on human monocytes and monocytic cell lines
,
,||
* Department of Public Health and Microbiology,
Laboratory of Cell Biology, Department of Genetics, Biology and Biochemistry, and
** Institute of Internal Medicine, University of Turin, Turin, Italy;
Biocrystallography Center CNR, University Federico II, Naples, Italy;
Institute G. Gaslini, Genoa, Italy;
|| Department of Biochemistry, University of Genoa, Genoa, Italy;
# Department of Pediatrics, University of Brescia, Brescia, Italy; and
Department of Medical Science, A. Avogadro University of Eastern Piedmont, Novara, Italy
Correspondence: Tiziana Musso, Ph.D., Department of Public Health and Microbiology, University of Turin, via Santena, 9, 10126 Torino, Italy. E-mail: musso{at}molinette.unito.it
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IL-2, LPS, TNF-
, and GM-CSF)
on the expression and function of CD38, starting from the observation
that human monocytes and the derived lines U937, THP-1, and Mono-Mac-6
bear the molecule on their surface. Our results indicate that IFN-
is a strong up-modulator of CD38, and IL-2 increases its expression
only modestly. LPS, TNF-, and GM-CSF had no detectable effects.
Treatment with IFN- produced a dose- and time-dependent
up-regulation of CD38 in monocytes and monocytic lines, which was
paralleled by increased ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
activities. Furthermore, CD38 ligation by specific MoAb reduced the
IFN--dependent enhancement of monocyte-dynamic adhesion to
endothelial monolayers. These findings identify IFN- as a modulator
of monocytic CD38 expression and indicate that CD38 plays a specific
role in the activation and adhesion processes performed by
monocytes.
Key Words: cytokines • ADP-ribosyl cyclase • cADPR hydropase
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(IFN-), and lipopolysaccharide
(LPS)] are known to enhance the adherence of leukocytes to endothelial
cells and their accumulation at inflammatory foci by increasing the
expression of selectins and/or integrins on monocytes and the
counter-receptor on endothelial cells [2
,
5
]. Moreover, IFN- enhances the expression of a
variety of surface molecules important in cell-mediated immune
responses, including major histocompatibility complex (MHC) class I and
II antigens, B7, cytokine and immunoglobulin (Ig)-Fc receptors
[5
6
7
8
]. CD38 is a type II transmembrane glycoprotein widely used as a marker to study T and B lymphocyte activation and differentiation: Resting T and B cells are CD38-, and thymocytes and activated lymphocytes are CD38+ [9 ]. The molecule is also expressed constitutively on mature plasma cells, natural killer (NK) cells, and resting monocytes [10 ]. These differences in the cellular expression of CD38 reflect important regulatory functions of the molecule on activation and/or proliferation processes. CD38 ligation by specific MoAb triggers calcium mobilization, cell proliferation, and cytokine release in T, B, and NK cells [11 12 13 ]. CD38 ligation has contrasting effects on B-lineage cells preventing apoptosis in mature B cells and inhibiting the growth of the specific precursors [14 15 16 ]. CD38 also has a role in regulating cell-to-cell interactions, as shown by the observation that T-lymphocyte adhesion to human umbilical vein endothelial cells (HUVEC) is blocked by CD38 MoAb binding [17 ].
CD38 ligation by specific MoAbs is believed to mimic events triggered by the binding with a natural ligand. Indeed, one CD38 ligand (CD38L) has been identified as a 130-Kd protein that corresponds to CD31, a well-characterized adhesion molecule highly expressed on endothelial cells and, to a lower extent, on T, B, and NK cells, monocytes, and platelets [18 ].
As predicted based on its homology with the ADP-ribosyl cyclase isolated from the Aplysia californica [19 ], CD38 acts as an ectoenzyme; an extracellular domain present in murine and human CD38 mediates the hydrolysis of NAD+ and the synthesis/hydrolysis of cyclic ADP-ribose (cADPR) [20 21 22 23 ]. This function is endowed with relevant biological implications, because cADPR regulates calcium release from intracellular stores through an independent pathway. cADPR formation and calcium mobilization are important signaling events that regulate several cellular activities including lymphocyte proliferation, activation, and adhesion [10 , 20 , 24 ].
