| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel, and
Department of Internal Medicine, Meir Hospital, Kfar Saba, Israel
Correspondence: Ofer Lider, Ph.D., Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: ofer.lider{at}weizmann.ac.il
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
acts as
an adhesion-strengthening and stop signal for T cells migrating toward
stromal cell-derived factor-1, while transforming growth factor-ß
down-regulates TNF--induced matrix metalloproteinase-9 secretion by
monocytes. These findings indicate the importance of how one cytokine,
such as TNF-, can transmit diverse signals to different subsets of
leukocytes, depending on its combination with other cytokines, its
concentration, and its time and sequence of exposure. The combinatorial
effects of multiple cytokines thus affect leukocytes in a
step-by-step manner, whereby cells react to cytokine signals in their
immediate vicinity by altering their adhesiveness, directional
movement, and remodeling of the ECM.
Key Words: chemokines • cytokines • cytoskeleton • metalloproteinase • T lymphocytes
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
To better understand these concepts, our laboratory posed several questions about the regulation of leukocyte interactions with ECM: (1) Do certain ECM-bound proinflammatory cytokines impede leukocyte migration, thus presenting a stop signal, in the presence of a chemoattractant gradient? (2) What are the net effects of two chemokines on leukocyte adhesion and migration through the ECM when both chemokines are encountered either sequentially or simultaneously? (3) Can an individual cytokine influence leukocyte adhesion to ECM glycoproteins in a particular way when encountered alone but in a different way when encountered together with other cytokines? (4) How do combinations of cytokines which are likely to be encountered in inflamed sites either sequentially or simultaneously affect MMP expression by leukocytes?
Herein, we describe the studies undertaken in our laboratory to address these issues. The results provide further evidence that the context of the ECM microenvironment, as encountered by infiltrating leukocytes, provides a fine-tuning of the inflammatory response through alterations in its balance of moieties, degradative enzymes, and bound cytokines or chemoattractants. These molecules guide leukocytes with informational cues as they travel in short trajectories through the ECM network, providing signals for how and in what direction the cells should negotiate their way through the ECM [2 ]. Thus, decision-making processes are largely dependent on the spatial arrangement and combination of inflammatory mediators, for which leukocytes express specific receptors, and the step-by-step encounters made with migrating leukocytes. We further believe that by being active participants in the regulation of ECM deposition and degradation, immune cells help to define the path toward their destined tissue sites, ultimately contributing to the restoration of homeostasis.
FN-associated tumor necrosis factor (TNF)-— a stop signal
for leukocyte chemotaxis
Although the use of Boyden chambers or transwell chemotaxis units
has long been a conventional method of studying cell migration toward
chemoattractants, these models are limited in their in vitro simulation
of three-dimensional (3-D) movement within the ECM. Analysis of cell
migration in 3-D matrices provides not only a means to study the rapid
interactions between cell surface receptors and their matrix ligands
but also the opportunity to follow cell movements by video microscopy.
Several studies have implemented 3-D matrices composed solely of
agarose [3
], collagen [4
5
6
7
8
], or fibrin
[9
, 10
] to track the movements of
leukocytes. However, chemotactic cell migration along gradients of
chemoattractants has not been extensively studied in complex ECM-like
matrices, particularly using T lymphocytes. Recently, we reported the
development of a novel system to track T-lymphocyte chemotaxis in real
time, within 3-D ECM-like gels composed of the major ECM glycoproteins
collagen type IV, FN, and laminin [11
]. This system,
which uses time-lapse video microscopy, was designed to facilitate the
differentiation between random and directional migration of individual
T cells in chemokine gradients and the accompanying changes in cell
morphology. This type of analysis also enables us to analyze the
kinetics of T-cell locomotion and the involvement of adhesion
molecules, such as ß1 integrins, and specific signaling pathways by
using neutralizing antibodies or compounds. As shown in Figure 1
, the migration chamber contains three depots of ECM which, when
connected, form a chemokine gradient [e.g. regulated on activation,
normal T expressed and secreted (RANTES)] for T cells to sense and
integrate into their movement. Thus, this system represents a useful
method for real-time and computer analysis of cell migration, as well
as a suitable model to study the combined effects of multiple cytokines
or mediators [11
].
