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,
*
Trudeau Institute, Saranac Lake, NY 12983;
Transplantation, Millennium Pharmaceuticals, Cambridge, MA 02139; and
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1), MIP-1
, MIP-2, and monocyte chemoattractant protein-1 are
fibrinogen inducible in the RAW264.7 mouse macrophage-like cell line,
and ELISA confirmed that both RAW264.7 cells and primary murine
thioglycolate-elicited peritoneal macrophages up-regulate the secretion
of monocyte chemoattractant protein-1 >100-fold upon exposure to
fibrinogen. Human U937 and THP-1 precursor-1 (THP-1) monocytic
cell lines also secreted chemokines in response to fibrinogen, upon
activation with IFN-
and differentiation with vitamin
D3, respectively. LPS contamination could not account for
our observations, as fibrinogen-induced chemokine secretion was
sensitive to heat denaturation and was unaffected by the pharmacologic
LPS antagonist polymyxin B. Nevertheless, fibrinogen- and LPS-induced
chemokine secretion both apparently required expression of functional
Toll-like receptor 4, as each was diminished in macrophages derived
from C3H/HeJ mice. Thus, innate responses to fibrinogen and bacterial
endotoxin may converge at the evolutionarily conserved Toll-like
recognition molecules. Our data suggest that extravascular fibrin(ogen)
induces macrophage chemokine expression, thereby promoting immune
surveillance at sites of inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the presence of extravascular fibrin(ogen) at sites of
inflammation has been documented by pathologists for decades, its full
physiologic significance has yet to be defined. Within the vasculature,
fibrin has critical blood coagulation functions, in part mediated by
binding sites for CD41/CD61
(IIb3, gpIIb/IIIa),
an integrin expressed by platelets (7). The
leukocyte-specific integrins CD11b/CD18
(M2, CR3, Mac-1) and
CD11c/CD18 (V2, CR4,
p150/95) also bind fibrin(ogen) (8, 9, 10, 11, 12, 13, 14, 15, 16). Indeed,
CD11b/CD18-fibrin(ogen) interactions mediate neutrophil adherence to
vascular blood clots (17, 18). As these
fibrin(ogen)-binding integrins are also expressed by
monocytes/macrophages and subsets of dendritic, NK, and T cells,
extravascular fibrin probably functions as an inflammation-inducible
adhesion substrate for leukocytes.
Extravascular fibrin(ogen) may also function by transmitting activating
signals to leukocytes. Integrin ligation stimulates "outside-in"
signaling (reviewed in Ref. 19), and fibrin(ogen)
reportedly promotes CD11b/CD18-dependent NF-
B activation and IL-1
expression by monocytic cells (20, 21). Although
relatively high concentrations of fibrin(ogen) are most effective, such
levels are probably achieved locally upon fibrin polymerization and
deposition. Thus, extravasated fibrin(ogen) may promote both leukocyte
adhesion and cytokine secretion at sites of inflammation.
In the current study we demonstrate that fibrinogen also stimulates macrophage production of a select set of chemokines that promote attraction of T cells, neutrophils, and additional macrophages. Moreover, we found that fibrinogen- and LPS-stimulated chemokine secretions share a common signaling pathway, each requiring expression of functional Toll-like receptor 4 (TLR4).3 Thus, evolutionarily conserved Toll proteins apparently signal in response to both foreign pathogens and host fibrinogen. We propose a model in which the relocation of certain host proteins from vascular to extravascular environments may constitute a general means to signal "danger."
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture medium, serum, and additives were obtained from
Life Technologies (Gaithersburg, MD). Human fibrinogen (certified free
of factor XIII, plasminogen, and fibronectin) was purchased from
American Diagnostica (Greenwich, CT). Fibrinogen was reconstituted in
endotoxin-free water (Sigma, St. Louis, MO), warmed to 37°C for 5 min
to complete dissolution, diluted to 2 mg/ml in culture medium,
sterile-filtered, and used immediately. Fibrinogen purchased from Sigma
and Enzyme Research Laboratories (South Bend, IN) generated similar
results. In the experiments reported here, culture medium contained <1
U/ml endotoxin (determined by Pyrochrome Limulus Amebocyte
Lysate Assay; Associates of Cape Cod, Falmouth, MA), and
supplementation with fibrinogen did not significantly increase
endotoxin levels. Fibronectin was purchased from Roche (Indianapolis,
IN), hirudin from American Diagnostica, human IFN- from PharMingen
(San Diego, CA), 1,25-dihydroxyvitamin D3 from
Calbiochem (San Diego, CA), and LPS (Escherichia coli,
0111:B4) and polymyxin B sulfate from Sigma.
