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Divisions of
* Gastroenterology and Hepatology and
General Internal Medicine, Department of Medicine, University Hospital Innsbruck, and
Department of Biostatistics, University of Innsbruck, Innsbruck, Austria
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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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In ACD, the imbalances of iron homeostasis lead to reduced serum iron
concentrations and transferrin saturation, whereas ferritin levels,
reflecting body iron stores, are often elevated (1, 2, 3, 4). In
addition, transferrin concentrations are usually normal, and serum TfR
levels are slightly increased (5). One central mechanism
underlying ACD is a diversion of iron traffic which leads to withdrawal
of iron from the sites of erythropoiesis and the circulation to the
storage compartment in the reticuloendothelial system, thus causing at
the same time hypoferremia and hyperferritinemia. Other mechanisms
involved in the pathophysiology of ACD may include marrow progenitor
inhibition and a poor response to erythropoietin (EPO). Several
cytokines have been demonstrated to affect iron homeostasis by various
mechanisms (6, 7). Proinflammatory cytokines, such as
IL-1
and TNF-
, induce hypoferremia by modulating macrophage iron
metabolism via induction of ferritin biosynthesis (8, 9, 10, 11).
The Th1 cytokine IFN-
may contribute to ACD mainly by blocking
erythropoiesis directly (3); however, its role in iron
homeostasis is controversial (6, 7, 12, 13, 14, 15).
Interestingly, recent in vitro evidence has suggested that the
anti-inflammatory cytokines IL-4 and IL-13 may contribute to the
diversion of iron traffic in ACD by increasing iron uptake and storage
in activated macrophages (16). Thus pro- and
anti-inflammatory cytokines may collaborate in the development
of ACD.
IL-10 suppresses inflammation by various pathways including diminished
production of IL-1, IL-1, TNF-, IL-8, and toxic radicals such
as NO (17). This cytokine has been recently introduced for
the treatment of chronic inflammatory conditions such as Crohn’s
disease (18). On the basis of in vitro evidence showing
profound effects of anti-inflammatory cytokines on iron homeostasis
(16), we assessed in the present study possible effects of
rHuIL-10 on iron metabolism in vivo and subsequently toward an
involvement of the cytokine in the anemia of inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with chronic active Crohn’s disease (CACD). Patients had to be between 18 and 65 years of age and to have active steroid-resistant Crohn’s disease involving the colon or both the ileum and colon, with or without external fistula. Active disease was defined as having a Crohn’s disease activity index of between 200 and 400 despite treatment with prednisone (10–40 mg/day for at least 3 mo) before study given alone or in combination with 6-mercaptopurine or azathioprine. These therapies had to be stable during the study. Patients were allowed to take aminosalicylates and/or antibiotics, providing that the used dosages were kept stable during the study. The protocols and consent procedure were approved by the local medical ethics committees.
Study design
One of four doses (1, 4, 8, and 20 µg/kg body weight) of IL-10 (Schering Plough, Kenilworth, NJ) was administered once daily s.c. during 28 consecutive days. A total of 329 patients were included in the study. Patients were screened for eligibility during a period of 14 days. Therapy was initiated at day +1. The study medication was administered at the same time of the day during the study period. After the 28-day treatment period, patients were followed up for 4 wk.
Measurement of hemoglobin and hematocrit
A total of 329 patients were analyzed for changes in hemoglobin and hematocrit concentrations during the study. The study population included 66 patients in the placebo group, 67 patients in the 1-µg/kg group, 64 patients in the 4-µg/kg group, 65 patients in the 8-µg/kg and 67 patients in the 20-µg/kg body weight IL-10 group. Analyses were performed twice in the pretreatment period, on days +8, +15, and +29 during therapy, and at wk 2 and 4 of follow-up.