|
[12
], interleukin [IL]-2 [13
],
transforming growth factor [TGF]-ß [14
], and RANTES
[15
]) it is likely that cytokine receptors and
ECM-specific integrins expressed on leukocytes cooperatively regulate
cell activation, adhesion, and migration. This concept was strongly
supported by previous studies demonstrating that TNF-, a potent
proinflammatory cytokine expressed in high concentrations at inflamed
sites, forms complexes with ECM-FN and enhances ß1 integrin-mediated
T-lymphocyte adhesion to FN [12
]. Deposition of TNF-
into the ECM and its subsequent binding to FN or other ECM moieties
could thereby yield highly localized signals that T lymphocytes
integrate with other signals as they adapt their activities to the
local microenvironment. Indeed, when peripheral-blood T lymphocytes
were incubated in wells containing FN that had previously formed a
complex with TNF-, with or without the addition of other agonists,
the bound cytokine augmented the adhesion induced by other agonists,
specifically RANTES and stromal-cell-derived factor (SDF)-1. In
contrast, immobilized TNF- alone caused only a marginal increase in
T-cell adhesion to FN [16
]. This suggested that the
complex comprising ECM and TNF- does not exhibit proadhesive
properties by itself but, rather, strengthens ß1-integrin binding to
FN.
We postulated that, in addition to its adhesion-strengthening
properties, TNF- in complex with FN elicits other effects on
cell-matrix interactions as T lymphocytes navigate through
ECM-containing gradients of chemokines. Thus, the combined effects of
FN-bound TNF- with those of either chemokine SDF-1 or RANTES on
T-cell migration were examined in the 3-D ECM gel system developed in
our laboratory [11
]. For these experiments, T cells were
placed in Drop I, TNF- previously formed into a complex with FN was
placed in Drop II, and either SDF-1 or RANTES was placed in Drop III,
as illustrated in Figure 1
. On connection of the ECM depots to form the
chemokine gradient, the migratory pathways of individual T cells were
tracked in real time for analysis of cell polarization, as well as
random and directional migration. Cell polarization, an early
activation-dependent step in cell adhesion and motility, is
characterized by the distribution of chemokine receptors to the leading
edge of migrating cells, as well as the formation of a rear uropod
[17
]. Although random migration may be defined as
nonspecific movements known as chemokinesis, directional migration
involves specific locomotion toward a source of chemoattractant.
We found that when TNF- (250 pg/mL) was placed in the migratory zone
(Drop II), T-cell polarization was altered in a time-dependent manner,
shifting to a spherical morphology. Furthermore, when T cells
encountered TNF- in the migratory zone, random migration also
decreased steadily over time. To examine whether such changes in
motility evoked by TNF- also affect directional migration
toward chemokines, CD45RO+ T lymphocytes were placed
in Drop I, RANTES (100 ng/mL) or SDF-1 (150 ng/mL) was added to Drop
III, and chemotaxis was analyzed in a migratory zone (Drop II)
containing FN and TNF- in complex. As expected, in the absence of
TNF-, directional T-cell migration was induced along the RANTES or
SDF-1 gradients within 60 min of the start of the assay. However,
the presence of TNF- in the migration zone resulted in nearly
complete suppression of directional migration toward the chemokines.
Microdynamic analyses indicated marked decreases in both the total
distance and vectorial path lengths of individual migrating cells,
caused specifically by a stop signal from TNF-. Computerized
tracking of the pathways taken by individual cells in the migration
zone further demonstrated that migration patterns along a chemokine
gradient in the presence of matrix-associated TNF- were
significantly altered. Although a fraction of cells retained their
directional migration toward the chemokine gradient, the majority of
cells either traveled short distances toward the chemokine before
completely stopping or their paths of directional migration were
shortened due to the presence of TNF-. The stop signal delivered by
TNF- was found to be dependent on signaling through TNF- receptor
II but independent of any changes in the expression of chemokine
receptors or ß1 integrins [16
].
