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Pulmonary Research Laboratory, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Recombinant human interleukin-6 (IL-6) causes both a thrombocytosis and leukocytosis. The thrombocytosis is caused by an accelerating thrombocytopoiesis, but the mechanism of the leukocytosis is unknown. This study was designed to determine the relative contributions of marrow stimulation and intravascular demargination to the IL-6 induced neutrophilia. IL-6 (2 µg/kg), administered intravenously to rabbits, caused a biphasic neutrophilia with an initial peak at 3 h and a second peak at 9 h. Using the thymidine analog 5'-bromo-2'-deoxyuridine (BrdU) to label dividing polymorphonuclear leukocytes (PMNs) in the bone marrow, we showed that IL-6 treatment mobilizes PMNs from the marginated pool into the circulating pool at 2-6 h with a decrease in L-selectin expression on PMNs and also accelerates the release of PMNs from the postmitotic pool in the bone marrow at 12-24 h. We have concluded that IL-6 causes a biphasic neutrophilia wherein the first peak results from the mobilization of PMNs into the circulating pool from the marginated pool and the second peak results from an accelerated bone marrow release of PMNs.
neutrophilia; cytokine; bone marrow; L-selectin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERLEUKIN-6 (IL-6) is a 26-kDa cytokine with pleiotropic activities in both the immune and hematopoietic systems. It is produced in response to inflammatory stress and is one of the major regulators of the acute-phase response (8, 15). Elevated blood levels have been implicated in the pathogenesis of sepsis, acute respiratory distress syndrome (4), and multiorgan failure (12) as well as in chronic inflammatory conditions such as rheumatoid arthritis (21). IL-6 has also been implicated in the pathogenesis of acute and chronic vascular diseases because of its ability to stimulate the production of prothrombotic factors such as fibrinogen (24) and its platelet enhancing properties (3, 15).
IL-6 is produced by different cell types that include T cells, macrophages, and fibroblasts and mediates a wide variety of biological activities (10, 20). It enhances differentiation and proliferation of multipotential hematopoietic progenitors in vitro (11, 20, 25). It stimulates the clonal growth of granulocyte and macrophage progenitor cells (18) and the multipotential hematopoietic progenitors (11) in synergy with IL-3 in spleen cells culture. IL-6 produced by stromal cells in the bone marrow induces the proliferation and differentiation of hematopoietic cells in the marrow microenvironment (9). Therefore, IL-6 produced either in the bone marrow (9) or at distant sites and released into the systemic circulation could have a profound effect on the production and the kinetics of polymorphonuclear leukocytes (PMNs).
Several studies have reported that a single intravenous injection of IL-6 causes a thrombocytosis by stimulating thrombopoiesis (14, 22, 28), an effect with potential therapeutic potential. IL-6 also causes a leukocytosis characterized by a rapid neutrophilia (28). The present study was designed to determine the mechanisms of this neutrophilia, specifically, the contribution of marrow release of PMNs and the behavior and clearance of PMNs from the circulation by using a novel technique that was developed in our laboratory (2, 17, 26). This approach allowed us to both quantitate the effect of IL-6 on the transit time of PMNs through the bone marrow and measure their clearance from the circulating blood and reentry into the circulation from the marginated pool.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. This study was approved by the Animal Experimentation Committee of the University of British Columbia and was based on 41 female New Zealand White rabbits with an average weight of 2.2 ± 0.2 kg.
