| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Renal and Inflammatory Disease, University Hospital, Nottingham, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) exposed to nonparticulate stimuli
can express cell surface Fas ligand (FasL) and release active soluble
FasL (sFasL). We now report that monocyte/M-ingesting opsonized
zymosan released sFasL and conditioned supernatants so that these
triggered Fas-mediated apoptosis of "bystander" monocytes and
FasL-negative neutrophils. Furthermore, identical results were seen
with M taking up apoptotic neutrophils, whereas medium conditioned
by M phagocytizing latex beads had no proapoptotic effects upon
neutrophils despite the presence of sFasL. These data suggest the
hitherto unrecognized existence of a feedback loop requiring soluble
factors in addition to sFasL that may promote resolution of
inflammation-phagocytic clearance of apoptotic cells leading to
Fas-mediated killing of bystander leukocytes by phagocytizing
macrophages. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
)2
lineage are multifunctional, orchestrating many aspects of inflammation
and tissue repair. A key property of the monocyte/M, first
recognized over a century ago by Metchnikoff (1), is the capacity to
phagocytize particulate debris, invading microorganisms and effete
cells. Indeed, there are now persuasive data to show that a critical
event in resolution of inflammation is nonphlogistic safe phagocytic
clearance of intact leukocytes undergoing deletion by apoptosis, also
known as programmed cell death (2, 3, 4, 5, 6, 7, 8, 9, 10, 11).
In addition to clearing away apoptotic cells, important new data (12, 13) suggest that monocyte/M can trigger apoptosis in other cells by
regulated surface expression of Fas ligand (FasL) and by release of
soluble FasL (sFasL). Since neutrophils, eosinophils, lymphocytes, and
monocytes themselves all express the Fas "death receptor" and may,
in certain circumstances, be susceptible to apoptosis triggered by
cross-linking of Fas (12, 14, 15, 16, 17, 18), it has been suggested that
monocyte/M expression of FasL may be an important factor in
regulating leukocyte populations at inflamed sites (12, 13). However,
to date there has been little study of stimuli that control FasL
expression/release by monocyte/M, although there are reports that
monocyte/M FasL is up-regulated by nonparticulate stimuli such as
soluble immune complexes, superantigen, phytohemagglutinin, and
Ab-mediated cross-linking of monocyte/M CD4 (13, 19, 20). In this
report, we have studied monocyte/M expression of FasL after
phagocytosis of opsonized zymosan or apoptotic neutrophils, asking
whether these stimuli induced release of sFasL from phagocytizing
monocyte/M and triggered Fas-mediated apoptosis in "bystander"
neutrophils and monocytes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All chemicals were of analytical reagent (AR) grade and were purchased from Sigma (Poole, U.K.), including zymosan (catalogue No. Z4250), latex particles (catalogue No. LB-8; Lot 11H0622), calcium ionophore A23187 (catalogue No. C7522), and the phorbol ester TPA (catalogue No. P8139), unless stated otherwise. Percoll was obtained from Pharmacia Biotech (St Albans, U.K.); sodium citrate solution from Pharma Hameln (Hanover, Germany); culture media (HBSS, RPMI-1640, Iscove’s modified Dulbecco’s medium), and supplements (penicillin, streptomycin, glutamine, FCS) from Life Technologies(Paisley, U.K.); FITC-conjugated anti-CD16 (mAb 3G8) from Caltag Laboratories (Bradsure Biologicals, Shepshed, U.K.); FITC-conjugated annexin-V from BioWhittaker U.K. (Wokingham, U.K.); anti-Fas mAbs CH-11 and ZB4 from TCS Biologicals (Botolph Clayton, U.K.); anti-FasL mAb (clone 33) from Transduction Laboratories (Affiniti Research Products, Mamhead, U.K.); and anti-FasL pAb (Ab-1) from Calbiochem-Novabiochem (U.K.)(Nottingham, U.K.). Opsonized zymosan (OpsZ) was prepared by washing zymosan particles exhaustively with endotoxin-free HBSS (without calcium and magnesium) before and following a 30-min incubation at 5 mg/ml with human clotted sera pooled from 10 different donors.
Leukocyte purification and isolation
Human neutrophils and monocytes were isolated from freshly
drawn venous blood following citration, dextran sedimentation, and
discontinuous plasma-Percoll density gradient centrifugation, as
previously described (3, 20, 21). Percoll density separation resulted
in two distinct leukocyte layers, a neutrophil-enriched fraction
(>98% purity), containing eosinophils as the only major contaminant,
and a mixed monocyte/lymphocyte fraction. The neutrophil fraction was
washed free of plasma and incubated at 37°C in Iscove’s modified
Dulbecco’s medium containing antibiotics and supplemented with 10%
autologous platelet-rich plasma-derived serum (PRPDS). In all
experiments, monocytes were further purified by counterflow
centrifugation (J2–21; Beckman Instruments, Palo Alto, CA) to yield
preparations greater than 95% purity (22). Monocyte-derived
macrophages (M) were obtained by the standard technique (3, 23) of
culture of adherent monocytes in Iscove’s medium plus 10% PRPDS for 3
or 6 days.
