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Receptors Induces the Expression of Macrophage-Inflammatory Protein (MIP)-1
, MIP-1
, and RANTES1
* Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, and
Unidad de Investigación, Hospital Clínico Universitario, Valladolid, Spain
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RI, FcRIIA, and FcRIII, LPS,
TNF-
, and the combination of ionomycin and phorbol ester, to address
their effects on the expression of the mRNAs encoding for chemokines.
Stimulation of monocytes with immune complexes induced a rapid
expression of macrophage-inflammatory protein (MIP)-1, MIP-1
, and
IL-8 mRNAs. In contrast, RANTES mRNA was already detectable in resting
cells and only increased after 16 h of stimulation. A similar
pattern was observed following homotypic stimulation of FcR with mAb
reacting with FcRI and FcRIIA, but not with a mAb reacting with
FcRIII, a subtype of receptor not expressed in THP-1 cells, thus
indicating that both FcRI and FcRIIA are involved in the
response. The pattern of chemokine induction elicited by LPS and the
combination of ionomycin and PMA showed some similarities to those
produced by FcR cross-linking, although expression of
IFN--inducible protein 10 mRNA was also observed in response to
those agonists. The production of MIP-1, MIP-1, and RANTES
proteins encompassing the induction of their mRNAs was confirmed by
specific ELISA. Experiments to address the transcription factors
involved in the regulation of MIP-1 using pharmacological agents and
EMSA showed the possible involvement of CCAAT/enhancer-binding protein
sites and ruled out the functional significance of both NF-AT and
AP-1 sites. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R) plays
a central role in immune-mediated tissue injury due to the ability of
these receptors to recruit effector mechanisms of inflammation. This
has been highlighted by studies in murine strains with targeted
disruption of the -chain of FcR, in which it has been possible to
uncouple immune complex
(IC)4 deposition from
the subsequent inflammatory response (1, 2, 3), thus
depicting a general model of IC-mediated injury in which
FcR-mediated events rather than the complement system are critical
to the tissue damage. The proinflammatory events to date associated
with activation of FcR include the induction of both proinflammatory
and chemotactic cytokines (4, 5, 6, 7, 8), the activation of the
mitogen-activated protein (MAP) kinase cascade (9, 10, 11),
and the induction of enzymes playing a role in the inflammatory
reaction, such as the inducible isoform of NO synthase and
cyclooxygenase-2. Regarding the induction of chemokine expression
elicited by FcR, most studies have focused on both monocyte
chemoattractant protein-1 (MCP-1) and IL-8, whereas few studies have
addressed the induction of other CC chemokines such as RANTES,
macrophage-inflammatory protein (MIP)-1, and MIP-1. In this
connection, RANTES has been characterized as a chemoattractant for
monocytes and lymphocytes, which has been implicated in several
clinical conditions such as allergic inflammation (12),
endotoxemia (13), the cytotoxic activity of human
HIV-specific CD8+ T cells (14), and
ulcerative colitis (15). The role of MIP-1 and MIP-1
deserves detailed attention, because these chemokines form a doublet
and are involved in the development of the acute lung injury induced by
IC (16, 17) and endotoxin (18), as it has
been shown in experimental studies by using specific Ab against these
molecules. Moreover, MIP-1 is rapidly induced by factors that
activate macrophages, thus belonging to the class of rapid-response or
immediate-early genes (19). Studies addressing the
transcriptional regulation of both MIP-1 (20) and
MIP-1 (21) have indicated a strong dependence on short
proximal promoter sequences containing activating transcription
factor/CREB, CCAAT/enhancer-binding protein (C/EBP), c-Ets, and
B sites, thus explaining the rapid and cell-specific induction of
these chemokines in macrophages by LPS, serum, and cycloheximide
(18, 22, 23). However, these data cannot be readily
extended, because some studies have been conducted on murine cells, and
promoter analyses have been conducted with early databases. In this
study, we have addressed the pattern of induction of several
functionally relevant chemokines following activation of FcR using
both homotypic and heterotypic cross-linking of the subtypes of FcR
expressed in THP-1 cells, and compared this pattern with that elicited
by other well-known activators of phagocytes. Our data show a rapid
induction of MIP-1, MIP-1, and IL-8 during the first 3 h
that follow the addition of the stimulus, and a more protracted
induction of RANTES. Analysis of the promoter regions of both MIP-1
and RANTES as well as studies of the binding activities for regulatory
sites in the nuclear extracts of monocytic cells suggest the
involvement of C/EBP rather than NF-B, AP-1, and NF-AT sites in
their induction. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IgG Ab were raised in rabbits by s.c. injections of OVA in CFA,
followed by booster i.m. IgG Ab were purified from heat-inactivated
serum by precipitation with ammonium sulfate. Solutions of both OVA and
Ab were sterilized by ultrafiltration before use. IgG-OVA equivalence
IC were made according to classical procedures (24), and
washed extensively to ensure the removal of remaining serum components.