This study also highlighted a putative hierarchy in the ability of
certain proinflammatory cytokines to serve as stop signals via
strengthening of T-cell adhesion. In contrast to TNF-, IL-2, another
proadhesive and promigratory cytokine involved in inflammation
[11
], did not cause a stoppage effect on T-cell
chemotaxis [16
]. Thus, while both cytokines have been
shown to interact with ECM moieties, augment T-cell adhesion to ECM
[12
, 13
], and regulate the expression of
chemokine receptors on immune cells [18
], the ability to
influence T cells to stop migrating is clearly specific to TNF- but
not to IL-2. Moreover, the proadhesive and ECM-binding capacities of
cytokines are separately regulated from the ability to deliver such
stop signals.
Our findings significantly support the idea that the step-by-step
navigation of leukocytes into tissues is regulated by the context of
the chemotactic field [3
]. Combinations of different
mediators such as chemokines and cytokines provided the appropriate
regulatory signals for determining the ultimate localization of
leukocytes. Figure 2
summarizes our observations of how T cells move within
ECM-associated chemotactic gradients. These factors likely present
checkpoints for leukocytes to integrate specific signals that, taken
together as a vector sum, affect cell orientation as well as cell
memory, whereas movements are prioritized according to the context of
their environment. Not only are the specific combinations important in
such regulation, but the concentrations, spatial arrangements, and
sequences of presentation also determine the ultimate positioning of a
leukocyte by affecting directional migration or random movement or by
causing complete arrest [2
, 16
]. Since
TNF- delivers a stop signal in a rapid manner (i.e., <60 min),
further studies should determine whether such depots of TNF- provide
other downstream migration-modifying signals, such as expression of
cytokines or degradative enzymes after a prolonged time.
|
A diverse array of biological characteristics and functions is shared
by chemokines, including promiscuous binding to multiple receptors
[23
, 24
], induction of cell adhesion and
migration [16
, 25
26
27
], and binding to ECM
moieties [15
]. Moreover, the binding of one chemokine to
its receptor(s) on leukocytes may lead to heterologous desensitization
of other receptors and thereby inhibit the binding of a second
chemokine [28
]. The putative role of these
characteristics in the regulation of leukocyte navigation led us to
preliminarily investigate the combined effects of two chemokines,
specifically SDF-1 and either macrophage inflammatory
protein-1ß (MIP-1ß) or RANTES [19
], on T lymphocyte
adhesion to ECM and chemotaxis.
The proadhesive properties of the C-X-C chemokine SDF-1 or the C-C
chemokines RANTES and MIP-1ß, when used alone, have been demonstrated
in their induction of T-cell adhesion to ECM and FN [16
,
29
]. We examined the adhesiveness of T lymphocytes to FN
when incubated with dual combinations of these chemokines. T cells were
preexposed to either RANTES or MIP-1ß for 30 min, then incubated
together with SDF-1 for 30 min on FN substrates. Analyses of cell
adhesion indicated that preexposure to the C-C chemokines (RANTES or
MIP-1ß) caused marked abrogations of cell adhesion induced
by any of the chemokines alone (i.e., RANTES, MIP-1ß, or SDF-1).
Such decreases in adhesion were selective and specific to chemokines,
since IL-2, which by itself induces T-cell adhesion, had no apparent
combinatorial effects when combined with SDF-1.
Leukocyte adhesion to ECM components via cell surface molecules is a
required and coupled step in leukocyte migration to adjacent inflamed
sites, such that modification of cell adhesion often leads to
alterations in cellular migration. Chemokines clearly play a
significant role in the trafficking of leukocytes into tissues by
affecting inflammatory-cell recruitment, adhesion, and migration
[30
, 31
]. The pronounced decrease found in
T-cell adhesion in response to two chemokines prompted us to explore
the effects of these combinations of chemokines on cell migration
through the ECM. Migration assays were performed in transwell chambers
containing FN-coated filters. The addition of SDF-1 (250 ng/mL) to
the lower chamber induced peripheral-blood T lymphocytes and CD45RO
memory T cells to migrate from the upper chamber through FN and into
the chemoattractant area. A coactivating chemokine (e.g., RANTES,
MIP-1ß, or SDF-1) or cytokine (e.g., IL-2) was placed in both the
upper and lower chambers to determine their combined effects with
SDF-1 on T-cell migration. We assumed that placement of the second
activator in both the upper and lower chambers did not create another
chemotactic gradient. We found that the migration toward SDF-1 by
either peripheral-blood T lymphocytes or memory T cells was
significantly reduced in the presence of RANTES, MIP-1ß, or SDF-1
in both chambers. Similar to our finding that IL-2 had no effect on
SDF-1-induced cell adhesion, chemotaxis toward SDF-1 was not
affected by IL-2. The antimigratory effects of RANTES and MIP-1ß were
not due to an enhancement or interference of SDF-1-induced CXC
receptor 4 internalization, as found using fluorescein-activated
cell sorter analysis. Therefore, the stoppage of T-cell migration or
its inhibition by two chemokines corroborated findings that their
antiadhesive effects occur, possibly through a cross-regulation or
heterologous desensitization of CXC receptor 4 by MIP-1ß or RANTES,
independently of receptor internalization [32
]. Taken
together, these results further supported the notion that the
combination of mediators encountered by leukocytes transmits complex
signals that are integrated into cell navigation.