The purpose of the present investigation was to determine if CD38
expression on peripheral blood monocytes and monocytic cell lines is
modulated by cytokines or other agents, such as LPS, involved in the
regulation of monocytic functions. The results obtained show that
IFN-, but not LPS, up-regulates surface expression of CD38.
Increased expression of CD38 following IFN- activation is paralleled
by a proportional increase in ectoenzymatic functions. In addition, the
adhesion of IFN--activated monocytes to endothelial cells is reduced
after CD38 ligation by specific MoAb. These results indicate that CD38
plays important roles in the activation and adhesion processes of
monocytes.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell lines
U937 (a promonocytic tumor cell line), THP-1 (a monocytic cell
line), and HL-60 (a promyelocitic cell line; American Type Culture
Collection, Manassas, VA) were cultured in RPMI 1640 containing
penicillin (100 U/ml), streptomycin (100 U/ml), L-glutamine (2 mM),
HEPES (20 mM; Sigma Chemical Co., St. Louis, MO), and 10% fetal calf
serum (FCS; HyClone Laboratories, Logan, UT; hereafter referred to as
RPMI 1640 complete medium). The acute leukemia monocytic cell line
Mono-Mac-6 (German Collection of Microorganism and Cell Cultures,
Braunschweig, Germany) was maintained in complete medium supplemented
with 1 mM sodium pyruvate and 9 µg/ml bovine insulin (Sigma).
Cytokines and reagents
LPS (from Escherichia coli 0111: B4) was purchased
from Sigma. Human recombinant interleukin-4 (rhIL-4), IL-2,
granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-,
IFN-, IL-10, and IL-13 were obtained from PeproTech (Rocky Hill,
NJ). TGF-ß was purchased from Genzyme (Boston, MA).
Antibodies
Anti-HLA class I (O1.65, IgG2a), anti-CD38 (IB4, IgG2a),
anti-CD31 (Moon-1, IgG1) [25
], anti-HLA class II (Ab2.9,
IgG1), anti-CD19 (CB19, IgG1), and anti-CD11a (Ab8.28, IgG1) JAS
(anti-gp 120) were used as isotype-matched IgG control. MoAbs were
produced and purified in the laboratory. The F(ab')2 fragmentation of
the IB4 MoAb was obtained, as previously described [12
].
Goat F(ab')2 anti-mouse Ig, FITC-labeled (GAMIg-FITC), was
obtained from Southern Biotechnology Associates, Inc. (Birmingham, AL).
Flow cytometry analysis
Cells for indirect immunofluorescence (IIF) tests were
collected, washed twice with phosphate-buffered saline (PBS) containing
1% bovine serum albumin (BSA), and 0.01% NaN3 and then
incubated with MoAbs for 1 h at 4°C. The cells were then washed
twice and incubated with GaMIg-FITC for a further 30 min at 4°C.
After incubation, the samples were washed twice and resuspended in PBS
containing 0.01% NaN3, and at least 10,000 viable cells
were analyzed on a FACSort (Becton-Dickinson, Rutherford, NJ).
Enzymatic activity assays
NGD+ (Sigma), a NAD+ analogue previously
shown to be a convenient substrate of ADP-ribosyl cyclase activity
[26
], was used to assay surface-cyclase activity as
shown elsewhere [27
]. Treated and untreated cells were
rinsed with PBS and counted after trypan blue staining. Cells
(2x105) were incubated at 37°C in 0.2 ml PBS, 5 mM
glucose, and 0.3 mM NGD+. At various incubation times (0-,
30-, 60-, 120-, and 180-min intervals), aliquots were withdrawn,
centrifuged, and the cyclic GDP-ribose (cGDPR) content of the
supernatants was determined directly by high-pressure liquid
chromatography (HPLC) analysis [27
]. Results were
expressed as nanomoles of cGDPR produced by 106 cells/min.