The purity of the IC was assayed by SDS-PAGE, which showed the presence
of IgG and OVA. mAb anti-FcRI (32.2), anti-FcRII (IV.3),
and anti-FcRIII (3G8) were from Medarex (Annandale, NJ). The
proteasome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal
(ALLN) was from Sigma-Aldrich (St. Louis, MO). The
2-hydroxy-4-trifluoromethylbenzoic acid (HTB), a salicylate derivative
with potent inhibitory effects on NF-B activation (25),
was from URIACH Laboratories (Barcelona, Spain).
Cell culture
THP-1 cells were cultured in plastic dishes in RPMI 1640 medium
supplemented with 10% heat-inactivated FBS. Cells were deprived of FBS
for 16 h, except in the samples used for the assay of MIP-1,
MIP-1, and RANTES proteins, in which the amount of serum was reduced
to 2%, according to the manufacturer’s instructions, to prevent loss
of chemokines in the culture supernatants before assay. Human monocytes
were isolated from peripheral blood of healthy donors (laboratory
staff) by centrifugation into Ficoll cushions and adherence to plastic
dishes. When the purpose of the experiment required nonadhered
monocytes, the adhered cells were detached by cold and scraping and
maintained in polypropylene tubes for 18 h before the addition of
the stimuli to avoid adherence.
RNA extraction and RNase protection assays
Total cellular RNA was extracted by the TRIzol method (Life
Technologies, Grand Island, NY) and used to assay the level of
expression of RANTES, MIP-1, IFN--inducible protein 10 (IP-10),
MIP-1, IL-8, L32, and GAPDH mRNAs by RiboQuant RNase protection
assay using the hCK-5 multiprobe template set from BD PharMingen (San
Diego, CA). For this purpose, riboprobes were labeled with
[-32P]UTP in the presence of T7 RNA
polymerase and used for overnight hybridization with 3 µg RNA. The
hybridized RNA was digested with RNase and proteinase K, and the
RNase-protected probes were purified and resolved on denaturing PAGE.
The identification of the specific chemokine bands was conducted on the
basis of their individual migration patterns in comparison with the
undigested probes. Radiolabeled bands on the gel were acquired using
the Personal Molecular Imager FX and quantitated using Quantity One
software (Bio-Rad, Hercules, CA). Sample loading was normalized by the
housekeeping genes L32 and GAPDH.
Electrophoretic mobility shift assay
THP-1 cells were washed with ice-cold hypotonic lysis buffer.
Unbroken cells were eliminated by centrifugation at 1,000 x
g for 10 min, and the nuclei were collected by
centrifugation at 15,000 x g for 1 min. The nuclear
pellet was resuspended in high salt extraction buffer containing 25%
glycerol and 0.5 M KCl, and the nuclear extract was obtained by
pelleting for 30 min at 105,000 x g. Double-stranded
oligonucleotide probes were end labeled with
[-32P]ATP using T4 polynucleotide kinase and
separated from the unincorporated label by minicolumn chromatography. A
total of 10 µg nuclear protein was incubated for 20 min on ice with
radiolabeled oligonucleotide probes (2–6 x
104 cpm) in a 25 µl reaction buffer containing
2 µg poly(dI-dC), 10 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM EDTA, 1
mM DTT, 8% Ficoll, and 4% glycerol. Nucleoprotein-oligonucleotide
complexes were resolved by electrophoresis in a 4% nondenaturing PAGE.
