| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The functional potential of leukocytes in inflammation is diverse and
depends heavily on the cytokine network that is activated after
stimulation of these cells by various inflammatory agents encountered
in the tissues. In this context, negative and positive regulation can
result in part from the action of functionally distinct subsets of T
helper cell-derived cytokines. IL-10, originally defined as a cytokine
synthesis inhibitory factor, is produced mainly by Th2 lymphocytes, by
B lymphocytes, and by monocytes/macrophages 8, 9 . IL-10 is a
pleiotrophic cytokine that can exert either immunostimulatory or
immunosuppressive effects on a variety of cell types. In vitro studies
have shown that this cytokine exhibits immunosuppressive functions like
down-regulation of T and NK cell activity and inhibition of Ag
presentation 10, 11, 12, 13 . IL-10 is also a potent inhibitor of
monocyte/macrophage activation and resultant cytotoxic effects. It can
suppress the production of numerous cytokines, including TNF-
, IL-1,
IL-6, IL-10, and IL-12, as well as the synthesis of reactive oxygen
intermediates by activated monocyte/macrophages 14, 15, 16 . Furthermore,
evidence for the in vivo antiinflammatory role of IL-10 was
demonstrated in different models 17, 18, 19 . Although IL-10 is being
billed as an immunosuppressive cytokine, numerous immumostimulatory
effects can be ascribed to this cytokine. Hence, IL-10 is one of the
primary stimulators of Ab production; it acts as a growth costimulator
for thymocytes, mast cells, and B cells, as well as an enhancer of
cytotoxic T cell development 20, 21, 22 ; it enhances
monocyte-mediated Ab-dependent cellular cytotoxicity and T cell
responses to IL-2 23, 24 ; it has also been suggested as a potent
recruitment signal for leukocyte migration in vivo 25, 26 . Therefore,
IL-10 has a variety of different activities, not all of which are
immunosuppressives.
Regulation of FMLP-R expression has not been extensively investigated
but was previously shown to be modulated by cAMP-elevating agents on
HL-60 cells and U937 27, 28 . Furthermore, recent studies demonstrated
that the inflammatory cytokines IFN-
and TNF- could regulate this
receptor, but cytokine modulation of FMLP-R has been reported for
granulocytes and granulocytic cells but not for monocytes. Hence, in
human neutrophils, TNF- was shown to promote expression of FMLP-R
29 , whereas IFN- was shown to induce the expression of these
receptors in HL-60 cells differentiated into neutrophils 30 .
Considering the important immunomodulatory effects of IL-10 and in
particular its capacity to antagonize the effects of IFN- and
TNF-, we were interested to study the effect of this cytokine on
chemotactic receptors, particularly FMLP-R. Here, evidence is provided
that IL-10 can also be implicated in controlling inflammatory processes
through modulation of chemotactic receptor expression.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-10 was obtained from Pepro Tech (Rocky Hill, NJ); FMLP and histamine were from Sigma (St. Louis, MO); PAF was from Biomol (Plymouth Meeting, PA); actinomycin D was from Merck Sharp & Dohme International (Rahway, NJ).
Preparation of monocytes
Human venous blood from healthy medication-free volunteers was collected on citrate/dextrose/adenine. The peripheral blood mononuclear leukocytes were enriched by dextran sedimentation, layered over a Ficoll-Hypaque cushion, and centrifuged at 400 x g for 20 min. Mononuclear leukocytes were collected at the interface and washed twice with PBS and resuspended in RPMI 1640 medium with 10% heat-inactivated FBS. Monocytes were then purified by adherence (60 min, 37°C) to the surface of plastic petri dishes coated with defibrinized autologous serum and removed with EDTA (0.01 M) in RPMI 1640, 10% FBS. This was effective in enriching the cell population to greater than 90% monocytes, with a viability greater than 98%, as assessed by Wright-Giemsa staining and trypan blue exclusion, respectively. Cells were resuspended in RPMI 1640, 10% FBS, at a final concentration of 2 x 106 cells/ml. Monocytes were allowed to rest overnight in polypropylene tubes to allow them to return to baseline status following initial activation by adherence. The medium was then removed by pipetting and replaced by fresh RPMI 1640, 10% FBS, before stimulation with the appropriate stimuli.