To test cADPR hydrolase activity, the rate of cADPR hydrolysis by intact cells was estimated for the cyclase activity, but the cells were incubated in the presence of 0.2 mM cADPR (Sigma). The amount of ADPR produced in the supernatants obtained at the same times of incubation was determined by HPLC analysis [27 ]. Activities are expressed as nanomoles of ADPR produced by 106 cells/min.
Adhesion assay
A dynamic adhesion assay was used to minimize integrin-mediated
adhesion [17
]. Adhesion was evaluated at 4°C on
24-well plates lying on a rocking shelf to prevent static interactions
between cells. Briefly, HUVEC were isolated from segments of
normal-term, umbilical-cord veins and cultured to confluence in RPMI
1640 complemented with 10% FCS and containing phorbol 12-myristate
13-acetate (PMA; 5 ng/ml) for 2 days in 24-well plates. HUVEC-coated
wells were then washed three times with complete medium. PMA treatment
was found to improve significantly the adhesion of HUVEC to the culture
wells and reduced the risk of HUVEC detachment during washing in the
adhesion assay. Cells to be tested in the adhesion assay were labeled
with 50 µl 51Cr (Amersham, Buckinghamshire, UK)
for 1 h, washed twice with PBS, and seeded at 5 x
105 cells/well on the HUVEC-coated plates in complete
medium in the presence of the appropriate MoAb (10 µg/ml). After 15
min incubation, plates were spun at 800 rpm for 30 sec, laid on a
rocking shelf, and incubated for a further 20 min. The experiment was
performed at 4°C by working in a cold room, keeping cells on ice, and
using cold medium (0.5 ml/well). The wells were then washed gently
three times with 1 ml cold, complete medium dispensed with a 10-ml
pipette. Bound cells were lysed with 1 ml 2% Triton X-100, and
radioactivity was measured using a -counter.
The absolute adhesion was calculated as follows: (sample counts - minimal control counts)/(maximal control counts - minimal control counts) x 100.
Minimal control counts were obtained by seeding cells in wells without HUVEC, whereas maximal control counts were obtained by measuring the total radioactivity of the cell aliquots seeded in each well.
The % relative adhesion was calculated as follows: (absolute sample adhesion/absolute control adhesion) x 100, where samples and control adhesion were measured in the presence and absence of the relevant MoAb, respectively.
Statistical analysis
Comparison among treatments was performed by Student’s
t-test or by analysis of variance as appropriate. When a
difference among multiple treatments was found, the Newman-Keuls,
multiple-comparison test was used to identify which of the means was
significantly different from the others at the 0.05 significance level.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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or LPS with phenotypical, functional,
and biochemical changes including up-regulation of several genes. Many
of the monocyte activities induced by IFN- as well as other monocyte
activators can be down-regulated by IL-4. In addition, IL-4 induces the
expression of selected monocyte-surface antigens including MHC class II
and CD23 [5
, 28
29
30
31
]. To examine whether
CD38 could be modulated significantly during activation, human
peripheral blood monocytes were cultured for 24 h with medium
alone or supplemented with IFN- (500 U/ml), LPS (1 µg/ml), IL-4
(100 U/ml), or their combination and then analyzed by flow cytometry
for the expression of CD38 and its ligand CD31.
As shown in Figure 1
, CD38 is expressed constitutively by the majority of peripheral
blood monocytes; treatment with IFN- increased CD38 expression, and
IL-4 alone did not influence CD38 expression nor affect the CD38
up-regulation induced by IFN-. Other cytokines known as inhibitors
of monocyte activation, such as IL-13 (100 U/ml), IL-10 (50 ng/ml), and
TGF-ß (100 U/ml), also failed to modulate CD38 expression
(unpublished results). IFN- treatment did not affect the expression
of CD31 significantly, and LPS alone reduced slightly the constitutive
levels of CD38 and CD31 on cell surface (Fig. 1)
.