The gel was dried, and the radiolabeled bands were acquired with the
personal imager FX. The oligonucleotide sequences used for the
detection of binding activity to the AP-1 and C/EBP sites from the
MIP-1 promoter are shown in Fig. 1
.
Additional experiments were conducted with an AP-1 consensus sequence,
which differs from the AP-1 site sequences from the MIP-1
promoter.
|
, MIP-1, and RANTES production
MIP-1, MIP-1, and RANTES were assayed in cell culture
medium. The procedure was conducted with reagents from Endogen (Woburn,
MA) in the case of MIP-1, and Amersham Pharmacia Biotech
(Piscataway, NJ) for the assay of MIP-1 and RANTES. These procedures
use Ab-precoated well plates, biotinylated rabbit anti-human Abs,
and streptavidin conjugated to HRP. The ELISA are developed using a
peroxidase reaction, and the minimum detectable doses of this assay are
5 pg/ml for MIP-1, and 2 pg/ml for RANTES.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI and FcRIIA induces chemokine mRNAs in THP-1
cells and peripheral blood monocytes
Stimulation of THP-1 cells with IC induced a strong expression of
the mRNA of RANTES, MIP-1, MIP-1, and IL-8 in a dose-dependent
manner (Fig. 2A). MIP-1 and
MIP-1 showed the most marked increase, because their mRNAs were
almost undetectable before the addition of the stimulus and strongly
increased between 10 min and 3–8 h (Fig. 2, B and
C). This temporal pattern was similar to that observed for
IL-8, although in this case it was difficult to detect mRNA expression
after 3 h. In contrast, the expression of RANTES mRNA showed a
different pattern, because it was already detectable before addition of
the stimulus, and showed a 
3-fold increase above prestimulation
levels between 16 and 48 h after addition of IC (Fig. 2B), as judged from densitometric scanning of the blot area.
The dose dependency of the response was studied at a fixed time of
3 h, and optimal induction was observed with concentrations above
20 µg/ml (Fig. 2A). To rule out whether some unidentified
contaminant of both OVA and Ab solutions could account for the effect
attributed to IC, THP-1 cells were incubated with 100 µg/ml of both
OVA and Ab. As shown in the rightmost panel of Fig. 2B, these treatments did not induce the expression of
chemokine mRNA, thus making it unlikely that contaminants as, e.g., LPS
could account for the observed effects. To address whether the results
obtained in THP-1 cells agreed with the response observed in human
monocytes, adhered monocytes from peripheral blood were stimulated with
IC. As shown in Fig. 2D, adhered resting monocytes showed a
slight expression of RANTES, MIP-1, and MIP-1, and a marked
expression of IL-8 mRNA; however, addition of IC significantly enhanced
the expression of MIP-1 and MIP-1. In contrast, when detached
monocytes were maintained for 18 h in polypropylene tubes, there
was a mild expression of RANTES, whereas IC induced a prominent
induction of MIP-1 and MIP-1 (Fig. 2D, right
panel), thus suggesting that purification of blood monocytes
taking advantage of their adherence to plastic dishes has a prominent
effect on IL-8 expression, whereas engagement of FcR by IC impinges
on the induction of both MIP-1 and MIP-1, as it was shown in
THP-1 monocytes. These findings make the THP-1 cell line a suitable
model for the study of monocytic cells, because it may grow without
adhering to plastic and then circumvents the occurrence of
adherence-mediated activation. Attempts to relate the expression of
chemokines to the cross-linking of the specific types of FcR
expressed in THP-1 cells were conducted by the homotypic approach by
incubating THP-1 cells with 10 µg/ml mAb reacting with FcRI,
FcRIIA, and FcRIII for 10 min at 4°C, followed by washing to
eliminate the Ab not bound to cell receptors and replacement by new
medium prewarmed at 37°C before the addition of goat anti-mouse
F(ab')2 (26). The pattern of
chemokine induction elicited by the mAb resembled one another, as well
as that produced by the combination of mAb (Fig. 3). In contrast, stimulation of THP-1
cells with the 3G8 mAb did not induce the expression of chemokine mRNA,
nor did anti-mouse F(ab')2 alone produce any
effect, thus agreeing with the absence of FcRIII expression in THP-1