To evaluate the possible signaling mechanisms involved in
RANTES-MIP-1ß inhibition of SDF-1-induced adhesion and migration,
we focused on the tyrosine kinase Pyk-2 and the mitogen-activated
protein kinase extracellular regulated kinase (ERK)-1/2. Pyk-2 is an
important participant in the formation of focal contacts, and its
phosphorylation is pivotal in the transduction of intracellular
signals, including the activation of ERK-1/2 [33
].
Recent evidence has shown that Pyk-2 is activated upon stimulation with
RANTES [34
]. We examined the phosphorylation and
activation of Pyk-2 and ERK-1/2, affected by combinations of RANTES or
MIP-1ß with SDF-1, in T cells incubated on FN. Whereas SDF-1
markedly up-regulated phosphorylation of both Pyk-2 and ERK-1/2,
the addition of RANTES or MIP-1ß inhibited such activation. These
findings thus support the notion that combinations of chemokines have
effects on intracellular signaling mechanisms which may differ
considerably from the effects of a single chemokine
[34
].
Collectively, these preliminary results lend strong support to the concept that multiple chemokines within inflamed loci selectively and competitively affect each other’s proadhesive and promigratory functions, depending on their concentrations, proximity, and simultaneous or sequential exposure to leukocytes. The redundancy in functions and promiscuous receptor binding among several individual chemokines illustrated that these mediators encompass an extensive range of overlapping bioactivities [23 , 24 ]. Further characterization of the mechanisms regulating such chemokine effects, particularly receptor desensitization and reciprocal downstream signaling events, will be the aim of future studies.
Context-dependent TGF-ß activities: Leukocyte adhesion
Since different inflammatory reactions require various leukocyte
effector functions, the components of extracellular matrices and
migration zones within inflamed tissues present a mixture of signals
necessary for directing leukocyte adhesion and migration into the
target locus. Considering the prominent role of cytokines and
chemokines in the regulation of leukocyte activities and their
abundance in sites of inflammation, it is likely that certain cytokines
have differential effects, depending on the context of the
microenvironment. Contextual changes may include modifications in the
spatial pattern, concentration, kinetics, and, as described thus far,
the combination of particular cytokines and ECM moieties. Thus, the
whole context may signal a given cytokine to induce certain leukocyte
activities or, conversely, to abate certain activities in the onset,
peak, or resolution phase of inflammation [1
,
2
, 35
].
The complexity of such processes is perhaps best illustrated by one of the most versatile and pleiotropic cytokines, namely TGF-ß. Originally described as a growth factor for various cell types, TGF-ß has been found to be a key inflammatory mediator involved in the regulation of many immune cell functions [36 , 37 ]. For example, TGF-ß induces the chemotaxis of mast cells [38 ], monocytes [39 ], dendritic cells [40 ], and neutrophils [41 ]; adhesion of monocytes to FN; and expression of ß1 integrins, MMP-9, and MMP-2 [42 ]. The diversity of these functions underscores the importance of other cytokines that, in various combinations, possibly serve to modify TGF-ß activity.