mRNA studies
After appropriate treatment, cells were pelleted in 15-ml
polypropylene tubes, and total cellular RNA was isolated by acid
guanidium thiocyanate-phenol-chloroform extraction according to
Chomczynski and Sacchi 31 . RNA (10 µg) was separated by
electrophoresis on 1% agarose and transferred onto a Hybond-N
(Amersham, Arlington Heights, IL) membrane for Northern analysis. A
1.75-Kb EcoRI fragment was used as FMLP-R probe (American
Type Culture Collection (ATCC), Manassas, VA) and a 1.0-Kb
PstI cDNA probe for the control gene
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ATCC). Alternatively,
a 0.7-Kb EcoRI fragment was used as PAF-R cDNA probe 32
whereas the C5a-R probe was generated by PCR from genomic DNA of Raji
cells using the primers 5'-ATGAACTCCTTCAATTATACCACCC-3' (sense),
and 5'-CACCACGTAGATGATGGGGTTGATGC-3' (antisense). The probes were
labeled with a multiprime DNA labeling system (Amersham) using
[-32P]dCTP (sp. act. > 3,000 Ci/mmol; Amersham).
Membranes were prehybridized for 4 h in a mixture containing Tris
120 mM, NaCl 600 mM, EDTA 8 mM, sodium pyrophosphate (NaPP) 0.1%, SDS
0.2%, and heparin 100 µg/ml; hybridization was performed overnight
at 68°C in the same mixture in which the concentration of heparin was
increased to 625 µg/ml and dextran sulfate at 10% was added. The
membranes were then washed once at room temperature for 20 min in 2x
SSC (1x SSC: 0.15 M NaCl, 0.015 M sodium citrate, pH 7); once with
0.1x SSC, 0.1% SDS at 68°C for 60 min, and then rinsed at room
temperature with 0.1x SSC. The membranes were exposed to Kodak XAR-5
film (Eastman Kodak, Rochester, NY) with intensifying screens for
24 h at -80°C. Signal intensity was quantitated by
densitometry using a LightningScan Pro 256 with the software
ThunderWorks 1.3.2 (Thunderware, Orinda, CA) and analyzed with the
software Scan Analysis 2.21 (Biosoft, Ferguson, MO) on a Macintosh
IIci computer. Densitometric values are expressed as ratios of
receptor/GAPDH densitometry quantification.
Flow cytometry
The expression of FMLP-R, PAF-R, and C5a-R on the surface of monocytes was monitored with a fluorescent analogue of FMLP, N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine-fluorescein (FLPEP) (Molecular Probes, Eugene, OR), our monoclonal anti-hPAF-R Ab, or the monoclonal anti-CD88 Ab (Serotec, Raleigh, NC). In brief, 3 x 105 treated cells were washed twice with PBS and labeled 30 min at 4°C with FLPEP (2 nM), anti-CD88 (0.5 µg), or anti-PAF-R (dilution 1:50). Alternatively, cells incubated with anti-PAF-R or anti-CD88 were then washed with cold PBS and incubated 30 min at 4°C with FITC-conjugated goat anti-mouse IgG (Bio/Can Scientific, Mississauga, Ontario, Canada). Finally, cells were washed in PBS and resuspended in PBS before flow cytometry analysis with a FACScan flow cytometer (Becton Dickinson, San Jose, CA). The acquisition was done with 2000 events per sample.