 View larger version (25K): [in a new window] |
Figure 1. Expression of CD38 on human peripheral blood monocytes. Human
peripheral blood monocytes were cultured for 24 h in complete
medium (shaded histogram) or in the presence of IFN- (500 U/ml),
IL-4 (100 U/ml), LPS (1 µ/ml), or their combinations (thick line).
CD38 and CD31 expression was analyzed by flow cytometry, using the
anti-CD38 MoAb IB4, the F(ab')2 fragment of the IB4, and
the anti-CD31 MoAb Moon-1. The thin line indicates the staining with
the isotype-matched control. Results are representative of three
independent experiments.
|
, stimulates several monocytic functions
[32
]. Treatment of human monocytes with IL-2 (1000 U/ml)
led to a reproducible increase in CD38 expression although smaller than
that produced by IFN-. Conversely, TNF- (100 U/ml) and GM-CSF
(100 U/ml) failed to induce any CD38 modulation (Fig. 2
).
 View larger version (34K): [in a new window] |
Figure 2. Effects of IFN-, IL-2, TNF-, and GM-CSF on CD38 expression on
human peripheral blood monocytes. Peripheral blood monocytes were
cultured for 24 h with IFN- (500 U/ml), IL-2 (1,000 U/ml),
TNF- (100 U/ml), or GM-CSF (100 U/ml) and stained with IB4 MoAb
using IIF. Percent variation of CD38 expression after exposure to the
different cytokines is shown in comparison with monocyte cultured in
complete medium, represented by the horizontal line. Results are
representative of three independent experiments.
|
and IL-2, both produced by activated T cells.
CD38 expression on myeloid cell lines
Cell lines representing different maturation stages of the
myelomonocytic cell lineage were studied for CD38 expression. As shown
in Table 1 , CD38 is expressed constitutively in U937, THP-1, and Mono-Mac-6.
In all these cell lines, IFN- treatment enhanced CD38 expression. In
contrast, no induction of CD38 expression was seen after IFN-
treatment in HL-60, a CD38- myeloid line (unpublished
results).
|
View this table: [in a new window] |
Table 1. CD38 Expression in Different Myelomonocytic Cell Lines
|
was determined after 24 h of treatment of U937 (Fig. 3A
). As little as 5 U/ml IFN- was sufficient to produce a 20%
increase in CD38 expression, and 500 U/ml IFN- induced a 38%
increase in the same experiment. The kinetic analysis of CD38 induction
on U937 demonstrates that the peak response occurs after 48 h of
treatment (Fig. 3B)
. Similar results were obtained with human
peripheral blood monocytes and THP-1 (unpublished results).
 View larger version (19K): [in a new window] |
Figure 3. Dose-response and time-response curves of IFN- effects on CD38
expression. U937 were cultured with complete medium alone or with the
indicated amount (U/ml) of IFN- for 24 h (A). (B) Cells were
treated with IFN- (500 U/ml) for the indicated times. Cells stained
with IB4-FITC MoAb were analyzed by FACSort, gating for viable cells,
and acquiring 10,000 events. Results are representative of three
independent experiments.
|
increases the CD38 ectoenzymatic activities in monocytes
and monocytic cell lines (500 U/ml) showed
increased cyclase activity compared with untreated cells (Fig. 4
). As shown for THP-1 in Figure 5
, increased cADPR hydrolase activity was also detected upon
treatment with IFN-, and the increment of both activities paralleled
the induction of CD38 membrane expression as measured by flow
cytometry. Similar results were obtained with human monocytes, U937,
and Mono-Mac-6 (unpublished results). These findings suggest that the
peculiar, bifunctional, enzymatic characteristics of CD38 in the
de novo-expressed glycoprotein are maintained upon IFN-
treatment.