Jurkat cell culture
The human T lymphoblastoid cell line Jurkat (kindly provided by Dr. C. Gregory, University of Birmingham) was maintained in RPMI 1640 supplemented with L-glutamine, 5 U/ml penicillin, 5 µg/ml streptomycin, and 10% FCS. Jurkat cells were free of mycoplasma contamination as assessed routinely by PCR. Expression of FasL and its secretion by Jurkat cells required stimulation with the calcium ionophore A23187 (2 µg/ml) and the phorbol ester TPA (10 ng/ml), with Jurkat cells typically treated for 4 h in serum-free media.
Assessment of apoptosis
In the present study, monocyte and neutrophil apoptosis was routinely quantified by flow cytometry using FITC-conjugated annexin V (24) and using a Becton Dickinson FACScan (Oxford, UK), as previously described (25). We have extensively validated this technique against apoptosis as quantified by morphology on Giemsa-stained cytospins (3) and by shedding of CD16 (26), and we agree with published data (24) that, in myeloid cells, these different approaches yield closely comparable results (25).
Phagocytic stimulation of monocytes and macrophages
M cultured in Costar plates (Wycombe, UK) or monocytes
cultured in teflon-lined wells were coincubated with washed particles
of OpsZ at a final concentration of 0.5 mg/ml for up to 7.5 h in
Iscove’s medium in the absence of autologous serum. Typically 4
x 105 M or 2 x 106 monocytes in a
final volume of 400 µl were used per equivalent experiment. Aliquots
of conditioned media were removed at times indicated and clarified by
sequential centrifugation at 300 x g for 5 min to
remove intact cells and cell debris and at 1200 x g
for 5 min to remove all traces of OpsZ before being used to resuspend
freshly isolated but untreated peripheral blood monocytes or
neutrophils. Monocytes were resuspended to a density of 2 x
106/ml in teflon wells and incubated at 37°C for up to
19 h in the absence of autologous serum. Neutrophils, on the
other hand, were cultured at 5 x 106/ml in the
presence of 10% autologous PRPDS to undergo constitutive apoptosis
without significant necrosis (3). In addition to OpsZ, 6-day
M were also incubated with latex beads at a final concentration of
0.5 mg/ml or with apoptotic neutrophils at 1 x
107/ml. When indicated, assays also contained the Fas
antagonistic Ab ZB4 or an isotype-matched control negative Ab at an
equivalent concentration.
FasL expression as determined by flow cytometry
Monocytes, maintained in the presence of 10% autologous PRPDS and cultured in teflon-lined "wells," were assessed for FasL protein expression by indirect immunofluorescent labeling and flow cytometric analysis. Cells (1 x 105), resuspended in 100 µl of 10% newborn calf serum, were coincubated with 100 ng of an anti-FasL mAb, clone 33 (or a control isotype-matched mAb), at 4°C for 60 min. Cells were washed and recovered by centrifugation at 300 x g for 5 min before resuspending in 10% newborn calf serum containing an FITC-conjugated F(ab')2 fragment of a sheep anti-mouse IgG polyclonal Ab. Cells were then analyzed by a Becton Dickinson FACScan flow cytometer for cell-associated fluorescence.
SDS-PAGE and protein blotting
Twelve percent SDS slab gels were prepared and run according to the method of Laemmli (27), with the exception that gels were ran with 1 mM thioglycollic acid added to the cathode buffer and with the anode buffer diluted twofold. Each sample was prepared on the basis of equal numbers of extracted cells rather than on protein content. A typical 100 x 100 x 1.5 mm gel was run at 25 mA for 2 h and transferred to polyvinylidene difluoride (PVDF) membranes at 2 mA/cm2 for 3 h at 4°C according to the methodology of Towbin et al. (28). Membranes were then blocked with 5% milk powder (Marvel, 99% fat-free) in PBS containing 0.2% Tween 20 for 1 h before probing overnight with either an anti-FasL mAb (clone 33) or pAb (Ab-1), with all steps maintained at 4°C. The presence of Tween 20 in buffers and maintaining immunoblotting conditions at 4°C were essential in minimizing cross-reactivity of clone-33 with ß-actin (our unpublished observations). Blots were then washed with ice cold PBS before probing with a peroxidase-conjugated secondary pAb of appropriate specificity and detection with 4-chloro-1-naphthol.