Although the majority of studies done with TGF-ß have focused on its
long-term effects on immune processes, it is reasonable to assume that
the cytokine may also rapidly exert its effects. We recently undertook
a study to examine the influence of TGF-ß, either alone or together
with IL-2 or SDF-1, on T-lymphocyte adhesion to FN. Incubation with
TGF-ß for 1 h was found to augment T-cell adherence in a VLA-4-
and -5-dependent manner. In contrast, combinations of TGF-ß with
either IL-2 or SDF-1, which by themselves increase T-cell adhesion,
resulted in a down-regulation of adhesion. Furthermore, the
combinatorial effects of TGF-ß on T-cell adhesion are apparently
selective for cytokines, as TGF-ß does not alter T-cell adhesion
induced by phorbol esters. These divergent actions of TGF-ß are
independent of changes in the cell surface expression of ß1 integrins
or cytokine receptors. Changes in the phosphorylation and thus
activation of Pyk-2 by TGF-ß may be a potential mechanism for
regulation of the dual contrasting effects of TGF-ß on T-cell
adhesion to FN. Although TGF-ß alone up-regulates the phosphorylation
of Pyk-2, it also inhibits the induction of Pyk-2 phosphorylation by
IL-2, and such effects depend on ß1 integrin and TGF-ß receptor II
binding.
In summary, TGF-ß appears to function in opposing ways during the regulation of T-cell adhesion to the ECM, depending on the combination of TGF-ß with other cytokines. Its action rapidly induces T-lymphocyte adhesion to the ECM, but it also rapidly inhibits adhesion induced by other cytokines. These findings may have significant meaning in the rapid attachment and detachment process, which is essential during cell migration through matrices [43 ]. These dual functions of TGF-ß also present another example of a combination of signals which, when encountered by leukocytes migrating toward a chemoattractant source, may provide important cell-navigational information. Future studies should concentrate on the regulatory effects of TGF-ß on leukocyte migration in combination with other modulatory cytokines or chemokines.
Context-dependent TGF-ß activities: MMP production
One of the most highly regulated groups of inflammatory mediators
secreted by leukocytes is the family of MMPs. Leukocyte extravasation
and penetration into tissues during inflammatory episodes is
facilitated by MMPs, which have a collective ability to degrade every
ECM substrate [35
]. Considering their significance in
numerous inflammatory diseases and pathologies, as well as normal
tissue remodeling during development and wound repair, MMP activities
demand a high degree of regulation at the levels of activation from
zymogenic to active forms, proteolytic activity, and gene
transcription. MMP zymogen activation is accomplished by proteolytic
conversion by other enzymes, such as plasmin or other active MMPs, and
thus, this activation involves a complicated regulatory network of
enzymes and inhibitors, including tissue inhibitor of
metalloproteinases [44
, 45
].
Several studies have highlighted the ability of certain cytokines to regulate MMP production by leukocytes [44 , 46 47 48 ]; however, few studies have characterized the effects of combinations of cytokines that cells are more likely to encounter at inflamed sites [49 ]. TGF-ß, in combination with other cytokines or stimuli, can inhibit induction of metalloelastase [50 ], gelatinase [51 ], and collagenase expression [52 ]. The duality of TGF-ß function as either a stimulator or suppressor of leukocyte adhesion, depending on its combination with other cytokines, prompted us to examine TGF-ß effects on MMP production in monocytes. We reasoned that by differentially regulating leukocyte-matrix interactions such as cell adhesion, migration, and MMP secretion, TGF-ß indeed functions as a versatile immunomodulatory agent at multiple steps in inflammation.
Recent findings in our laboratory and others have indicated that
soluble TNF- and FN-associated TNF- stimulate the expression of
MMP-9 in human monocytes [1
, 46
,
48
]. We extended these findings by examining the
combinatorial effects of TGF-ß on TNF--induced monocyte MMP-9
expression. Although TGF-ß alone was found to up-regulate the amount
of MMP-9 secreted from both peripheral-blood monocytes and the
monocytic cell line MonoMac-6, lower doses decreased the basal levels
of MMP-9. It is interesting that TGF-ß also markedly reduced
TNF--induced MMP-9 gene expression, protein synthesis, and
secretion, with a bell-shaped, dose-dependent inhibition optimum at 1
ng/mL. The concentration of TNF- used to induce MMP-9 was not a
significant factor, as TGF-ß inhibited even the highest concentration
of TNF- studied (50 ng/mL). We also found that tissue inhibitor of
metalloproteinase-1 secretion was unaffected by TGF-ß, indicating
that TGF-ß regulation of MMP-9 is independent of modifications to one
of the enzyme’s natural inhibitors [53
].