cells (26) (Fig. 3). In keeping with previous studies
addressing homotypic stimulation of FcR, the responses were less
robust, thus suggesting that cross-linking of FcR by mAb does not
produce strong Fc-FcR interactions, such as those required for
optimal activation of monocytes (26, 27). Noteworthy, the
pattern of induction elicited by other stimuli was somewhat different
from that elicited by IC, albeit the induction of both MIP-1 and
MIP-1 was again most prominent. Thus, the combination of ionomycin
and PMA, which activates both Ca2+- and protein
kinase C-dependent pathways, produced a strong induction of IL-8 mRNA,
whereas ionomycin alone failed to produce IL-8 induction, and LPS
induced IP-10 mRNA as well (Fig. 4A). Interestingly, TNF-
produced a distinct pattern of induction of chemokines characterized by
a delayed induction of RANTES, IP-10, MIP-1, MIP-1, and MCP-1
(Fig. 4B).
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Initial attempts to disclose the transcription factors that
could be involved in the regulation of the different chemokines were
conducted with pharmacological agents well known as selective
inhibitors of transcription factors. Because the cross-linking of
FcR activates NF-B and this has functionally been associated with
the expression of MCP-1 (8), the effect of inhibiting
NF-B was addressed by using two structurally unrelated inhibitors of
NF-B. As shown in Fig. 4
C, both HTB and ALLN decreased
the mRNA expression of both MIP-1 and MIP-1 in response to IC. In
contrast, the expression of RANTES mRNA did not show any significant
change as a result of these treatments, and the expression of IL-8 mRNA
was enhanced in a dose-dependent manner by ALLN, which represented an
unexpected result in view of the documented presence of functional B
binding sites in the IL-8 promoter (28, 29, 30). As shown in
Fig. 4D, cyclosporin A did not influence the effect of IC,
i.e., less than 20% inhibition in three independent experiments, thus
suggesting that NF-AT sites do not exert a central role in the
transcriptional regulation of MIP-1, MIP-1, RANTES, and
IL-8.
Cross-linking of FcR activates AP-1 and C/EBP
Incubation of THP-1 cells with IC increased AP-1-binding activity
in the nuclear extracts in a time-dependent manner, as judged from the
results of EMSA conducted with a probe containing the 5'-TGAGTCA-3'
core consensus sequence for AP-1. As shown in Fig. 5A, increased binding activity
was already observed 5–10 min after addition of the stimulus, reached
maximal intensity at 20 min, and was completely reversed by
incubation with a 100-fold excess of unlabeled
oligonucleotide with the AP-1 consensus sequence. However, no
binding activity was observed when the reaction was conducted with a
probe designed on the basis of the AP-1 site sequences of the
MIP-1 promoter (Fig. 5B), thus indicating that even
though activation of FcR activates AP-1, its involvement in the
transcriptional regulation of MIP-1 is unlikely. In contrast,
the nuclear extracts showed binding activity to the probe containing
the -122–100 C/EBP sequence of the sense strand. Maximal binding
activity was seen between 20 and 45 min after addition of IC (Figs. 5C and 6A), and showed a clear dose dependency,
because this was already observed with concentrations of IC above 20
µg/ml (Fig. 5D). Binding to the MIP-1C/EBPwt probe
was reversed by a 100-fold excess of the unlabeled oligonucleotide
(Fig. 5C, lane marked "competitor"). Experiments
conducted with the MIP-1wt oligonucleotide that contains both the
putative AP-1 and the C/EBP binding sites (Fig. 6B, lanes 5–8)
showed a binding pattern similar to that observed with the
MIP-1C/EBPwt probe, which again was reversed by the
unlabeled oligonucleotide sequence (Fig. 6B,
lane 8). Furtherattempts to assess the selectivity of the
binding reactions were addressed with mutated oligonucleotides designed
to disrupt the C/EBP site according to the TRANSFAC database. In
fact, no binding activity was observed when labeled
*MIP-1C/EBPm and *MIP-1m probes
were used in the binding reactions (Fig. 6A, lanes
4–6 and 8, respectively), and
MIP-1C/EBPm did not reverse the binding of the labeled
*MIP-1C/EBPwt probe (Fig. 6A, lane 7).