SDS-PAGE and sample preparation
Serum-free media conditioned by neutrophils, monocytes, or M
were prepared for protein analysis by SDS-PAGE by first clarifying the
supernatant at 500 x g, adding SDS to 0.1%, and
immediately placing into a boiling water bath for 5 min. Aliquots (0.4
ml each) were then concentrated by centrifugation using Millipore
Ultrafree filter units with a 10-kDa "cut-off." The retentate was
recovered with Laemmli sample buffer and boiled ready for SDS-PAGE
analysis. The initial boiling of samples in the presence of 0.1% SDS
was necessary for reproducible results, optimized with conditioned
media taken from activated Jurkat T cells. Total cell protein was
prepared by immediately resuspending cell pellets in hot Laemmli sample
buffer and placing in a boiling water bath for 5 min.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
expression of surface FasL and release into supernatants
In keeping with earlier reports (16, 20), we were unable to detect
surface expression of FasL by normal human peripheral blood monocytes
prepared by elutriation of mixed mononuclear cells obtained from
plasma-Percoll density gradient centrifugation of dextran-sedimented
blood (Fig. 1
A). Furthermore,
we were also able to confirm (13) that freshly isolated monocytes did
not release FasL into supernatants during 3-h culture, as assessed by
immunoblotting (Fig. 1B). However, monocytes are believed to
contain intracellular pools of FasL that can be rapidly mobilized to
the cell surface by soluble stimuli, including immune complexes (13, 20). We examined whether uptake of opsonized zymosan (OpsZ), a
well-established model of Ig/complement-mediated phagocytosis, might
have similar effects. By 3 h, we observed increased surface
expression of FasL by monocyte/M and release of FasL into the
supernatant by monocytes or monocyte-derived M taking up OpsZ (Fig. 1, A and B).
|
phagocytizing OpsZ promote
Fas-mediated apoptosis of monocytes
Freshly isolated monocytes cultured in the absence of serum are
susceptible to apoptosis induced by Fas ligation (12, 14, 17, 28).
Preliminary experiments (data not shown) indicated that supernatants
freshly obtained from monocyte/M taking up OpsZ could induce
apoptosis in "target" monocyte populations; a supernatant transfer
approach was taken in preference to coculture to avoid underestimation
of apoptosis in the target population because of phagocytic removal of
apoptotic cells by M. Unfortunately, the proapoptotic effects of
media conditioned by monocyte/M-ingesting OpsZ were poorly preserved
by freezing or storage at 4°C, despite no significant changes in
sFasL protein as assessed by Western blot analysis (data not shown).
Therefore, we designed an experiment (Fig. 2A) in which two populations
of monocytes ("donor" and "target") were prepared at the same
time from any given donor. As previously reported (29),
monocytes in the target population cultured in the absence of serum
underwent apoptosis (
30% at 19 h), and this could be partially
inhibited by the function-blocking Fas mAb ZB4 (Fig. 2A,
left bars), in keeping with data implicating
Fas/FasL-mediated fratricide in such cultures (12). However, when
supernatants conditioned by donor monocytes ingesting OpsZ were
transferred to target monocytes at the end of the conditioning period
(either 2.5 h or 7.5 h), increased apoptosis in the target
monocytes was observed when the experiment was terminated at 19 h
after cell isolation (Fig. 2A, center and
right bars). With increasing conditioning time the
proapoptotic effect of supernatants from monocytes ingesting OpsZ
increased. Nevertheless, stimulated apoptosis of target monocytes was
partially abrogated by Fas blockade with ZB4. Supernatants conditioned
by donor monocytes cultured in medium alone had no proapoptotic effect
(Fig. 2A, right bar). Essentially similar
results were obtained when 3-day monocyte-derived M were employed as
the donor population (Fig. 2B), except that medium
conditioned by M cultured without OpsZ protected monocytes against
constitutive apoptosis (Fig. 2B, right
bar).
|
phagocytizing OpsZ accounted for the
proapoptotic effect of conditioned medium. However, the possibility
remained that some other factor might have up-regulated
Fas/FasL-mediated fratricide in the target monocyte population.
Therefore, we went on to seek target cells of relevance to the
inflammatory response that did not exhibit Fas/FasL fratricide.