Calcium fluorometry
For Ca2+ mobilization assays, 3 x 106 cells were loaded in HBSS (Life Technologies, Gaithersburg, MD) containing 350 mg/L NaHCO3 and 10 mM HEPES, pH 7.0, with the calcium indicator fura 2-AM (Molecular Probes) for 30 min at room temperature. Loaded cells were washed twice, suspended in fresh loading buffer, and added to a constantly stirred cuvette in a SLM/Aminco spectrofluorometer (SLM Instruments, Urbana IL). The concentration of Ca2+ was brought to 1.5 mM by adding a solution of CaCl2 into the cuvette 10 min before recordings. Maximal fluorescence (Fmax) was obtained by adding Triton X-100 to a final concentration of 0.5%. Minimal fluorescence (Fmin) was determined by subsequent addition of EGTA, in Tris-HCl buffer (100 mM, pH 9.0) to 125 mM. Stimuli consisted of FMLP, PAF, and histamine.
Chemotaxis assay
Monocyte chemotactic activity was performed with Boyden chambers using a modified Boyden chamber chemotaxis assay. FMLP or control medium were added to the lower chamber and 200 µl of monocytes (6 x 105) in Gey’s BSS (Life Technologies) supplemented with 2% BSA were added to the upper chamber. The two chambers were separated by a 5-µm pore size polycarbonate filter (Neuroprobe, Cabin John, MD). After incubation for 2 h, the filter was disassembled, and the upper side of the filter was scraped free of cells. Cells on the lower side were removed with EDTA (5 mM) and centrifuged before counting by FACScan (Becton Dickinson) analysis with scatter-gating on monocytes. The results were then converted to a chemotaxis index (mean number of cells migrating to a specific stimulus/mean number of cells migrating to control medium). The statistical significance of the chemotactic indices of cells migrating in response to FMLP vs medium control was evaluated using the Student’s t test.
Statistical analysis
Results are expressed when possible as mean ± SE, and data were analyzed for statistical significance using the Student’s t test for paired values. Differences were considered significant at p < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To test the effect of IL-10 on the expression of FMLP-R,
human monocytes were incubated 4 h with different concentrations
of the cytokine and examined for their FMLP-R mRNA levels. As shown in
Fig. 1
, stimulation with increasing
concentrations of IL-10 resulted in a gradual augmentation in the
levels of FMLP-R transcripts. Whereas 1 ng/ml of IL-10 was effective to
induce a significant augmentation in the levels of FMLP-R expression,
concentrations from 5 to 20 ng/ml resulted in a 2.5- to more than
threefold augmentation of the transcripts. The maximal effect was
observed with 10 ng/ml of IL-10, and this concentration was used for
subsequent experiments. In additional experiments, we tested whether
IL-10 could modulate other chemotactic receptors. In these experiments,
monocytes were cultured in the presence or absence of IL-10 (10 ng/ml)
for up to 24 h. At selected time points (1, 2, 4, 8, and 24 h
poststimulation), RNA was isolated, and the levels of FMLP-R, PAF-R,
and C5a-R mRNA were determined. As shown in Fig. 2, IL-10 treatment differentially
modulated the levels of expression of these genes. Hence, as for
FMLP-R, PAF-R gene expression was shown to be up-regulated by IL-10.
Kinetic studies revealed that IL-10-mediated up-regulation for both
genes was rapid, observed as early as 1 h, peaked in less than
4 h poststimulation, and was still noticeable at 24 h. In
contrast to FMLP-R and PAF-R, the expression of C5a-R was unaffected by
IL-10.
|
|
,
IL-10 induced FMLP-R mRNA accumulation in PMN, but to a lesser extent
than in monocytes. In contrast, PMN PAF-R and C5a-R mRNA expression was
not significantly affected by IL-10 (data not illustrated).
|
The drastic up-regulation of FMLP-R mRNA accumulation in monocytes
secondary to IL-10 treatment could result from a transcriptional
activation of the FMLP-R gene. To assess this issue, we performed
experiments in which monocytes were pretreated with the transcriptional
inhibitor actinomycin D for 15 min, and then stimulated with IL-10 (10
ng/ml) for 2 h before RNA extraction and Northern blot analysis.