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R elicits MIP-1, MIP-1, and RANTES protein
production
Because stimulation of THP-1 cells by IC led to an enhanced
expression of both MIP-1 and MIP-1 mRNAs, it was addressed
whether this was accompanied by a parallel production of MIP-1 and
MIP-1 proteins. As shown in Fig. 7A, MIP-1 and MIP-1
proteins were undetectable in resting cells and increased in a
time-dependent manner after incubation with IC. Interestingly, MIP-1
protein showed a higher increase than that observed for MIP-1,
because levels of 25 ng/ml were assayed at 8 h after addition of
the complexes as compared with 2–4 ng/ml for MIP-1, even though
more prolonged incubations showed in some cases a significant reduction
of the protein, thus suggesting that changes related to the stability
and/or degradation of MIP-1 might occur. RANTES protein was already
detectable in cell cultures of resting THP-1 cells, but it
significantly increased up to 48 h after the addition of the
stimulus to reach a 5-fold increase above resting levels (Fig. 7B). The production of both MIP-1 and RANTES was dose
dependent, as measurable amounts of MIP-1 were detected with
concentrations of IC above 50 µg/ml, and the production of RANTES
also increased with this concentration of stimulus above the level
detected in resting cells. Interestingly, the production of MIP-1
and RANTES elicited by IC was comparable with those elicited by PMA and
TNF- (Fig. 7C), thus indicating that it might reach
concentrations similar to those elicited by other stimuli.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R in monocytic cells by showing
a widespread pattern of induction of chemokines, in which the
expression of MIP-1 and MIP-1 reaches the highest level of
expression. This is somewhat surprising, because most studies have
stressed the production of MCP-1 and IL-8 in response to the activation
of FcR. In keeping with the functional association of both MIP-1
and MIP-1, studies in a rat model of IC lung injury have shown a
role for both MIP-1 and MIP-1 in macrophage activation, because
despite a wide induction of other CC chemokines, only the blockade of
either MIP-1 or MIP-1 reduced the recruitment of neutrophils and
the production of lung injury (16, 17, 18).
The comparison of the effect of FcR activation with that elicited by
other stimuli provides some hints as to the involvement of different
chemokines in distinct pathophysiological conditions. Thus, the set of
chemokines elicited by FcR engagement shows some differences with
those triggered by TNF-, LPS, and the combination of ionomycin and
PMA. In fact, LPS and ionomycin shared the feature of inducing IP-10,
whereas this was not observed in response to IC. In contrast, ionomycin
alone did not induce IL-8. Many different monocytic cell lines,
including THP-1 cells, show constitutive nuclear B activity
(31), and unlike MIP-1, RANTES has two B sites near
the TATA signal, thus explaining possible interactions with components
of the general transcription machinery that could account for the
expression of RANTES detected in resting cells. In contrast, the
delayed pattern of RANTES mRNA induction by IC agrees with the
characterization of RANTES as an unusual gene induced late after T
lymphocyte activation, the expression of which has been related to a
novel transcription factor termed RANTES factor of late activated T
lymphocytes, which belongs to the Kruppel-like family of transcription
factors (32), although other factors have been associated
with the cell-specific pattern of transcriptional
regulation of RANTES, among them NF-B (33), C/EBP
(34), and IFN regulatory factor (35).