Supernatants from monocyte/M-ingesting OpsZ also induced
Fas-mediated death in FasL-negative neutrophils
Neutrophils are widely recognized to express Fas and to be
moderately sensitive to apoptosis induced by Fas ligation (14). We
confirmed that relatively high concentrations of the agonistic Fas mAb
CH-11 were able to accelerate constitutive apoptosis in highly purified
neutrophils prepared from normal human blood by plasma-Percoll density
gradient centrifugation (Fig. 3A). However, by contrast with
monocytes prepared by the same techniques (Fig. 2
), there was no
evidence of Fas/FasL-mediated fratricide, in that Fas blockade with mAb
ZB4 had no effect on constitutive apoptosis of neutrophils. This was
despite the ability of ZB4 being able to block CH-11-induced apoptosis
(Fig. 3A). Furthermore, ZB4 did not inhibit constitutive
apoptosis in neutrophils cultured in the absence of serum (data not
shown), indicating that serum was not masking Fas/FasL-mediated
fratricide.
|
B). Furthermore, we were
unable to detect sFasL in the supernatants of highly purified
neutrophil preparations (data not shown), important evidence against
the possibility that failure to detect FasL might reflect cleavage from
the cell surface. Previous reports that have used different granulocyte
isolation protocols (16, 20) suggest that neutrophils may express FasL,
in a manner that may be dependent upon techniques of preparation (20).
However, no FasL expression could be detected by immunoblotting of
highly purified neutrophils subjected to deliberate activation by
adherence to plastic, exposure to various concentrations of FMLP and
LPS, or phagocytosis of OpsZ (Fig. 3B), data independently
confirmed by flow cytometry and where the presence or absence of serum
(human or bovine) had no effect (data not shown). Furthermore, medium
conditioned by cultured neutrophils that possessed no sFasL by Western
blot analysis had no proapoptotic effect when used to resuspend
neutrophils, monocytes, or Jurkat T cells (data not shown).
Nevertheless, it was possible to detect FasL in neutrophil
lysates/culture supernatants when these were deliberately contaminated
by as few as 1% monocytes (not shown), evidence against the
possibility that degradation of FasL by neutrophil proteases might mask
FasL expression.
When highly purified, FasL-negative neutrophils were employed as a
"target" population, essentially similar results to those observed
with monocyte targets were obtained: medium conditioned by "donor"
monocyte/M taking up OpsZ accelerated constitutive apoptosis in
target neutrophils in a manner that was partially inhibitable with
Fas-blocking ZB4 (Fig. 3, C and D; compare with
Fig. 2). Again, supernatants conditioned by donor M not receiving
OpsZ had a protective effect (Fig. 3D). These data suggested
that monocyte/M might have an important role in regulating apoptosis
in neutrophils that have also been summoned to inflammatory sites.
Since there is now compelling evidence that granulocytes undergoing
apoptosis at inflamed sites are phagocytically cleared by monocyte/M
(3, 4, 5, 7, 8), we went on to examine whether M ingestion of apoptotic
neutrophils might also promote release of FasL.
Monocyte/M ingestion of apoptotic neutrophils also stimulates
FasL release and Fas-mediated apoptosis of FasL-negative neutrophils
"Donor" monocyte-derived M were cocultured with various
particulate stimuli for 4 h, the medium was harvested and
clarified, and then it was incubated with freshly isolated neutrophils
for 15 h, after which time apoptosis in the "target"
neutrophils was assayed (Fig. 4). M
taking up apoptotic neutrophils not only released FasL into the
supernatant but also yielded conditioned medium that accelerated
neutrophil apoptosis to a degree almost completely inhibitable by
Fas-blocking ZB4 (Fig. 4 (inset), lane iv).
However, no proapoptotic effect was observed with medium conditioned by
M cultured for 4 h with freshly isolated neutrophils that are
not taken up (2, 3), or by M-ingesting latex beads. However,
although fresh neutrophils did not incite FasL release by M (Fig. 4
(inset), lane ii), uptake of latex beads did
cause FasL release (Fig. 4 (inset), lane iii),
indicating that additional M-derived factors are required to
contribute to the Fas-mediated proapoptotic effects of M-conditioned
medium.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-ingesting opsonized zymosan, a model of phagocytosis
of Ab and complement-coated particles, releases FasL and
triggers Fas-mediated apoptosis in "target" neutrophils.
Furthermore, identical results were seen with M taking up apoptotic
neutrophils, whereas medium conditioned by M-ingesting latex beads
had no proapoptotic effect.
The in vivo relevance of these data needs very cautious interpretation,
but the findings suggest a hitherto unrecognized role for phagocytizing
macrophages in directing neutrophil (and monocyte) elimination from
inflamed sites. It is particularly intriguing that the data point to a
new feedback loop promoting resolution of inflammation (phagocytic
clearance of apoptotic neutrophils by macrophages causes release into
the microenvironment of factors triggering accelerated removal of
neutrophils by Fas-mediated apoptosis), which not only down-regulates
the injurious potential of this cell but also targets the neutrophil
for injury-limiting phagocytic removal (3, 31, 32). Indeed, our data
support reports that M-ingesting apoptotic cells may generate
antiinflammatory responses such as IL-10 release (33, 34), because
M-derived FasL might be expected to promote "antiinflammatory"
elimination of other leukocytes, including eosinophils, monocytes, and
activated T cells (8, 11, 13). A further speculation of interest is
that a similar negative feedback might occur when M take up
particles (such as bacteria) coated with Ig and complement.
