liver or to the spleen and regulate their differentiation.
It has recently been demonstrated that the presence of sIL-6R on the plasma membrane of hepatocytes, which are responsive toward IL-6, leads to their sensitization with regard to the IL-6 stimulation.12 Moreover, the time course of the IL-6-induced acute-phase response in the liver was drastically prolonged.12 In this respect, the earlier onset and increased occurrence rate of plasmacytomas in IL-6/sIL-6R transgenic mice in comparison with IL-6 transgenic mice16,17 can be explained by the presence of the sIL-6R. This raises the question as to whether the sIL-6R or soluble cytokine receptors of other IL-6 family members contribute to pathophysiological manifestations caused by this cytokine family.24
IL-6 is known to be involved in bone diseases and hematologic disorders, such as Castleman's disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, and multiple myeloma.24 So far, however, little information is available as to whether in vivo concentrations of soluble cytokine receptors correlate with the course of these diseases. In three recent clinical studies, the presence of elevated levels of the sIL-6R was associated with reduced therapeutic response,25 increased disease activity,26 and poor survival27 in patients with plasmacytomas. However, further clinical studies will have to address the question as to whether serum sIL-6R concentrations in patients suffering from multiple myeloma correlate with clinical stage and disease progression and thus influence therapeutic aggressiveness.
It has recently been shown that the sIL-6R acts predominantly in a paracrine rather than in a systemic fashion.28 Therefore, local concentrations of soluble cytokine receptors appear to be even more relevant than serum concentrations. Highly elevated levels of sIL-6R have been detected in patients with chronic lymphocytic leukemia and leukemic centrocytic lymphoma.29 From the in vivo effect of coordinate IL-6/sIL-6R overexpression on plasmacytoma development, it can be hypothesized that elevated levels of soluble cytokine receptors of the IL-6 family lead to increased severeness of IL-6-mediated diseases.
In contrast to IL-6 and sIL-6R single-transgenic mice, severe liver pathology was observed only in IL-6/sIL-6R double-transgenic mice from the age of 4 weeks on. Peliosis and necrosis, although sometimes significant, appear to be rather secondary phenomena due to disturbed blood flow caused either by altered blood composition or hepatocellular hyperplasia. Detailed proliferation assays have clearly shown that increased hepatocellular proliferation occurs independently of hepatic necrosis and hematopoiesis. These results demonstrate that the highly increased hepatocellular proliferation is a direct consequence of the constitutive overexpression of IL-6 and the sIL-6R, leading to a permanent stimulation of gp130 molecules on hepatocytes. At present, however, it is unclear as to whether this effect is mediated directly by IL-6/sIL-6R or indirectly, eg, by activation of hepatocellular growth-stimulating factors in other cell types such as extramedullary hematopoietic cells.
Two recent studies have suggested a role of IL-6 in liver cell
proliferation. First, Cressman et al30
have shown that
IL-6-deficient mice have a severely impaired capacity for liver
regeneration after partial hepatectomy. Secondly, after partial
hepatectomy in rats, there is a marked rise of TNF- followed by an
increase of IL-6-serum levels, suggesting an active role of TNF- and
IL-6 in liver regeneration.31
DNA synthesis as well as
STAT3 and nuclear factor-
B activation is severely compromised in
TNF- type 1 receptor-deficient mice after partial
hepatectomy.32
These findings can be corrected after the
injection of IL-6.32
These data suggest that TNF- acts
upstream of IL-6 and that one of its major roles could be the
regulation of IL-6 secretion.
We have now for the first time demonstrated that the combination of IL-6 and the soluble IL-6R synergize to promote liver cell hyperplasia in vivo. After hepatectomy and perhaps in clinical situations associated with acute liver failure, there might be a significant production of IL-6 and the soluble IL-6R from different cells (Kupffer cells, hepatocytes) in the remaining liver. This could be an intrinsic mechanism of the organ to initiate and drive liver regeneration. The presented in vivo data now provide direct evidence that liver cells proliferate in vivo in response to the combination of IL-6 and sIL-6R, but not in response to IL-6 alone.
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Acknowledgements |
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Footnotes |
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Supported by grants from the Deutsche Forschungsgemeinschaft, Bonn, Germany (to MP, SR-J) and from the Stiftung Rheinland-Pfalz für Innovation (PS, SR-J). MB is supported by the Boehringer Ingelheim Foundation.
Peter Schirmacher and Malte Peters contributed equally to this work.
Accepted for publication May 19, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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