The combined induction of both MIP-1 and MIP-1 fits well with the
presentation of these molecules as a doublet; however, it is more
difficult to address the functional significance of the different
regulatory elements located to their promoter regions. Early studies
have restricted the functional relevance for transcription to a
proximal promoter region of 256 bp (20), in which several
binding sites for members of the C/EBP family of transcription factors
were characterized, as well as a GGAAA motif homologous to a highly
conserved half site of a putative consensus NF-B recognition
sequence. Taking into account these early functional studies and the
quality of the matches of the matrix analysis of the promoter sequence
with MatInspector software and the updated data of the TRANSFAC
database (36), we have defined some binding sites that
could have functional significance (Fig. 1A). These binding
sites include three AP-1 sites, a GATA-1 site, and a C/EBP site in
the sense strand; and two more AP-1 sites, two C/EBP sites, which
also encompass a NF-AT site, and an additional NF-AT site in the
antisense strand. In contrast, no B sites have been detected using
updated database. Analysis of the binding activity associated with the
nuclear extracts from cells stimulated with IC has shown abundant
AP-1-binding activity; however, this only could be disclosed with the
AP-1 consensus sequence, and not with those found in the MIP-1
promoter region, thus suggesting that AP-1 sites are not involved in
the regulation of MIP-1 expression. Moreover, pharmacological
approaches using compounds with known activity on the NF-B system
have provided contradictory results. For instance, the salicylate
derivative HTB, which has been found to inhibit NF-B activation in
several cell systems (25, 37, 38), inhibited the induction
of MIP-1 and MIP-1 without influencing IL-8 expression. In
contrast, the proteasome inhibitor ALLN showed unexpected effects,
because in addition to an inhibitory effect on the expression of both
MIP-1 and MIP-1, this compound increased the expression of IL-8
mRNA in a dose-dependent manner. These results are reminiscent of those
recently reported in human monocytes. Thus, triggering of
2 integrins by both Ab and soluble CD23 has
shown a strong induction of both MIP-1 and MIP-1, which was
sensitive to proteasome inhibitors, whereas this treatment enhanced
IL-8 expression (39). In addition, treatment of human
monocytes with 15-deoxy-
12,14
PGJ2 has been found to produce IL-8 gene
expression (40), although the function of this peroxisome
proliferator-activated receptor- activator has been
associated with an anti-inflammatory effect linked to the
inhibition of the NF-B route (41). Previous studies
have suggested that NF-B was involved in the induction of MIP-1
and MIP-1; however, the evidence was indirect and only stemmed from
the coincidental presence of binding activity to a consensus B site
in the nuclear extracts obtained under these conditions, and from the
effect of pharmacological treatments. Regarding GATA-1 sites, their
involvement in the transcriptional regulation of MIP-1 and RANTES is
unlikely for a number of reasons. First, these sites differ somewhat
from the consensus (T/A)GATA(A/G), which accounts for most of the sites
in which a functional role for GATA-1 has been demonstrated. Moreover,
GATA-1 expression shows a restricted level of expression among cells
derived from hemopoietic progenitor cells, for instance,
megakariocytes, mast cells, basophils, and eosinophils
(42). In fact, we have not detected the expression of
GATA-1 mRNA by the RT-PCR approach in THP-1 cells (data not shown). In
contrast, the functional relevance of the C/EBP site in the
transcriptional regulation of MIP-1 can be supported by several
arguments: 1) the presence of a high homology C/EBP site on the
proximal promoter region according to rigorous criteria; 2) the
appearance of binding activity to this site in the nuclear extracts
displaying a strong dependency on critical bases in the core sequence,
before the induction of MIP-1 expression; 3) the similar
dose-response pattern of both MIP-1 expression and appearance of
C/EBP-binding activity; 4) the parallel pattern of MAP kinase
activation (26) and C/EBP-binding activity in the
nuclear extracts elicited by FcR cross-linking, which agrees with
the reported phosphorylation at threonine-235 of C/EBP by MAP kinase
as an essential step for C/EBP activation (43).