However, it is important to note that the proapoptotic effects of
medium conditioned by phagocytizing monocyte/M appear to be only
partially mediated by ligands of Fas, since mAb ZB4-mediated blockade
of Fas on target monocytes and neutrophils was not completely
protective. Indeed, the probable production by phagocytizing M of
factors that sensitize target cells to FasL, or possible M release
of alternative ligands for Fas, is emphasized by the observation that
supernatants obtained from M-ingesting latex beads were not
proapoptotic for neutrophils, despite containing FasL demonstrable by
immunoblot. Clearly, further work would be required to characterize
such factors, which preliminary work suggests are unstable at 4°C but
likely to be of 10 kDa or greater.
These findings add to data indicating that various inflammatory
mediators may regulate susceptibility of myeloid cells to Fas-mediated
apoptosis (28) and are not inconsistent with recent reports suggesting
that soluble FasL cleared from cell surfaces may not, in certain
circumstances, promote apoptosis in "target" cells expressing Fas
(35). Clearly, future studies will need to clarify the mechanisms by
which monocytes/M release FasL and related proapoptotic factors.
The current data clearly indicate that highly purified neutrophils did not express FasL at levels sufficient to be detected by immunofluorescence and immunoblotting or to induce Fas/FasL-mediated fratricide in culture. Preliminary RT-PCR experiments, employing appropriate positive controls, confirm lack of FasL mRNA expression by neutrophils (F. Salway and S. Brown, unpublished data). Different experimental conditions, as suggested by the studies of Mincheff et al. (20), could explain the apparent discrepancy between the current data and those of Liles et al. (16), particularly since that group’s own work demonstrated that, under some conditions, freshly isolated monocytes did not express FasL (16) whereas, under others, they did (12, 13). Furthermore, a recent report (36) suggests that the polyclonal Abs used in these later studies (12, 13) may be inappropriate for probing cell surface FasL expression by flow cytometric analysis (36). As for Western blot analysis, it may be pertinent that, in our experiments, neutrophil populations contaminated with as little as 1% mononuclear cells appeared to express FasL, a finding that also indicates that we were unlikely to be missing a possible intracellular pool of FasL in neutrophils (20). We conclude from the available data that, while FasL is not expressed at detectable levels by neutrophils under the conditions employed in this study, this does not discount the possibility of FasL expression under other conditions. However, debate over whether neutrophils are truly able to indulge in Fas/FasL-mediated fratricide may be somewhat academic, in that acutely inflamed tissues are rapidly infiltrated by Fas-bearing neutrophils and by monocytes, which are generally agreed to be capable of FasL expression.
Finally, the data also demonstrate that cultured unstimulated M
secrete factors that suppress apoptosis in both monocytes and
neutrophils, consistent with previous data indicating that cytokines
known to be elaborated by M, such as granulocyte-macrophage
(GM)-CSF, can inhibit apoptosis in both cell types (29, 37). These
findings serve only to emphasize the potentially central importance of
the macrophage in regulating elimination from inflamed sites of other
leukocytes by apoptosis.
To conclude, our studies demonstrate that monocyte/M taking up OpsZ
or apoptotic neutrophils release FasL and promote Fas-mediated
apoptosis of monocytes and neutrophils. This may represent a hitherto
unrecognized negative feedback loop serving to promote resolution of
inflammation by accelerating deletion of leukocytes by apoptosis.
|
Footnotes |
|---|
2 Abbreviations used in this paper: M, macrophage; OpsZ, opsonized zymosan; PRPDS, platelet-rich plasma-derived serum; sFasL, soluble Fas ligand; TPA, O-tetradecanoylphorbol 13-acetate; PMN, polymorphonuclear leukocyte.