Measurement of iron, transferrin, transferrin saturation, soluble TfR (sTfR), ferritin, and hematological laboratory variables
Serum levels of iron, transferrin, sTfR, and ferritin were analyzed in a subgroup of the patients described above consisting of 10 patients treated with placebo, 12 patients treated with 1 µg/kg, 12 patients treated with 4 µg/kg, 10 patients treated with 8 µg/kg, and 10 patients treated with 20 µg/kg body weight IL-10 s.c. for 28 days. Serum levels of iron, transferrin, sTfR, and ferritin were assessed on days -1, +15, and +29 of therapy and after 4 wk of follow-up. Serum levels of transferrin and ferritin were determined using an immunoturbimetric assay (both from Roche Diagnostics, Mannheim, Germany) and sTfR was assessed using a specific ELISA (Orion Diagnostics, Helsinki, Finland). Serum EPO concentrations were determined by ELISA (DRG Diagnostics, Marburg, Germany), lactate dehydrogenase (LDH) as well as reticulocyte, erythrocyte, and platelet counts were assessed by automated laboratory test systems.
In vitro studies
THP-1 cells, a human myelomonocytic cell line, were investigated
in this study. Cells were cultured in RPMI 1640 supplemented with 10%
(v/v) heat-inactivated FCS, 2 mM L-glutamine, 100 U/ml
penicillin, and 100 µg/ml streptomycin (Life Technologies, Vienna,
Austria) at 37°C in humidified air containing 5%
CO2. Cells were treated with 100–500 U/ml of
human rIFN- (Life Technologies) for 24 h, with no further
supplements or after preincubation with rHuIL-10 (Schering-Plough) for
1 h. Treatment with the indicated concentrations of IFN- and/or
IL-10 did not result in reduced viability of cells in comparison with
untreated controls as checked by trypan blue exclusion (data not
shown).
Northern blotting
After 24 h, cells were harvested and washed, and RNA was extracted by a guanidinium thiocyanate method and further subjected to Northern hybridization exactly as described elsewhere (16).
Metabolic labeling and immunoprecipitation
THP-1 cells (1 x 107) were stimulated with cytokines as described above for 24 h. After this, cells were washed twice with methionine-free medium and labeled with [35S]methionine (50 µCi) for 2 h. Quantitative immunoprecipitation of equal amounts of trichloroacetic acid-insoluble radioactivity was conducted with polyclonal ferritin Abs (Roche Diagnostics, Indianapolis, IN) and analyzed by 12.5% SDS-PAGE with subsequent autoradiography as described (16).
For determination of intracellular ferritin content, cell extracts were prepared by repeated freezing and thawing, and ferritin concentrations were then determined in the supernatants using a commercially available ELISA (DRG Diagnostics).
Statistical analysis
ANOVA for repeated measurements was used to analyze differences in means between and within treatment groups. Hypotheses were tested two-sided on a global significance level of 0.05. Post hoc multiple comparisons between IL-10 groups and placebo were performed with Dunnett’s t test. Descriptive statistics are presented using means ± SEM. Comparisons within groups were assessed by ANOVA. Calculation of correlations was assessed by Spearman rank correlation technique using Bonferroni correction for multiple tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a total of 329 patients, hemoglobin and hematocrit values were
evaluated before IL-10 treatment, on days +15 and +29 of therapy and at
4 wk of follow-up. As hematocrit values paralleled hemoglobin values,
only hemoglobin values are reported. Pretreatment hemoglobin values did
not differ significantly between the various treatment groups (Fig. 1
A). Although no changes in
hemoglobin levels during treatment were observed in the placebo group
and in patients receiving the lowest dose of IL-10 (1 µg/kg),
treatment with higher dosages of IL-10 (
4 µg/kg) resulted in a
highly significant decrease of hemoglobin concentration (Fig. 1A). This effect was dose dependent and most pronounced in
patients receiving 20 µg/kg body weight IL-10. In these patients, a
significant decrease in hemoglobin developed even within 1 wk of
cytokine treatment, and hemoglobin levels further decreased
progressively, reaching the lowest values at the end of therapy (day
+29) (Fig. 1A). One patient randomized to receive 20 µg/kg
IL-10 developed anemia (hemoglobin, 6.5 mg/dl) at day +15 of therapy
(pretreatment value 12.1 mg/dl) and received a blood transfusion.