Experimental Design
Effect of IL-6 on transit time of PMNs through bone marrow. 5'-Bromo-2'-deoxyuridine (BrdU; 100 mg/kg; Sigma Chemical, St. Louis, MO) was infused into rabbits through the marginal ear veins at a concentration of 10 mg/ml in sterile saline over a period of 15 min. Twenty-four hours later, recombinant human IL-6 (2 µg/kg; lot no. 118H0227, purity >97%, endotoxin <0.1 ng/µg IL-6; Sigma) was infused through the marginal ear veins (n = 6), and control rabbits (n = 4) received an equivalent volume of saline. In this study, a dose of 2 µg/kg of IL-6 was selected on the basis of dose-response studies (22) in rabbits that produce circulating IL-6 levels similar to those in major stress such as surgery (1, 30). Blood samples (2.0 ml) were obtained from the central ear artery just before the BrdU, IL-6, or saline injection and at 0.5, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, 144, and 168 h after the IL-6 or saline injection. Blood (1 ml) was collected in tubes containing EDTA for leukocyte counts, and an additional 1 ml was collected in tubes containing acid-citrate dextrose (ACD) for the detection of BrdU-labeled PMNs. Fentanyl (20 µg/kg) and droperidol (1 mg/kg) were administered by subcutaneous injection as sedation at each time point of blood collection.
Effect of IL-6 on margination and demargination of PMNs. Donor rabbits (n = 5) received an intravenous injection of BrdU (25 mg/kg) for 7 days following a protocol that labels ~80% of PMNs in donor's blood with BrdU (2, 17). Whole blood from the donors containing BrdU-labeled PMNs was transfused to serum-compatible recipients (15 ml/kg with ACD) via the marginal ear vein over a 15-min period. One hour after this blood transfusion, the recipients received either IL-6 (2 µg/kg, n = 5) or saline (n = 5) intravenously. This time point was selected on the basis of previous studies from our laboratory that showed that BrdU-labeled PMNs reached a steady state ~1 h after transfusion (2). Blood samples were obtained just before IL-6 or saline injection and at 1, 2, 4, 6, 12, 24, and 36 h after IL-6 or saline injection.
Leukocyte Counts
Total white blood cell (WBC) counts were determined on a model SS80 Coulter Counter (Coulter Electronics, Hilaeh, FL). Differential counts were obtained by counting 100 leukocytes in randomly selected fields of view on Wright's-stained blood smears, and 100 PMNs were evaluated in randomly selected fields of view to determine the changes in the number of segmented and nonsegmented PMNs (band cells).Immunocytochemical Detection of BrdU-Labeled PMNs
Blood collected in ACD was used to obtain leukocyte-rich plasma (LRP). Erythrocytes in the ACD blood sample were allowed to sediment for 25-30 min after the addition of an equal volume of 4% dextran (average molecular weight 162,000; Sigma) in PMN buffer. The resulting LRP was cytospun onto 3-aminopropryl triethoxysilane-coated slides by cytocentrifugation at 180 g with a Cytospin 2 (Shandon Scientific, Runcorn, UK) for 5 min. The cytospun specimens were air dried and stained using the alkaline phosphatase and anti-alkaline phosphatase (APAAP) method (2, 5) to determine the fraction of the BrdU-labeled PMNs in each specimen (2) and calculate the transit of cells through the bone marrow as previously described (26) in detail. All slides were coded and examined by investigators without knowledge of the group or sampling time, fields were selected in a randomized fashion, and 200 cells were evaluated per specimen.Transit Time of PMNs Through Bone Marrow
BrdU-labeled PMNs were divided into three groups according to the intensity of nuclear staining (G1-G3) with the use of an arbitrarily designated grading system as previously described (26). Briefly, G3 cells represent myeloid cells that were in their last division in the mitotic pool when exposed to BrdU, G2 cells represent those that were in the middle, and G1 cells represent those that were in their first division. This system allowed us to calculate the transit time of cells in the different pools of the marrow. The transit times were calculated from the appearance of BrdU-labeled PMNs in the circulation over time and corrected for the disappearance of cells in the circulation with the use of a previously measured half-life (t1/2) of 4.5 h (2).Disappearance of Donor BrdU-Labeled PMNs From Circulating Pool