Received for publication May 13, 1998. Accepted for publication September 21, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
RIII and acquire annexin V binding sites during apoptosis in vitro. Blood 85:532.RIII) expression. J. Immunol. 153:1254.[Abstract]
and interleukin-1ß prevent programmed cell death (apoptosis) in human peripheral blood monocytes. J. Immunol. 146:1541.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  A. Paunel-Gorgulu, M. Zornig, T. Logters, J. Altrichter, U. Rabenhorst, J. Cinatl, J. Windolf, and M. Scholz Mcl-1-Mediated Impairment of the Intrinsic Apoptosis Pathway in Circulating Neutrophils from Critically Ill Patients Can Be Overcome by Fas Stimulation J. Immunol., November 15, 2009; 183(10): 6198 - 6206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Remijsen, T. Vanden Berghe, E. Parthoens, B. Asselbergh, P. Vandenabeele, and J. Willems Inhibition of spontaneous neutrophil apoptosis by parabutoporin acts independently of NADPH oxidase inhibition but by lipid raft-dependent stimulation of Akt J. Leukoc. Biol., March 1, 2009; 85(3): 497 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Drakopanagiotakis, A. Xifteri, V. Polychronopoulos, and D. Bouros Apoptosis in lung injury and fibrosis Eur. Respir. J., December 1, 2008; 32(6): 1631 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Holt, L. Cheng, and C. Ju Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury J. Leukoc. Biol., December 1, 2008; 84(6): 1410 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Fielding, R. M. McLoughlin, L. McLeod, C. S. Colmont, M. Najdovska, D. Grail, M. Ernst, S. A. Jones, N. Topley, and B. J. Jenkins IL-6 Regulates Neutrophil Trafficking during Acute Inflammation via STAT3 J. Immunol., August 1, 2008; 181(3): 2189 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Conus, R. Perozzo, T. Reinheckel, C. Peters, L. Scapozza, S. Yousefi, and H.-U. Simon Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation J. Exp. Med., March 17, 2008; 205(3): 685 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Cruz, M. W. Moore, C. J. La Vake, C. H. Eggers, J. C. Salazar, and J. D. Radolf Phagocytosis of Borrelia burgdorferi, the Lyme Disease Spirochete, Potentiates Innate Immune Activation and Induces Apoptosis in Human Monocytes Infect. Immun., January 1, 2008; 76(1): 56 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Y. Tyurina, L. V. Basova, N. V. Konduru, V. A. Tyurin, A. I. Potapovich, P. Cai, H. Bayir, D. Stoyanovsky, B. R. Pitt, A. A. Shvedova, et al. Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment: IMPLICATIONS FOR THE RESOLUTION OF INFLAMMATION J. Biol. Chem., March 16, 2007; 282(11): 8498 - 8509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Kim, D. H. Choi, M. L. Block, S. Lorenzl, L. Yang, Y. J. Kim, S. Sugama, B. P. Cho, O. Hwang, S. E. Browne, et al. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation FASEB J, January 1, 2007; 21(1): 179 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kipari, J.-F. Cailhier, D. Ferenbach, S. Watson, K. Houlberg, D. Walbaum, S. Clay, J. Savill, and J. Hughes Nitric Oxide Is an Important Mediator of Renal Tubular Epithelial Cell Death in Vitro and in Murine Experimental Hydronephrosis Am. J. Pathol., August 1, 2006; 169(2): 388 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosas, P. F. Dijkers, C. L. Lindemans, J.-W. J. Lammers, L. Koenderman, and P. J. Coffer IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with {beta}-catenin relocalization J. Leukoc. Biol., July 1, 2006; 80(1): 186 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Straszewski-Chavez, V. M. Abrahams, and G. Mor The Role of Apoptosis in the Regulation of Trophoblast Survival and Differentiation during Pregnancy Endocr. Rev., December 1, 2005; 26(7): 877 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Allen, D. H. Dockrell, T. Pattery, D. G. Lee, P. Cornelis, P. G. Hellewell, and M. K. B. Whyte Pyocyanin Production by Pseudomonas aeruginosa Induces Neutrophil Apoptosis and Impairs Neutrophil-Mediated Host Defenses In Vivo J. Immunol., March 15, 2005; 174(6): 3643 - 3649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hu, X. Lin, Q. Du, E. J. Miller, P. Wang, and H. H. Simms Regulation of polymorphonuclear leukocyte apoptosis: role of lung endothelium-epithelium bilayer transmigration Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L266 - L274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Merched and L. Chan Absence of p21Waf1/Cip1/Sdi1 Modulates Macrophage Differentiation and Inflammatory Response and Protects Against Atherosclerosis Circulation, December 21, 2004; 110(25): 3830 - 3841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Brown, J. Hutcheson, E. Bickel, J. C. Scatizzi, L. D. Albee, G. K. Haines III, J. Eslick, K. Bradley, E. Taricone, and H. Perlman Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo J. Immunol., December 15, 2004; 173(12): 7584 - 7593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kotone-Miyahara, K. Yamashita, K.