Because this patient achieved clinical remission, she was kept on IL-10
and her anemia recovered at follow-up wk 2. Hemoglobin values recovered
4 weeks after discharge of therapy in all IL-10 treatment groups, and
hemoglobin values were comparable with those before initiation of
therapy (Fig. 1A).
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To see whether the observed decrease in hemoglobin levels and the
development of anemia in patients receiving IL-10 are paralleled by
disturbances of iron homeostasis, we investigated serum parameters of
iron metabolism. In patients receiving 4 µg/kg IL-10 or more, serum
ferritin levels increased within 2 wk (Fig. 1
B and Table I), and the maximum differences were
observed at the end of therapy (day +29) as compared with patients
receiving placebo (Fig. 1B and Table I). Although there was
a significant increase in ferritin levels during therapy in patients
receiving 4 µg/kg IL-10 as estimated by ANOVA (Table I), differences
in ferritin concentrations at day +15 and day +29 as compared with
patients treated with placebo at the same time points became
significant only in the 8-µg/kg and 20-µg/kg IL-10 group as
estimated by Dunnett’s test (Fig. 1B). After the end of
therapy, ferritin levels returned to normal or to pretreatment levels
within 4 wk (Fig. 1B and Table I).
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). However, sTfR increased
with a much slower kinetics than ferritin levels showing significant
differences as compared with pretreatment sTfR levels only at the end
of therapy (day +29; p <0.05). Thereafter, sTfR levels
returned to pretreatment levels (Table I). No significant changes or
trends were observed for serum iron, serum transferrin levels, total
iron-binding capacity, and transferrin saturation in either treatment
group (details not shown). Chancing associations between hemoglobin and iron parameters under IL-10 therapy
To determine whether the changes in ferritin, sTfR, and hemoglobin
levels may be interconnected, we separately calculated Spearman rank
correlations in patients receiving IL-10 at dosages 8 mg/ml and in
patients receiving placebo or the lowest dose of IL-10 (1 µg/kg). In
both groups, sTfR levels were inversely related to hemoglobin
concentrations, which supports the role of sTfR in indicating iron
availability to erythroid progenitor cells, with sTfR being high when
iron supply to progenitor cells is limited (5, 20). When
investigating the interactions of ferritin with hemoglobin and sTfR,
contrasting differences become evident between the two groups. Whereas
ferritin is positively related to hemoglobin levels in placebo patients
(Table II) a significant inverse
relationship is found in patients receiving IL-10 at higher dosages
(Table II). Moreover, whereas sTfR was negatively correlated to
ferritin levels in the placebo group, just the opposite was true in
patients receiving IL-10 (8 µg/dl) (Table II).
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To study whether or not other mechanisms may also be
involved in the development of anemia in patients treated with IL-10,
we retrospectively analyzed additional hematological parameters.
Neither mean corpuscular hematocrit nor mean corpuscular volume changed
in patients receiving placebo or IL-10 at the dosages used (details not
shown). To examine a possible hemolysis-inducing effect of IL-10, we
analyzed serum levels of LDH. As demonstrated in Fig. 2A, LDH concentrations did not
change significantly over time in control patients, whereas a
significant reduction during therapy was observed in patients receiving
the highest dosage of IL-10 (20 µg/kg).
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A). No changes in platelet counts
were observed in patients receiving placebo.
We then analyzed a possible effect of IL-10 on erythropoiesis. When
investigating reticulocyte counts, no significant changes over time
were observed in patients receiving placebo (Fig. 2B). In
patients receiving the highest dose level of IL-10, reticulocyte
numbers progressively increased during IL-10 treatment
(p < 0.001 by ANOVA) and were almost 2-fold higher
at the end of therapy (day +29, 0.45 ± 0.03%) than at baseline
(Fig. 2B). After the end of therapy, reticulocyte counts
returned to pretreatment values during 4 wk of follow-up (Fig. 2B).