As shown in Fig. 4, this pretreatment
completely abolished the IL-10-induced accumulation of human FMLP-R
mRNA and suggested a transcriptional effect on the FMLP-R gene.
|
We next evaluated whether the IL-10-induced augmentation of FMLP-R
transcripts was paralleled by a concomitant up-regulation of surface
FMLP-R expression. In these experiments, human PMN or monocytes were
incubated for 24 h with or without IL-10 (10 ng/ml) before flow
cytometry analysis using FLPEP, a fluorescent analogue of FMLP. As
illustrated in Fig. 5, PMN treated with
IL-10 showed an augmented expression of surface FMLP-R protein, which
was significant (IL-10-treated, 21.2 ± 1.8, vs control cells,
12.7 ± 1.7; p < 0.0139) 24 h after their
initial exposure to this stimulus. Monocytes treated with IL-10 also
showed a significant increase in the peak channel fluorescence, as
compared with untreated cells (Fig. 6).
IL-10-induced up-regulation of FMLP-R protein expression was maximal by
24 h (IL-10-treated, 60.5 ± 6.2, vs control cells, 26.8
± 3.6; p < 0.0001). By 48 h, the difference had
vaned (IL-10-treated, 51.0 ± 5.2, vs control cells,
40.2 ± 4.6, p < 0.01; data not illustrated).
Parallel cytometry experiments were performed to evaluate the effect of
IL-10 on PAF-R and C5a-R expression. As illustrated in Figs. 5 and 6,
IL-10 induced a significant increase in PAF-R expression (IL-10-treated
PMN, 7.3 ± 0.8, vs control cells, 4.5 ± 0.5;
p < 0.0384, and IL-10-treated monocytes, 29.1 ±
4.2, vs control cells, 13.8 ± 1.8; p < 0.0009),
whereas it had no effect on C5a-R expression (IL-10-treated PMN,
5.9 ± 0.7, vs control cells, 7.5 ± 1.2; p
< 0.1682, and IL-10-treated monocytes, 14.5 ± 2.2, vs control
cells, 14.8 ± 6.5; p < 0.9262).
|
|
We next investigated whether the IL-10-induced increase in FMLP-R
expression was associated with an augmentation of biologic
responsiveness to FMLP. The biological activity of the receptor on
monocytes was evaluated for chemotactic response and calcium
mobilization at 24 h after exposure to IL-10 (10 ng/ml). As
illustrated in Fig. 7, IL-10-treated
monocytes showed a significantly (p < 0.04)
increased migration to FMLP when compared with medium-treated cells.
Similarly, PMN pretreated with IL-10 showed an increased migration to
FMLP when compared with medium-treated cells (data not illustrated).
Furthermore, as shown in Fig. 8,
monocytes pretreated for 24 h with IL-10 showed an increase in
their response to FMLP in terms of intracellular Ca2+
mobilization (
[Ca2+]i = 329 nM ±
45.8 for control cells vs 543 nM ± 89.4 for IL-10-treated cells,
p < 0.045). Similarly, the
[Ca2+]i rise induced by PAF was also enhanced
by a prior stimulation with IL-10. In counterpart, IL-10 had no effect
on the response of monocytes to a different stimulus, namely histamine.