-K. Lee, S. Yonehara, T. Uchiyama, M. Sasada, and A. Takahashi Short-term delay of Fas-stimulated apoptosis by GM-CSF as a result of temporary suppression of FADD recruitment in neutrophils: evidence implicating phosphatidylinositol 3-kinase and MEK1-ERK1/2 pathways downstream of classical protein kinase C J. Leukoc. Biol., November 1, 2004; 76(5): 1047 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Scheel-Toellner, K. Wang, R. Craddock, P. R. Webb, H. M. McGettrick, L. K. Assi, N. Parkes, L. E. Clough, E. Gulbins, M. Salmon, et al. Reactive oxygen species limit neutrophil life span by activating death receptor signaling Blood, October 15, 2004; 104(8): 2557 - 2564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Kotecha, R J Mildner, L R Prince, J R Vyas, A E Currie, R A Lawson, and M K B Whyte The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants Thorax, November 1, 2003; 58(11): 961 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chakour, R. Guler, M. Bugnon, C. Allenbach, I. Garcia, J. Mauel, J. Louis, and F. Tacchini-Cottier Both the Fas Ligand and Inducible Nitric Oxide Synthase Are Needed for Control of Parasite Replication within Lesions in Mice Infected with Leishmania major whereas the Contribution of Tumor Necrosis Factor Is Minimal Infect. Immun., September 1, 2003; 71(9): 5287 - 5295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Chen, C.-W. Chi, H.-L. Chen, C.-P. Wan, W.-C. Yang, and A.-H. Yang TNF-{alpha} renders human peritoneal mesothelial cells sensitive to anti-Fas antibody-induced apoptosis Nephrol. Dial. Transplant., September 1, 2003; 18(9): 1741 - 1747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fukui, R. Imamura, M. Umemura, T. Kawabe, and T. Suda Pathogen-Associated Molecular Patterns Sensitize Macrophages to Fas Ligand-Induced Apoptosis and IL-1{beta} Release J. Immunol., August 15, 2003; 171(4): 1868 - 1874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Renshaw, J. S. Parmar, V. Singleton, S. J. Rowe, D. H. Dockrell, S. K. Dower, C. D. Bingle, E. R. Chilvers, and M. K. B. Whyte Acceleration of Human Neutrophil Apoptosis by TRAIL J. Immunol., January 15, 2003; 170(2): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mor, E. Sapi, V. M. Abrahams, T. Rutherford, J. Song, X.-Y. Hao, S. Muzaffar, and F. Kohen Interaction of the Estrogen Receptors with the Fas Ligand Promoter in Human Monocytes J. Immunol., January 1, 2003; 170(1): 114 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Arroyo, M. Modriansky, F. B. Serinkan, R. I. Bello, T. Matsura, J. Jiang, V. A. Tyurin, Y. Y. Tyurina, B. Fadeel, and V. E. Kagan NADPH Oxidase-dependent Oxidation and Externalization of Phosphatidylserine during Apoptosis in Me2SO-differentiated HL-60 Cells. ROLE IN PHAGOCYTIC CLEARANCE J. Biol. Chem., December 13, 2002; 277(51): 49965 - 49975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L. M. Esnault Apoptosis: the central actor in the three hits that trigger anti-neutrophil cytoplasmic antibody-related systemic vasculitis Nephrol. Dial. Transplant., October 1, 2002; 17(10): 1725 - 1728. [Full Text] [PDF]
|
|
|
|
|
|
S. H. Gregory and E. J. Wing Neutrophil-Kupffer cell interaction: a critical component of host defenses to systemic bacterial infections J. Leukoc. Biol., August 1, 2002; 72(2): 239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shimizu, K. Fukuo, S. Nagata, T. Suhara, M. Okuro, K. Fujii, Y. Higashino, M. Mogi, Y. Hatanaka, and T. Ogihara Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris J. Am. Coll. Cardiol., February 20, 2002; 39(4): 585 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Usher, R. A. Lawson, I. Geary, C. J. Taylor, C. D. Bingle, G. W. Taylor, and M. K. B. Whyte Induction of Neutrophil Apoptosis by the Pseudomonas aeruginosa Exotoxin Pyocyanin: A Potential Mechanism of Persistent Infection J. Immunol., February 15, 2002; 168(4): 1861 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Magnus, A. Chan, O. Grauer, K. V. Toyka, and R. Gold Microglial Phagocytosis of Apoptotic Inflammatory T Cells Leads to Down-Regulation of Microglial Immune Activation J. Immunol., November 1, 2001; 167(9): 5004 - 5010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Borges, H. Falcao, J. H. Leite-Junior, L. Alvim, G. P. Teixeira, M. Russo, A. F. Nobrega, M. F. Lopes, P. M. Rocco, W. F. Davidson, et al. FAS Ligand Triggers Pulmonary Silicosis J. Exp. Med., July 16, 2001; 194(2): 155 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Nichols, J. A. Niles, and N. J. Roberts Jr. Human Lymphocyte Apoptosis after Exposure to Influenza A Virus J. Virol., July 1, 2001; 75(13): 5921 - 5929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. d. C. Bittencourt, S. Perruche, E. Contassot, S. Fresnay, M.