We then investigated the possibility that IL-10 may affect the
endogenous production of EPO. EPO levels increased significantly over
time in patients receiving the highest IL-10 dosages
(p < 0.01 by ANOVA) and paralleled the increase in
reticulocyte counts (Fig. 2B). Moreover, EPO concentrations
in the IL-10 treatment group were inversely correlated to hemoglobin
levels at these time points (p < 0.001 at day +29
as estimated by Spearman rank correlation). EPO levels returned to
normal after the end of IL-10 therapy and the subsequent normalization
of hemoglobin levels.
In vitro effects of IL-10 on ferritin production in human monocytic cells
To see whether or not changes in ferritin levels observed in vivo
may be caused directly by IL-10, we studied the effects of IL-10 on
ferritin synthesis in activated THP-1 cells. Treatment of THP-1 cells
with IFN- slightly increased ferritin mRNA levels (Fig. 3A), whereas IL-10 added alone
had no effect on ferritin mRNA levels compared with controls. Moreover,
IL-10 did not counteract the slightly increased ferritin mRNA
expression observed after IFN- treatment when THP-1 cells were
incubated with IL-10 before stimulation with IFN- (Fig. 3A).
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increased ferritin mRNA levels, ferritin synthesis was not
significantly changed as compared with untreated control cells (Fig. 3B). IL-10 alone did not affect ferritin translation as
compared with the control (lane 4). However,
preincubation of IFN--stimulated cells with IL-10 led to an increase
of ferritin de novo synthesis (Fig. 3, lanes 5 and
6) as compared with cells treated with IFN- alone (Fig. 3, lanes 2 and 3).
These results were confirmed on determination of intracellular ferritin
concentrations by an ELISA-based assay. The increased de novo synthesis
of ferritin in cells treated with IL-10 before IFN- stimulation
(Fig. 3, lanes 5 and 6) was paralleled by
significantly higher amounts of ferritin in cytoplasmic cell extracts
than in cells treated with IFN- alone. These results go along
with a posttranscriptional regulation of ferritin expression by IL-10
via modulation of iron-regulatory protein (IRP)-controlled ferritin
mRNA translation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on the proliferation of
erythroid progenitor cells, 3) erythrophagocytosis which may also
contribute to these imbalances in iron distribution, and 4) a blunted
response to EPO (for review, see Refs. 1, 2, 3, 4). Our data now suggest that the anti-inflammatory cytokine IL-10, which is up-regulated in most inflammatory disorders of the body, alters iron metabolism in vivo, induces anemia, and may thus be involved in the pathogenesis of ACD.
Previous studies have suggested that proinflammatory cytokines, such as
IL-1, IL-6, or TNF- cause disturbances of iron homeostasis. These
cytokines induce hypoferremia by increasing ferritin synthesis via both
transcriptional and translational mechanisms in various cell types
(8, 9, 10, 11). However, IL-1 and TNF- are at the same time
potent inducers of IL-10 formation in vitro and in vivo
(17). Thus, it would appear also reasonable that the
observed effects of IL-1 and TNF- on ferritin synthesis in vitro
and in vivo can be in part referred to induction of IL-10 synthesis by
these proinflammatory cytokines.
Recent observations demonstrated that IL-4 and IL-13, both cytokines
with an anti-inflammatory profile, modulate iron metabolism in
activated macrophages by different pathways (16): 1) by
opposing activation of IRP thus increasing ferritin translation; and 2)
by an IRP-independent augmentation of TfR mRNA expression. Thus,
Th2-derived cytokines are able to increase iron uptake and storage in
activated macrophages. These in vitro data are in accordance with our
in vivo findings in patients with CACD treated with IL-10, another
Th2-derived anti-inflammatory cytokine, and are further confirmed
by our in vitro data demonstrating that IL-10 increases ferritin
expression in activated/IFN--treated monocytic cells although mRNA
levels are unchanged (Fig. 3). This suggests that, as in murine
macrophages, IL-10 increases ferritin translation in human monocytes by
decreasing the binding affinity of IRPs to the ferritin iron-responsive
element.