 View larger version (12K): [in a new window] |
Figure 4. Levels of cyclase-ectoenzyme activity in untreated and IFN--treated
monocytic cells. Peripheral blood monocytes (A), THP-1 (B), and U937
(C) cells treated for 48 h with complete medium alone (solid bar)
or with IFN- (500 U/ml; open bar) were incubated for 2 h at
37°C with 0.3 mM NGD+ as described in Materials and
Methods. Aliquots of the incubation medium were removed, and their
cGDPR content was determined by HPLC. Results are expressed as the
means of triplicates ± SD.
|
 View larger version (16K): [in a new window] |
Figure 5. Level of cyclase and hydrolase activities after IFN- treatment of
THP-1 parallels CD38 expression. Following 48 h incubation in
complete medium alone or with IFN- (500 U/ml), THP-1 were assayed
for GDPR cyclase and cADPR hydrolase activities and for CD38
cell-surface expression as detailed in Materials and Methods. Log x mean fluorescence is represented by lines, and histograms represent
cyclase (A) and hydrolase (B) activities. Results are expressed as
mean ± SE of three different experiments. *,
Significant increase P < 0.05.
|
on cell adhesion to
HUVEC. Assays were performed in conditions that minimize the
integrins-mediated adhesion and allowed to detect the adhesion mediated
by CD38 [17
]. The adhesion between peripheral blood
monocyte and HUVEC is potentiated by treatment with IFN-: Similar
effects were seen using Mono-Mac and U937 lines (Fig. 6
). The contribution of CD38 and CD31 to the adhesion was tested by
performing blocking experiments with specific MoAbs. As expected,
monocyte, Mono-Mac, and U937 adhesion to HUVEC was inhibited by MoAbs
to CD38 or CD31, but the inhibition was increased significantly for
cells treated with IFN- (percent inhibition was 42%, 60%, and 70%
with anti-CD38 and 41%, 55%, and 70% with anti-CD31 for monocytes,
Mono-Mac, and U937, respectively) compared with untreated cells
(percent inhibition was 14%, 36%, and 30% with anti-CD38 and 12%,
30%, and 42% with anti-CD31 for monocytes, Mono-Mac, and U937,
respectively). Further adding to the specificity of the event is the
observation that control MoAbs to CD11a and HLA class II did not
interfere with the adhesion process.
 View larger version (19K): [in a new window] |
Figure 6. Effect of anti-CD38 on dynamic adhesion to HUVEC by monocytes,
Mono-Mac-6 cells, and U937 cells. Monocytes, Mono-Mac, and U937 were
cultured in complete medium alone (solid bar) or with IFN- (500
U/ml; open bar) for 24 h and incubated on HUVEC in the absence
(control) or presence of anti-CD38, anti-CD31, anti-CD11a, and
anti-HLA-DR MoAbs. Results are expressed as relative adhesion % (see
Materials and Methods) and represent the mean ± SE of
three different experiments. The cell adhesion displayed by untreated
cells in the absence of MoAbs (control) is 100% relative adhesion and
corresponds to a mean absolute cell adhesion (i.e., the percentage of
seeded cells that were bound to the cell-coated plates, see Materials
and Methods) of 20% for monocytes, 23% for Mono-Mac cells, and 21%
for U937 cells. *, Significant inhibition P < 0.05.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
IL-2 that activate monocytes by increasing tumoricidal and microbicidal
activities and other functions related to antigen presentation
[5
, 32
]. Our results indicate that IFN-
up-regulates constitutive CD38 expression on peripheral blood monocytes
and monocytic cell lines. In addition, we demonstrate that IL-2
treatment of monocytes increases CD38 expression, although to a lesser
extent than IFN-. Conversely, other monocyte activators such as LPS
do not affect CD38 expression by monocytes, thereby suggesting that the
observed up-regulation is not a general consequence of monocyte
activation but is induced specifically by IFN- and IL-2. Other
cytokines, such as IL-4, IL-13, or IL-10, known to counteract
IFN--mediated activation of monocytes, failed to influence in any
way the constitutive expression of CD38 or to affect the up-regulation
of the molecule induced by IFN- [29
30
31
].