Many studies have identified the prostaglandin
E2 (PGE2)-cyclic AMP (cAMP)
signaling pathway as an important mechanism in the regulation of
cytokine-induced monocyte MMP expression [49
,
54
55
56
]. To determine whether this pathway also mediates
TGF-ß suppression of MMP-9 secretion, PGE2 secretion was
measured from the supernatants of monocytes treated with TNF-,
TGF-ß, or TNF- + TGF-ß. These treatments were also used to
study the effects of a specific inhibitor of the PGE2-cAMP
pathway, namely indomethacin. Our findings indicated that TGF-ß
caused a significant decrease in the amount of PGE2
secreted from control and TNF--treated cells. Moreover, exogenous
PGE2 and the cAMP analogue Bt2cAMP restored the
blockage effects of both TGF-ß and indomethacin on MMP-9 secretion.
Thus, the PGE2-cAMP pathway, as well as the cytokine
concentrations and order of encounters with the cells, are elemental
components of the signaling network involved in TGF-ß-mediated MMP-9
suppression. Taken together, the results we have described of the
combined effects of TGF-ß and TNF- on leukocyte-ECM interactions
may lead to the study of other combinations of cytokines. Such studies
will likely reveal many different modes of regulation of leukocyte
activities through an overall dependency on the context of the
inflammatory milieu.
Concluding remarks
As leukocytes make their passage from the vascular system into
tissues, they encounter an assortment of molecules within the ECM that
likely govern their subsequent activities. This mélange of ECM
moieties, cytokines, and enzymes seems to engage in important
"dialogues" with migratory leukocytes, which ultimately determine
the fate of these cells. By presenting intrinsic signals to immune
cells, cellular navigation can be controlled in a progressive manner by
the ECM microenvironment, whereby each contact with an ECM
component or ECM-associated factor may communicate a signal that is
integrated through cell surface receptors or adhesion molecules.
Through their spatial arrangement, specific ECM signals may mark a
trail for incoming leukocytes. Reciprocal cell responses to these
signals may, in turn, further alter the environmental composition,
through the secretion of modifying enzymes or other mediators of
cell-matrix interactions. Perhaps even more remarkable changes in
immune cell behavior are brought about by combinations of these
signals, which cells may encounter sequentially or simultaneously, in
different concentrations, at highly localized sites within their
surroundings (Table 1
). Such signals may dictate, step-by-step, in which direction a
cell must orient itself, what enzymes or other mediators the cell must
produce to reach its destination, and what effector functions are
needed for a specific inflammatory episode [57
]. As we
discuss herein, excellent examples of these scenarios include TNF-
and TGF-ß, both of which exhibit differential effects such as
chemotactic stop signals and MMP induction or suppression, depending on
their concentrations, combination with other cytokines, and sequence of
encounters with leukocytes. Furthermore, specific subsets of recruited
leukocytes may react differently to the same combination of signals
within the ECM milieu, thereby providing a fine-tuning of the
inflammatory response.