Moreover, the pattern of MIP-1 induction in this system is similar
to that disclosed for cyclooxygenase-2 (26), a gene the
expression of which has been found to be strongly dependent on C/EBP
in both human and mouse macrophages (44, 45). Taken
together, these findings extend previous studies showing the activation
of a set of transcription factors by FcR signaling, i.e., NF-B
(6, 8), AP-1, and C/EBP, and suggest the coupling of
C/EBP to the induction of some elements of the chemokine family
involved in the production of immune-mediated tissue injury.
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Acknowledgments |
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Footnotes |
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2 N.F., M.R., and C.G.-R. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Mariano Sánchez Crespo, Instituto de Biología y Genética Molecular, Facultad de Medicina, 47005-Valladolid, Spain. E-mail address: mscres{at}ibgm.uva.es
4 Abbreviations used in this paper: IC, immune complex; ALLN, N-acetyl-leucinyl-leucinyl-norleucinal; C/EBP, CCAAT/enhancer-binding protein; HTB, 2-hydroxy-4-trifluoromethylbenzoic acid; IP-10, IFN--inducible protein 10; MAP, mitogen-activated protein; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage-inflammatory protein.
Received for publication April 12, 2002. Accepted for publication July 8, 2002.
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  J. L. Dooley, D. Abdel-Latif, C. D. St. Laurent, L. Puttagunta, D. Befus, and P. Lacy Regulation of inflammation by Rac2 in immune complex-mediated acute lung injury Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1091 - L1102. [Abstract] [Full Text] [PDF]
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 L. G. Perez, M. R. Costa, C. A. Todd, B. F. Haynes, and D. C. Montefiori Utilization of Immunoglobulin G Fc Receptors by Human Immunodeficiency Virus Type 1: a Specific Role for Antibodies against the Membrane-Proximal External Region of gp41 J. Virol., August 1, 2009; 83(15): 7397 - 7410. [Abstract] [Full Text] [PDF]
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 Y. Alvarez, C. Municio, S. Alonso, M. Sanchez Crespo, and N. Fernandez The Induction of IL-10 by Zymosan in Dendritic Cells Depends on CREB Activation by the Coactivators CREB-Binding Protein and TORC2 and Autocrine PGE2 J. Immunol., July 15, 2009; 183(2): 1471 - 1479. [Abstract] [Full Text] [PDF]
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D. N. Forthal, P. B. Gilbert, G. Landucci, and T. Phan Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate J. Immunol., May 15, 2007; 178(10): 6596 - 6603. [Abstract] [Full Text] [PDF]
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E. Cittera, M. Leidi, C. Buracchi, F. Pasqualini, S. Sozzani, A. Vecchi, J. D. Waterfield, M. Introna, and J. Golay The CCL3 Family of Chemokines and Innate Immunity Cooperate In Vivo in the Eradication of an Established Lymphoma Xenograft by Rituximab J. Immunol., May 15, 2007; 178(10): 6616 - 6623. [Abstract] [Full Text] [PDF]
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 M. Fiorucci, S. Boulant, A. Fournillier, J. D. Abraham, J. P. Lavergne, G. Paranhos-Baccala, G. Inchauspe, and C. Bain Expression of the alternative reading frame protein of Hepatitis C virus induces cytokines involved in hepatic injuries J. Gen. Virol., April 1, 2007; 88(4): 1149 - 1162. [Abstract] [Full Text] [PDF]
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A. Berndt, F. J. Derksen, P. J. Venta, S. Ewart, V. Yuzbasiyan-Gurkan, and N. E. Robinson Elevated amount of Toll-like receptor 4 mRNA in bronchial epithelial cells is associated with airway inflammation in horses with recurrent airway obstruction Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L936 - L943. [Abstract] [Full Text] [PDF]