This leads to the question of whether the induction of
hyperferritinemia by IL-10 and the development of anemia are cause
effective. Such a notion is supported by the results obtained by
calculation of Spearman rank correlations (Table II). In patients
receiving placebo, hemoglobin concentrations were associated positively
with ferritin and negatively with sTfR, indicating that under these
conditions sufficient erythropoiesis depends on a normal supply of iron
to erythroid progenitor cells. This is also reflected by the negative
association between sTfR and ferritin, given that high sTfR indicated
low iron availability to erythroid cells as does low ferritin under
normal conditions (Table II).
In contrast, in patients receiving IL-10 therapy, we found ferritin to
be associated negatively with hemoglobin levels and positively with
sTfR concentrations. Moreover, we demonstrated that ferritin levels at
day 15 were more closely associated to hemoglobin and sTfR levels at
day 29 than the opposite, namely, correlation of hemoglobin or sTfR
levels at day 15 with ferritin levels at day 29 (Table II). This
provides strong evidence that an IL-10-induced increase in serum
ferritin concentrations leads to a subsequent decrease of iron
availability to erythroid cells as indicated by a rise in sTfR levels
and the development of anemia according to a cause and effect
relationship.
Anemia may result from stimulation of ferritin translation by IL-10 in cells of the reticuloendothelial system and consecutive incorporation of metabolically available iron into the protein (16). This decreases the amount of metabolically available iron to erythroid progenitor cells, thus resulting in impaired heme biosynthesis and subsequent development of anemia. However, one might claim that we did not observe significant changes in serum iron levels or transferrin saturation, although ferritin and sTfR levels progressively increased during IL-10 therapy. This could be because: 1) sTfR is a more sensitive parameter for reflecting the need of iron in tissues and/or the bone marrow than serum iron levels and transferrin saturation (5); or 2) the increase of sTfR levels observed in patients treated with the highest IL-10 dosage may also be influenced by a regulatory effect of IL-10 on TfR mRNA expression as indicated from in vitro data (16).
Nevertheless, other mechanisms by which IL-10 could induce anemia have also be taken into account.
First, there is the possibility that like IL-6 the application of IL-10 may cause a dilution anemia even if ferritin levels increase (20). However, because neither mean corpuscular hematocrit nor mean corpuscular volume changed significantly during therapy, nor did patients under IL-10 therapy had a significant gain in weight (details not shown), this is a rather unlikely explanation.
Second, IL-10 could cause growth-depressing effects toward erythroid progenitor cells. Such a possibility is supported by in vitro data showing direct negative effects of IL-10 toward erythroid progenitor cell proliferation (21) and by the observations that ferritin may also inhibit cell proliferation (22).
However, reticulocyte levels did not chance over the first 2 wk of
treatment and then progressively increased under IL-10 therapy. This
increase in reticulocyte counts was paralleled by an increase of
endogenous EPO levels, the latter being negatively associated with
hemoglobin concentrations at these time points (Fig. 2B).
This suggests that the increase of EPO may results from the
physiological response to anemia/hypoxia which then leads to
stimulation of reticulocyte proliferation.
These observations argue against a strong inhibitory effect of IL-10 toward erythroid cell proliferation and against an inhibition of EPO production by IL-10. This is supported by a recent finding showing that the administration of IL-10 to healthy volunteers in a dose of 8 µg/kg did not result in a chance of granulocyte-macrophage CFUs, mixed lineage CFUs (granulocyte-macrophage-monocyte-CFUs); or erythroid burst-forming units when comparing the IL-10- vs placebo-treated groups (23).