The number of BrdU-labeled PMNs in the circulation of each recipient was expressed as a fraction (%PMN) of the total number of labeled PMNs originally infused corrected for the calculated blood volume (23) of the recipient as
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Flow Cytometry
Blood collected in EDTA tubes was used to immunolabel circulating PMNs for the presence of surface L-selectin and CD18 with a commercially available kit (Coulter Clone, Coulter Electronics) using a whole blood method. Use of this method could avoid possible cell activation associated with purification of PMNs (32). The anti-L-selectin monoclonal antibody (MAb) DREG-200 (kind gift of Dr. E. C. Butcher, Stanford University, School of Medicine, Stanford, CA) or the anti-CD18 MAb 60.3 (kind gift of Dr. J. Harlan, University of Washington, Seattle, WA) were used, and the PMNs were labeled, as previously described (13). Analysis gates for PMNs were selected from typical forward- and side-angle light scattering, and a total of 3,000 cells/specimen were evaluated using a Profile Epics 2 flow cytometer (Coulter Electronics). Results are expressed as mean fluorescence intensity.Evaluation of Myeloid Cells in Bone Marrow
To evaluate the acute effect of IL-6 on the cells in the bone marrow, 26 rabbits were killed at 24 h after treatment separately from those in the BrdU study. At 24 h after IL-6 (2 µg/kg; n = 8) or saline (n = 8) injection and 168 h after IL-6 (2 µg/kg; n = 6) or saline (n = 4) injection, all of the rabbits were killed with an overdose of pentobarbitone sodium. Bone marrow was harvested from both femurs by carefully removing the cortical bone of the femur, and marrow smear slides were prepared. Differential counts of myeloid or erythroid cells were performed on precoded May-Gruenwald-Giemsa-stained slides, and at least 500 cells/smear were counted using standard morphologic criteria (28).Statistical Analysis
All values are expressed as means ± SE. Analysis of variance (ANOVA) for repeated measures was used for continuous data. The effect of multiple comparisons was corrected using the Bonferroni method. Transit times of BrdU-labeled PMNs and the differentiation of bone marrow cells were compared between IL-6 and control groups using Students t-test, and statistical significance was defined as a P value <0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of IL-6 on Release of PMNs From Bone Marrow
Leukocytes in circulation.
Figure 1 shows that WBC, PMNs, and band
cell counts were similar at baseline in both control and experimental
groups and that IL-6 caused a biphasic leukocytic response
characterized by a rapid increase in WBC counts that peaked 3 h
after IL-6 increase (P < 0.05), with a temporary
decrease at 6 h followed by a second increase at 9 h (Fig.
1A). A similar response was observed for PMNs [from
3.8 ± 0.1 × 109 cells/l at baseline to 7.0 ± 0.2 × 109 cells/l at 3 h (P < 0.05), 5.9 ± 0.1 × 109 cells/l at 6 h,
and 6.6 ± 0.1 × 109 cells/l at 9 h], with a
return to baseline values by 48 h (Fig. 1B). The
percentage of nonsegmented PMNs (band cells) increased from 4.0 ± 0.4% at baseline to 8.5 ± 0.6% at 9 h (P < 0.05) and returned to the baseline values by 24 h (Fig.
1C). The circulating band cell counts followed the same
pattern [from 1.5 ± 0.2 × 108 cells/l at
baseline to 5.8 ± 0.5 × 108 cells/l at 9 h
(P < 0.05)], with a return to baseline values by
36 h (Fig. 1D). WBC, PMNs, and band cell counts
remained unchanged in the control group.
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Release of BrdU-labeled PMNs into circulation.
Figure 2 shows the appearance of
BrdU-labeled PMNs in the circulation after the bolus injection of BrdU.
BrdU-labeled PMNs appeared in the circulation at 24 h after
labeling of the bone marrow and then rapidly rose and peaked at
24-36 h (IL-6 group) and at 48 h (control group). The number
of BrdU-labeled PMNs in the peripheral blood of IL-6-treated animals
was higher at 9, 12, and 24 h compared with that in blood of
control animals (Fig. 2A, P < 0.05). Figure
2B shows highly stained BrdU-labeled PMNs (G3 cells), and
Fig. 2C shows weakly stained BrdU-labeled PMNs (G1 cells).