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 P. Hernandez-Vargas, G. Ortiz-Munoz, O. Lopez-Franco, Y. Suzuki, J. Gallego-Delgado, G. Sanjuan, A. Lazaro, V. Lopez-Parra, L. Ortega, J. Egido, et al. Fc{gamma} Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice Circ. Res., November 24, 2006; 99(11): 1188 - 1196. [Abstract] [Full Text] [PDF]
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 J.-S. Kim, J.-G. Kim, M.-Y. Moon, C.-Y. Jeon, H.-Y. Won, H.-J. Kim, Y.-J. Jeon, J.-Y. Seo, J.-I. Kim, J. Kim, et al. Transforming growth factor-beta1 regulates macrophage migration via RhoA Blood, September 15, 2006; 108(6): 1821 - 1829. [Abstract] [Full Text] [PDF]
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D. N. Forthal, G. Landucci, K. S. Cole, M. Marthas, J. C. Becerra, and K. Van Rompay Rhesus macaque polyclonal and monoclonal antibodies inhibit simian immunodeficiency virus in the presence of human or autologous rhesus effector cells. J. Virol., September 1, 2006; 80(18): 9217 - 9225. [Abstract] [Full Text] [PDF]
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 S. Devaraj, B. Davis, S. I. Simon, and I. Jialal CRP promotes monocyte-endothelial cell adhesion via Fc{gamma} receptors in human aortic endothelial cells under static and shear flow conditions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1170 - H1176. [Abstract] [Full Text] [PDF]
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 A. G. Trinidad, M. L. de la Puerta, N. Fernandez, Y. Bayon, M. S. Crespo, and A. Alonso Coupling of C3bi to IgG inhibits the tyrosine phosphorylation signaling cascade downstream Syk and reduces cytokine induction in monocytes J. Leukoc. Biol., May 1, 2006; 79(5): 1073 - 1082. [Abstract] [Full Text] [PDF]
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 A. I Duenas, M. Aceves, A. Orduna, R. Diaz, M. Sanchez Crespo, and C. Garcia-Rodriguez Francisella tularensis LPS induces the production of cytokines in human monocytes and signals via Toll-like receptor 4 with much lower potency than E. coli LPS Int. Immunol., May 1, 2006; 18(5): 785 - 795. [Abstract] [Full Text] [PDF]
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N. Fernandez, S. Alonso, I. Valera, A. G. Vigo, M. Renedo, L. Barbolla, and M. S. Crespo Mannose-Containing Molecular Patterns Are Strong Inducers of Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Macrophages J. Immunol., June 15, 2005; 174(12): 8154 - 8162. [Abstract] [Full Text] [PDF]
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 T R D J Radstake, R van der Voort, M ten Brummelhuis, M de Waal Malefijt, M Looman, C G Figdor, W B van den Berg, P Barrera, and G J Adema Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors Ann Rheum Dis, March 1, 2005; 64(3): 359 - 367. [Abstract] [Full Text] [PDF]
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M. Aceves, A. Duenas, C. Gomez, E. San Vicente, M. S. Crespo, and C. Garcia-Rodriguez A New Pharmacological Effect of Salicylates: Inhibition of NFAT-Dependent Transcription J. Immunol., November 1, 2004; 173(9): 5721 - 5729. [Abstract] [Full Text] [PDF]
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 A. B. Stavitsky Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis Infect. Immun., January 1, 2004; 72(1): 1 - 12. [Full Text] [PDF]
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 N. Fernandez, M. Renedo, S. Alonso, and M. S. Crespo Release of Arachidonic Acid by Stimulation of Opsonic Receptors in Human Monocytes: THE Fc{gamma}R AND THE COMPLEMENT RECEPTOR 3 PATHWAYS J. Biol. Chem., December 26, 2003; 278(52): 52179 - 52187. [Abstract] [Full Text] [PDF]
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 T. Waehre, J. K. Damas, L. Gullestad, A. M. Holm, T. R. Pedersen, K. E. Arnesen, H. Torsvik, S. S. Froland, A. G. Semb, and P.a. Aukrust Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1460 - 1467. [Abstract] [Full Text] [PDF]
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