-H. Baron, R. Angonin, F. Aubin, P. Herve, P. Tiberghien, and P. Saas Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers Blood, July 1, 2001; 98(1): 224 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Jaber, M. C Perianayagam, V. S Balakrishnan, A. J King, and B. J. G. Pereira Mechanisms of neutrophil apoptosis in uremia and relevance of the Fas (APO-1, CD95)/Fas ligand system J. Leukoc. Biol., June 1, 2001; 69(6): 1006 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. E. Nwakoby, K. Reddy, P. Patel, N. Shah, S. Sharma, M. Bhaskaran, N. Gibbons, A. A. Kapasi, and P. C. Singhal Fas-Mediated Apoptosis of Neutrophils in Sera of Patients with Infection Infect. Immun., May 1, 2001; 69(5): 3343 - 3349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baran, K. Weglarczyk, M. Mysiak, K. Guzik, M. Ernst, H.-D. Flad, and J. Pryjma Fas (CD95)-Fas Ligand Interactions Are Responsible for Monocyte Apoptosis Occurring as a Result of Phagocytosis and Killing of Staphylococcus aureus Infect. Immun., March 1, 2001; 69(3): 1287 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Goth and R. S. Stephens Rapid, Transient Phosphatidylserine Externalization Induced in Host Cells by Infection with Chlamydia spp. Infect. Immun., February 1, 2001; 69(2): 1109 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schmidt, N. Lugering, A. Lugering, H.-G. Pauels, K. Schulze-Osthoff, W. Domschke, and T. Kucharzik Role of the CD95/CD95 Ligand System in Glucocorticoid-Induced Monocyte Apoptosis J. Immunol., January 15, 2001; 166(2): 1344 - 1351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Greenstein, J. Barnard, K. Zhou, M. Fong, and B. Hendey Fas activation reduces neutrophil adhesion to endothelial cells J. Leukoc. Biol., November 1, 2000; 68(5): 715 - 722. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Niinobu, K. Fukuo, O. Yasuda, M. Tsubakimoto, M. Mogi, H. Nishimaki, S. Morimoto, and T. Ogihara Negative feedback regulation of activated macrophages via Fas-mediated apoptosis Am J Physiol Cell Physiol, August 1, 2000; 279(2): C504 - C509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Meszaros, J. S. Reichner, and J. E. Albina Macrophage-Induced Neutrophil Apoptosis J. Immunol., July 1, 2000; 165(1): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. A. Hirt, F. Gantner, and M. Leist Phagocytosis of Nonapoptotic Cells Dying by Caspase- Independent Mechanisms J. Immunol., June 15, 2000; 164(12): 6520 - 6529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Norian, K. M. Latinis, S. L. Eliason, K. Lyson, C. Yang, T. Ratliff, and G. A. Koretzky The Regulation of CD95 (Fas) Ligand Expression in Primary T Cells: Induction of Promoter Activation in CD95LP-Luc Transgenic Mice J. Immunol., May 1, 2000; 164(9): 4471 - 4480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jiang, M.-W. H. Wu, P. Sternberg, and D. P. Jones Fas Mediates Apoptosis and Oxidant-Induced Cell Death in Cultured hRPE Cells Invest. Ophthalmol. Vis. Sci., March 1, 2000; 41(3): 645 - 655. [Abstract] [Full Text]
|
|
|
|
|
|
J. S. Duffield, L.-P. Erwig, X.-q. Wei, F. Y. Liew, A. J. Rees, and J. S. Savill Activated Macrophages Direct Apoptosis and Suppress Mitosis of Mesangial Cells J. Immunol., February 15, 2000; 164(4): 2110 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. McCarthy and M. Bennett The regulation of vascular smooth muscle cell apoptosis Cardiovasc Res, February 1, 2000; 45(3): 747 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pongracz, P. Webb, K. Wang, E. Deacon, O. J. Lunn, and J. M. Lord Spontaneous Neutrophil Apoptosis Involves Caspase 3-mediated Activation of Protein Kinase C-delta J. Biol. Chem., December 24, 1999; 274(52): 37329 - 37334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Perlman, L. J. Pagliari, C. Georganas, T. Mano, K. Walsh, and R. M. Pope Flice-Inhibitory Protein Expression during Macrophage Differentiation Confers Resistance to FAS-Mediated Apoptosis J. Exp. Med., December 6, 1999; 190(11): 1679 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hernandez, L. Fuentes, F. J. Fernandez Aviles, M. S. Crespo, and M. L. Nieto Secretory Phospholipase A2 Elicits Proinflammatory Changes and Upregulates the Surface Expression of Fas Ligand in Monocytic Cells: Potential Relevance for Atherogenesis Circ. Res., January 11, 2002; 90(1): 38 - 45. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