Collectively, these data show that elevation of FMLP-R expression
following stimulation with IL-10 is accompanied by an enhanced
functional activity of these receptors.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and IL-10, is markedly inhibited by IL-10
14, 15, 16 . Moreover, PMN, often regarded as terminally differentiated
cells devoid of transcriptional activity, were recently shown to
release, like monocytes, proinflammatory cytokines such as TNF-,
IL-1ß, and IL-8 that can by suppressed by IL-10 (Ref. 37 and
therein). Other effector functions of PMN were also shown to be
modulated by IL-10, such as PAF production, phagocytic and bactericidal
activities, and oxidative metabolism 34, 35, 36 . Data presented here
provide evidence that, in addition to its immunosuppressive potential,
IL-10 may regulate leukocyte trafficking through modulation of FMLP-R
expression on these cells. In fact, we have shown that FMLP-R mRNA is
rapidly induced by IL-10, within 2 h, and that this induction is
primarily due to transcriptional activation. According to our data, the
IL-10-induced accumulation of FMLP-R mRNA level was accompanied by an
augmentation of FMLP-R expression at the cell surface. The
up-regulation was evident at 24 h of stimulation with IL-10 and
declined thereafter. We demonstrated that these newly induced receptors
were functional since pretreatment with IL-10 was associated with an
augmentation of biologic responsiveness to FMLP in terms of chemotaxis
and calcium mobilization. Whereas IL-10 concentrations in the range of
10 ng/ml may not be quite physiological, pathophysiological
concentrations, especially at the local level, such as those that may
be expected to modulate chemotactic receptor expression in inflammatory
sites, could well be quite elevated. Moreover, concentrations in the
ng/ml level have been used in various studies to demonstrate the
regulatory potential of IL-10 in a number of immune and inflammatory
events. Moreover, we found that IL-10 up-regulation was not restricted to FMLP-R and could also be observed for PAF-R expression. In contrast to FMLP-R and PAF-R, the expression of C5a-R was shown to be unaffected by IL-10. During the course of this work and in concordance with our observations, another family of chemotactic receptors, the CC chemokine receptors CCR5, CCR2, and CCR1, were recently shown to be up-regulated by IL-10 on human monocytes (Ref. 38, and our unpublished results).
Whereas coupling and desensitization processes for FMLP-R have been
extensively investigated 39 , only a few studies describing the
regulation of FMLP-R expression have been reported. Augmentation of
FMLP-R expression in HL-60 cells was observed following elevation of
cAMP levels 27, 28 . Cytokine modulation of FMLP-R has been reported
for granulocytic cells but not for monocytes. Hence in human
neutrophils, TNF- was shown to promote expression of FMLP-R 30 ,
whereas IFN- was shown to induce the expression of these
receptors by HL-60 cells differentiated into neutrophils 29 . The
mechanisms involved in IL-10-mediated up-regulation of FMLP-R
expression remain to be elucidated.
The mechanisms underlying the various actions of IL-10 are partially
understood. In monocytes, it was shown that IL-10 signaling pathway
promotes the activation of the Janus kinase (JAK) 1 and TYK2
tyrosine kinases, leading to the tyrosine phosphorylation of the signal
transducers and activators STAT1 and STAT3 40 ; the resulting STAT
proteins form DNA binding complexes that bind as homo- and heterodimers
to GAS (IFN- activation sequence) in the regulatory regions
of target genes 41, 42 . Recently, detectable amounts of transcription
factors such as STAT1 and STAT3 were demonstrated in human neutrophils,
which further emphasized the potential ability of these cells to be
functionally regulated at the level of gene transcription 33 .
According to our data, IL-10 mediated the up-regulation of FMLP-R
expression through a transcriptional mechanism. Whether the signaling
events triggered by IL-10 involve GAS-related elements in the promoter
region of the FMLP-R gene remains to be demonstrated.
In summary, our results suggest that IL-10, a known immunosuppressive cytokine, could contribute to proinflammatory processes through up-regulation of FMLP-R. In which physiological or pathophysiological circumstances such events may play a significant role remains to defined. This paradoxical situation suggests that IL-10 can sequentially combine proinflammatory and immunosuppressive actions on target cells. In a context of an inflammatory reaction, N-formyl peptides released by invading bacteria and lysed cells could promote migration of leukocytes such as monocytes and PMN, the principal targets of formyl peptides, and generally considered to be the central players in the process of inflammation. Once in the inflamed tissue, they can release inflammatory mediators and cytokines. In such a context, IL-10 may provide both a mechanism for accumulation of mononuclear and polymorphonuclear cells within the inflammatory lesion and a feedback mechanism to counteract an overwhelming response by controlling their oxidative metabolism and their production of proinflammatory cytokines.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Marek Rola-Pleszczynski, Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke, Québec, J1H 5N4, Canada. E-mail address:
3 Abbreviations used in this paper: PAF, platelet-activating factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FLPEP, N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine-fluorescein; PMN, polymorphonuclear neutrophils; GAS, IFN- activation sequence.