|
|
ACKNOWLEDGEMENTS |
|---|
Received December 18, 2000; revised February 8, 2001; accepted February 9, 2001.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
binds to the N-terminal domain of fibronectin and augments the ß1-integrin-mediated adhesion of CD4+ T lymphocytes to the glycoprotein J. Immunol. 152,1304-1313[Abstract]
associated with extracellular matrix fibronectin provides a stop signal for chemotactically migrating T cells J. Immunol. 165,2738-2747 and MIP-1ß Science 260,355-358 and IL-1ß selectively induce expression of 92-kDa gelatinase by human macrophages J. Immunol. 157,4159-4165[Abstract]
, granulocyte-macrophage CSF, and IL-1ß through prostaglandin-dependent and –independent mechanisms J. Immunol. 161,3071-3076-induced matrix metalloproteinase-9 (MMP-9) expression in monocytes J. Leukoc. Biol. 68,737-747
blocks endogenous prostaglandin E2-dependent collagenase production J. Immunol. 144,3518-3522[Abstract]
: dependence on 5ß1 and ß2 integrins Exp. Cell Res. 222,209-217[Medline]
This article has been cited by other articles:
|
|
 |
|
  M. T. Pritchard, S. Roychowdhury, M. R. McMullen, L. Guo, G. E. Arteel, and L. E. Nagy Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1124 - G1133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-T. Hsu, W.-H. Kan, C.-H. Hsieh, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation J. Leukoc. Biol., October 1, 2007; 82(4): 1019 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-P. Yu, Y.-C. Hsieh, T. Suzuki, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of the PI-3K/Akt pathway J. Leukoc. Biol., September 1, 2007; 82(3): 774 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Marom, M. A. Rahat, N. Lahat, L. Weiss-Cerem, A. Kinarty, and H. Bitterman Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9 J. Leukoc. Biol., June 1, 2007; 81(6): 1466 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-C. Hsieh, M. Frink, C.-H. Hsieh, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1227 - L1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Montgomery, C. J. Booth, X. Wang, V. A. Blaho, S. E. Malawista, and C. R. Brown Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis Infect. Immun., February 1, 2007; 75(2): 613 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Imtiaz, J. H. Schripsema, I. M. Sigar, J. N. Kasimos, and K. H. Ramsey Inhibition of Matrix Metalloproteinases Protects Mice from Ascending Infection and Chronic Disease Manifestations Resulting from Urogenital Chlamydia muridarum Infection. Infect. Immun., October 1, 2006; 74(10): 5513 - 5521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-P. Yu, T. Shimizu, Y.-C. Hsieh, T. Suzuki, M. A. Choudhry, M. G. Schwacha, and I. H. Chaudry Tissue-specific expression of estrogen receptors and their role in the regulation of neutrophil infiltration in various organs following trauma-hemorrhage J. Leukoc. Biol., May 1, 2006; 79(5): 963 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-P. Yu, M. A. Choudhry, T. Shimizu, Y.-C. Hsieh, M. G. Schwacha, S. Yang, and I. H. Chaudry Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1 J. Leukoc. Biol., February 1, 2006; 79(2): 277 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Dimitriadis, C.A. White, R.L. Jones, and L.A. Salamonsen Cytokines, chemokines and growth factors in endometrium related to implantation Hum. Reprod. Update, November 1, 2005; 11(6): 613 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Sano, A. Tessitore, A. Ingrassia, and A. d'Azzo Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology Blood, October 1, 2005; 106(7): 2259 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.V. Fahey, T.M Schaefer, J.Y. Channon, and C.R. Wira Secretion of cytokines and chemokines by polarized human epithelial cells from the female reproductive tract Hum. Reprod., June 1, 2005; 20(6): 1439 - 1446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Saunders, S. Tran, S. Ruuls, J. D. Sedgwick, H. Briscoe, and W. J. Britton Transmembrane TNF Is Sufficient to Initiate Cell Migration and Granuloma Formation and Provide Acute, but Not Long-Term, Control of Mycobacterium tuberculosis Infection J. Immunol., April 15, 2005; 174(8): 4852 - 4859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Jones, N. J. Hannan, T. J. Kaitu'u, J. Zhang, and L. A. Salamonsen Identification of Chemokines Important for Leukocyte Recruitment to the Human Endometrium at the Times of Embryo Implantation and Menstruation J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6155 - 6167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Katakai, T. Hara, M. Sugai, H. Gonda, and A. Shimizu Lymph Node Fibroblastic Reticular Cells Construct the Stromal Reticulum via Contact with Lymphocytes J. Exp. Med., September 20, 2004; 200(6): 783 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. M.P. Marino, A. da Silva, P. dos Santos, L. M. d. O. Pinto, R. T. Gazzinelli, M. M. Teixeira, and J. Lannes-Vieira Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) Antagonist (Met-RANTES) Controls the Early Phase of Trypanosoma cruzi-Elicited Myocarditis Circulation, September 14, 2004; 110(11): 1443 - 1449. [Abstract] |
, TNF-