G3 cells peaked at 36 h in the control group and at 24 h in
the IL-6 group. The earlier peak of BrdU-labeled PMNs in the IL-6 group
was mostly due to the earlier release of these G3 cells. The curves for
the percentage of BrdU-labeled PMNs were similar to the curves for the
numbers of BrdU-labeled PMNs (data not shown). Figure
3 shows the accumulative number of all
BrdU-labeled PMNs and G1 cells in the circulation (using daily
measurements) over the study period. The data show that IL-6 treatment
causes an increase in the pool of BrdU-labeled PMNs (P < 0.01) in the bone marrow and that this increase was mainly due to an
increase in G1 cells (P < 0.01).
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Mobilization of BrdU-Labeled PMNs From Marginated Pool
Circulating PMN counts.
Figure 4 shows the data from the animals
that received BrdU-labeled PMNs from donor animals. The IL-6 group
showed the same biphasic response in PMN counts as that shown in Fig. 1
with no response in the saline-treated control group. Figure
4B shows that, when BrdU-labeled PMNs reached steady state
between the circulating and marginated cells within the vascular space,
the circulating blood contained 38.9 ± 1.7% of the infused
BrdU-labeled PMNs in the experimental group and 40.2 ± 1.0% of
those in the control group. After IL-6 treatment, the percentage of the
transferred BrdU-labeled PMNs in the circulating blood increased in the
experimental group by 2 h and remained above control values from 2 to 6 h (P < 0.05) (Fig. 4B). The rate
of disappearance of BrdU-labeled PMNs from the circulation as measured
from the slopes of these curves between 4 and 36 h was 4.75 h
in the IL-6 group and 4.88 h in the control group
(P > 0.05).
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Distribution of PMNs between marginated and circulating pools.
Figure 5 shows the calculated
(17) total and marginated pools of BrdU-labeled PMNs in
the intravascular space. Eighty-six percent of the total
BrdU-labeled PMNs transferred from the donor animals remained
intravascular just before IL-6 treatment. Fifty-five percent of these
cells had entered the marginated pool, and forty-five percent were in
the circulation. The decrease in the total number of cells in the
vascular space was calculated by using the t1/2 of BrdU-labeled PMNs. After IL-6 treatment, the proportion of BrdU-labeled PMNs in the circulating pool increased from 45% to 67%
(2 h) and 75% (4 h) with a corresponding decrease in the percentage of
marginated cells. This indicates that IL-6 caused a major shift from
the marginated to the circulating pool over this period.
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Effect of IL-6 on L-Selectin and CD18 Expression on PMNs in Circulation
IL-6 decreased the mean fluorescence intensity of L-selectin on circulating PMNs at 3-12 h (Fig. 6A, P < 0.01). The maximum effect was seen at 6 h after IL-6 treatment, and L-selectin levels were back to pretreatment levels at 24 h (Fig. 6A). CD18 expression was also measured as a marker of cell activation, but it did not change with IL-6 treatment (Fig. 6B).
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Effect of IL-6 on Myeloid Cells in Bone Marrow
The bone marrow differential counts performed 24 h and 168 h after IL-6 and saline-treatment are shown in Table 2. At 24 h after IL-6 treatment, the percentage of myeloblasts and promyelocytes were approximately double that of the control group (P < 0.05). However, there was no measurable change in the number of mature neutrophils or other cell lines. The differential counts at 168 h between IL-6- and saline-treated rabbits were similar.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The biphasic neutrophilia following a single intravenous injection of IL-6 was first reported by Ulich and colleagues (28) in rats. These workers showed that IL-6 induced myeloid proliferation in the bone marrow, suggesting that the marrow stimulation is an important reason for the neutrophilic response following IL-6 treatment. The present study confirms this finding in rabbits and extends it by showing that IL-6 induces a biphasic neutrophilia with distinctly different reasons for the two peaks in circulating PMNs.
Our data show that the first peak in circulating PMNs following IL-6 treatment is due to the mobilization of PMNs from the marginated pool (Figs. 4 and 5), and the lack of a band cell response or release of BrdU-labeled PMNs during this period confirms that the initial peak is not related to the bone marrow response. Furthermore, this demargination cannot be attributed to hemodynamic factors because IL-6 has little or no effect on hemodynamics (7).