Received for publication May 8, 1998. Accepted for publication December 4, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production. J. Immunol. 150:3755.[Abstract]
-activated macrophages. J. Immunol. 148:1792.[Abstract]
R surface expression and cytotoxic activity: distinct regulation of antibody-dependent cellular cytotoxicity by IFN-, IL-4, and IL-10. J. Immunol. 149:4048.[Abstract]
-chain on T cells. Immunology 83:329.[Medline]
regulates expression of receptors for formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and platelet-activating factor. J. Immunol. 147:3842.[Abstract]
enhances expression of formyl peptide receptors and guanine nucleotide-binding proteins by HL-60 granulocytes. J. Immunol. 148:2483.[Abstract]
RI/CD64) gene and STAT protein binding to the IFN- response region (GRR) are regulated differentially in human neutrophils and monocytes by IL-10. J. Immunol. 160:911. and STAT3 complexes in human T cells and monocytes. J. Immunol. 155:1079.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  P. M.-C. Dang, C. Elbim, J.-C. Marie, M. Chiandotto, M.-A. Gougerot-Pocidalo, and J. El-Benna Anti-inflammatory effect of interleukin-10 on human neutrophil respiratory burst involves inhibition of GM-CSF-induced p47PHOX phosphorylation through a decrease in ERK1/2 activity FASEB J, July 1, 2006; 20(9): 1504 - 1506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Anstead, B. Chandrasekar, Q. Zhang, and P. C. Melby Multinutrient undernutrition dysregulates the resident macrophage proinflammatory cytokine network, nuclear factor-{kappa}B activation, and nitric oxide production J. Leukoc. Biol., December 1, 2003; 74(6): 982 - 991. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. Stankova, S. Turcotte, J. Harris, and M. Rola-Pleszczynski Modulation of Leukotriene B4 Receptor-1 Expression by Dexamethasone: Potential Mechanism for Enhanced Neutrophil Survival J. Immunol., April 1, 2002; 168(7): 3570 - 3576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Kuhns, E. L. Nelson, W. G. Alvord, and J. I. Gallin Fibrinogen Induces IL-8 Synthesis in Human Neutrophils Stimulated with Formyl-Methionyl-Leucyl-Phenylalanine or Leukotriene B4 J. Immunol., September 1, 2001; 167(5): 2869 - 2878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Xu, T. Yen, and C. L. Geczy IL-10 Up-Regulates Macrophage Expression of the S100 Protein S100A8 J. Immunol., May 15, 2001; 166(10): 6358 - 6366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Masur, B. Niggemann, K. S. Zanker, and F. Entschladen Norepinephrine-induced Migration of SW 480 Colon Carcinoma Cells Is Inhibited by {beta}-Blockers Cancer Res., April 1, 2001; 61(7): 2866 - 2869. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. Nardelli, O. Belvedere, V. Roschke, P. A. Moore, H. S. Olsen, T. S. Migone, S. Sosnovtseva, J. A. Carrell, P. Feng, J. G. Giri, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells Blood, January 1, 2001; 97(1): 198 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Brocheriou, D. Stengel, L. Mattsson-Hulten, J. Stankova, M. Rola-Pleszczynski, F. Koskas, O. Wiklund, Y. Le Charpentier, and E. Ninio Expression of Platelet-Activating Factor Receptor in Human Carotid Atherosclerotic Plaques : Relevance to Progression of Atherosclerosis Circulation, November 21, 2000; 102(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Terkeltaub IL-10: An "Immunologic Scalpel" for Atherosclerosis? Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2823 - 2825. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