However, a mild antiproliferative effect of IL-10 toward erythroid
progenitor cells cannot be fully excluded by our investigation (see
below). Such an effect could be exerted directly by IL-10 or indirectly
via induction of ferritin or cytokine synthesis, a notion which is
supported by the finding that in high doses IL-10 induces the formation
of IFN- (24), a potent inhibitor of erythroid
progenitor cell development (3).
Third, we also investigated whether or not IL-10 may induce hemolysis
by monitoring LDH levels. In contrast to what would be expected on
hemolysis, IL-10 significantly reduced LDH levels. At the same time, a
substantial decline in platelet numbers was observed (Fig. 2A), whereas white blood cell counts were not significantly
affected by IL-10 therapy (not shown). This suggests that IL-10 may not
cause hemolysis but rather negatively affects the possibility of
megakaryopoiesis via modulation of the activity or formation of
proteins needed for stimulation of platelet formation, such as
thrombopoietin, or GM-CSF or by influencing platelet pooling in the
spleen (23, 25).
Fourth, recent data provide evidence that IL-10 induces the expression of heme oxygenase 1 (26). This may lead to excessive heme degradation, an increase in the amount of iron within monocytes, and a subsequent incorporation of the metal into ferritin which may thus contribute to iron retention within the reticuloendothelial system and the development of anemia.
In summary, our data provide direct evidence for an involvement of IL-10 in the pathogenesis of anemia of inflammation. This can be mainly referred to a direct effect of IL-10 on ferritin translation and presumably subsequently storage of iron within activated monocytes/macrophages which may limit the availability of iron to erythroid progenitor cells. The cause and effect relationship of IL-10 for inducing hyperferritinemia and anemia is sustained by the finding that after the end of cytokine therapy all abnormalities in iron homeostasis and anemia returned to normal without any further intervention.
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Acknowledgments |
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We are grateful to the following colleagues for providing patient samples: S. Schreiber (Department of Medicine, Christian-Albrechts University, Kiel, Germany); M. Gregor (Department of Medicine, Eberhard-Karls University, Tübingen, Germany); S. J. H. van Deventer (Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands); P. Rutgeerts (Department of Gastroenterology, U. Z. Gasthuisberg, Catholic University Leuven, Leuven, Belgium); C. Gasche (Department of Gastroenterology, University of Vienna, Vienna, Austria); J. C. Koningsberger (Department of Gastroenterology, University of Utrecht, Utrecht, The Netherlands); L. Abreu (Servicio de Patologia Digestiva, Clinica Puerta de Hierro, Madrid, Spain); B. Duclos (Department of Gastroenterology, University of Strasbourg, Strasbourg, France); R. A. van Hogezand (Department of Gastroenterology, University of Leiden, Leiden, The Netherlands); I. Kuhn AESCA (Traiskirchen, Austria); M. Cohard and P. Grint (Schering-Plough Research Institute, Kenilworth, NJ).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Günter Weiss, Department of Internal Medicine, University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail address: guenter.weiss{at}uibk.ac.at
3 Abbreviations used in this paper: ACD, anemia of chronic disease; CACD, chronic active Crohn’s disease; EPO, erythropoietin; TfR, transferrin receptor; IRP, iron-regulatory protein; sTfR, soluble TfR; rHuIL-10, recombinant human IL-10; LDH, lactate dehydrogenase.
Received for publication April 1, 2002. Accepted for publication June 12, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Nucleic Acids Res. 20:2997.. J. Clin. Invest. 91:969.
-Interferon modulates human monocyte/macrophage transferrin receptor expression. Blood 71:1590.. Gut. 50:191.
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and 
) or 20 µg/kg (
and 
) are
shown before (day -1), after 2 wk (day 15), and at the end of
treatment (day 29) and 4 wk after end of treatment (follow-up, fu wk4)
are presented as means ± SEM. A, LDH serum
concentrations (