Interleukin-6 induces an acute phase response that includes stimulation of the hypothalamic-pituitary-adrenal axis, resulting in a threefold increase in cortisol levels, which peak 2 h after the administration of IL-6 (27). We previously showed that steroids cause a rapid demargination of PMNs (17) and that this demargination is accompanied by a decrease in L-selectin levels on circulating PMNs (16). The reduction in L-selectin on PMN observed in these studies could be a direct effect of IL-6 treatment or a secondary effect related to an increase in circulating corticosteroids, and we postulate that it may play an important role in the demargination induced by IL-6. Alternatively, the demargination that we observed could be due to a change in deformability of PMNs because PMN deformability is one of the major determinants of PMN sequestration in the pulmonary microcirculation (29, 31).
We have used the nonisotopic thymidine analog BrdU to calculate bone marrow transit times based on a defined population of dividing myeloid progenitors being labeled in the bone marrow following a bolus injection of the tracer. This study shows that a single injection of IL-6 shortened the PMN transit time to a degree that is comparable to the effect of an inflammatory stimulus such as pneumococcal pneumonia (26). IL-6 treatment was also associated with an increase in the calculated size of marrow pools (Fig. 3), particularly the mitotic pool (Fig. 3B) that is supported by the increase in myeloblasts and promyelocytes observed 24 h after IL-6 treatment (Table 2). These data suggest expansion of the mitotic pool to replenish the loss from the postmitotic pool that occurs as an acute effect of IL-6 treatment. This effect of IL-6 on early myelocytes confirms reports of other investigators (11, 20, 25) and extends them by showing that the proliferative effect of IL-6 disappeared 1 wk after IL-6 treatment (Table 2).
The bone marrow response observed in these studies could be due to either a direct effect of IL-6 on the bone marrow or secondary effects of other mediators released by IL-6. The magnitude of change in PMN transit times and the increase in the size of the bone marrow pool of myeloid cells induced by IL-6 (Table 2) are greater than those produced by glucocorticoids (17). Other cytokines such as granulocyte colony-stimulating factor (G-CSF) induce IL-6 production (6, 19), but there are no reports of IL-6 inducing the release of G-CSF or other hematopoietic growth factors to account for this prominent marrow response to IL-6. Therefore, we suspect that IL-6 exerts an important primary effect on the bone marrow by releasing PMNs from the postmitotic pool and inducing accelerated myeloid turnover in the mitotic pool.
The data reported here show that IL-6 causes a rapid neutrophilia by mobilization of PMNs from the marginated pool into the circulating pool and a delayed neutrophilia by the release of PMNs from the bone marrow. We postulate that these effects of IL-6 on the bone marrow and the intravascular marginated pool of PMNs are critically important in mounting an appropriate host response, but they may also be detrimental in conditions such as septicemia and multiorgan failure, in which an excessive inflammatory response causes tissue damage.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Jennifer Hards and Beth Whalen for technical assistance.
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FOOTNOTES |
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This work was supported by a grant from the Medical Research Council of Canada (Grant No. 4219) and the Toxic Substance Research Initiative.
Address for reprint requests and other correspondence: S. F. van Eeden, Pulmonary Research Laboratory, Univ. of British Columbia, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada V6Z1Y6 (E-mail: svaneeden{at}mrl.ubc.ca).
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.
Received 28 April 2000; accepted in final form 21 July 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.01; *P < 0.05 compared with control.
,
Measured percentage of BrdU-labeled PMNs in the circulating pool;
, calculated disappearance of BrdU-labeled PMNs in the
total blood pool of BrdU-labeled PMNs, using a half-life of 4.75 h. The percentage of BrdU-labeled PMNs in the circulating pool of PMN
increased with IL-6 treatment to 75% at 4 h and returned to
baseline values by 12 h (see text for calculations).
Nt is number of PMNBrdU in the
circulation at time t, and N0 is the
number of PMNBrdU in the circulation at 0 h.