On the basis of our observation that IFN- enhances CD38 expression
by monocytes, we analyzed whether CD38 was involved in functional
activities regulated by this cytokine, such as monocyte-endothelial
cell interactions. Previous studies demonstrated that lymphocyte
rolling on endothelial monolayers is in part mediated by interaction of
CD38 with its ligand CD31 expressed on the surface of endothelial cells
[17
]. Because we found that the increase of dynamic
adhesion induced by IFN- was inhibited by MoAbs directed against
CD31 or CD38, it is reasonable to hypothesize that these molecules may
increase low-affinity interactions of circulating monocytes with
endothelium, enhancing monocyte extravasation to the tissues.
The specific role of IFN- in CD38 induction is supported by the
identification of three interferon-responsive elements (IRF-1) in the
CD38 promoter [34
]. Analysis of cell-surface expression
of CD38 in myelomonocytic cell lines such as HL-60, U937, and THP-1,
representative of distinct steps of myeloid differentiation, revealed
that IFN- up-regulates CD38 expression on cells that are already
committed toward monocyte differentiation (e.g., U937, THP-1,
Mono-Mac-6) but does not induce CD38 on the promyelocytic line HL-60
[35
].
The different outcome of CD38 expression following IFN- treatment
also recurs in other cell types responsive to the cytokine, such as T
and B lymphocytes [33
, 35
]. IFN-,
endowed with a potent ability to up-modulate CD38 in B cells, has
indeed no influence on the expression of this molecule in activated T
cells [10
, 36
]. A likely interpretation of
this observation is that the IFN--signaling pathway ruling CD38
induction can be controlled differently in different cells depending on
other transcription factors that are specific to these cell types.
The extracellular portion of CD38 encompasses a domain acting as
ectoenzyme and controlling synthesis and hydrolysis of cADPR, a
universal second messenger that mediates mobilization of
Ca2+ independently from inositol
trisphosphatase (IP3) [20
, 21
,
37
, 38
]. We observed that the up-regulatory
effects mediated by IFN- on CD38 expression are paralleled by
simultaneous increases of cyclase and hydrolase activities, suggesting
that IFN- was inducing the expression of a fully functional
molecule.
The role of CD38 in vivo is still a matter of debate, as
well as its role as ectoenzyme in a milieu where NAD+ is present in
amounts close to nil. Moreover, a link between the enzymatic and
receptorial functions is still missing. Although Zocchi et
al. [39
] showed that CD38 activation and
internalization could result in increased, intracellular concentrations
of cADPR, other data point to a vision where receptor and enzyme
operate in a dichotomous fashion [40
]. The modalities
through which CD38 delivers its messages are also a matter of fierce
controversies, because of the intrinsic inability of the molecule to
transduce signals via its short cytoplasmic domain. A possible
explanation is that CD38 signals by exploiting other molecules
specialized in signaling such as CD3 in T cells, BCR in B lymphocytes,
and CD16 in NK cells [41
42
43
]. The candidate molecules
associated with CD38 in monocytes are FcRII and HLA class II
[44
]. In fact, it has been shown recently that human
CD38 may cooperate with MHC class II by acting as co-receptor in
superantigen-induced activation [45
]. Moreover, the role
of CD38 as transducing molecule in monocytes is supported by the study
that CD38 stimulation in monocytes results in regulation of their
functional response to respiratory-burst activators such as
formyl-Met-Leu-Phe (fMLP) [46
]. In addition, CD38
triggering in macrophage or monocytic cell lines increases cytokine
release and enhances antigen-presentation ability by increasing
cell-surface expression of MHC class II and B7 [12
,
47
].
Our observation that IFN- induces enhancement of CD38
expression leads us to speculate that IFN- stimulation of monocytes
may affect other functional activities involving CD38, such as antigen
presentation or T-cell activation. In addition, our findings suggest
that the effect of IFN- in the up-regulation of CD38/CD31
interaction may play a critical role during extravasation of monocytes
from vessels in conditions such as bacterial infections or autoimmune
diseases characterized by the prevalence of Th1 cells
[48
, 49
].
Received July 27, 2000; revised December 5, 2000; accepted December 6, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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