Cells
Mouse RAW264.7, human U937, and human THP-1 monocytic cell lines were obtained from American Type Culture Collection (Manassas, VA) and cultured as recommended by the supplier. Mouse peritoneal exudate cells (PEC) were elicited by i.p. injection of 3 ml 1% thioglycolate broth (Sigma) into 8-wk-old female C57BL/6, C3H/HeOuJ, and C3H/HeJ mice (The Jackson Laboratory, Bar Harbor, ME). After 72 h, peritoneal cavities were flushed with 7 ml PBS containing 5% FCS and 5 mM EDTA. PEC were then collected by centrifugation and washed with culture medium.
Cell culture
Human and mouse cells were cultured in RPMI and DMEM,
respectively. All cultures were supplemented with 10% FCS, 2 mM
glutamine, 50 U/ml penicillin, 50 µg/ml streptomycin, 50 µM 2-ME,
and 10 mM HEPES. For some experiments, U937 cells were precultured in
500 U/ml human IFN-, and THP-1 cells were precultured in 50 ng/ml
1,25-dihydroxyvitamin D3. Cells were
harvested, counted, and seeded at 2 x 105
cells/well in 24-well dishes. Inhibitors and stimuli were added to
achieve a final volume of 1 ml/well. Supernatants were harvested
24 h later for ELISA. In some experiments cells were precultured
for 2–16 h to permit adherence, but this did not significantly affect
the results.
Expression arrays and RNase protection assays
For RNA analyses, RAW264.7 cells were harvested 6 h poststimulation with fibrinogen. RNA was prepared using RNeasy kits (Qiagen, Valencia, CA). Labeled cDNA was prepared, and blots were hybridized as instructed by the Atlas Mouse cDNA Expression Array Kit (CLONTECH Laboratories, Palo Alto, CA). The same RNA was also analyzed by mCK-5 RNase protection assay (PharMingen) as directed by the manufacturer.
ELISA
We used human and mouse OptEIA Kits (PharMingen) to quantify
macrophage inflammatory protein-1 (MIP-1) and monocyte
chemoattractant protein-1 (MCP-1) protein in culture supernatants.
Samples were always sufficiently diluted to ensure that values fell
within the linear range of the assay. The values reported depict
averages of duplicate cultures, each of which was also diluted and
assayed in duplicate. SEMs were always within 15% of the reported mean
values.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, MIP-1, MCP-1,
and MIP-2 upon exposure to fibrinogen
As macrophages express receptors for fibrin(ogen), and
extravascular fibrin(ogen) is frequently associated with inflammatory
responses, we examined functional consequences of macrophage exposure
to fibrin(ogen). Prior studies established that fibrin(ogen) can
stimulate IL-1 and TNF- expression by human monocytic cells
(21, 22). We confirmed those findings (data not shown) and
sought to identify other fibrin(ogen)-inducible monocyte/macrophage
genes. We cultured the murine RAW264.7 macrophage-like cell line with
fibrinogen (500 µg/ml) for 6 h, prepared RNA, converted the RNA
to cDNA, and hybridized the cDNA to commercially available filters
spotted with probes for 600 mouse genes. Compared with the medium
control (Fig. 1
A), only one
fibrinogen-up-regulated gene was detected: the chemokine MIP-1 (Fig. 1B). Using RNase protection assays, we confirmed MIP-1
up-regulation and also identified three other fibrinogen-inducible
chemokine mRNA: MIP-1, MIP-2, and MCP-1 (Fig. 1C).
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We next evaluated whether fibrinogen-stimulated increases in
chemokine mRNA levels led to corresponding increases in protein
secretion. We harvested supernatants from RAW264.7 cells cultured in
the presence or the absence of fibrinogen for 24 h and assayed
chemokine secretion by ELISA. MCP-1 levels increased >15- and 100-fold
above baseline upon exposure of RAW264.7 cells to 50 and 500 µg/ml
fibrinogen, respectively (Fig. 2A). Statistically significant
(3- to 5-fold) increases were also evident in cultures supplemented
with as little as 5 µg/ml fibrinogen. Thus, fibrinogen stimulates
RAW264.7 cells to secrete MCP-1 in a dose-dependent manner.
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B). Again, 500 µg/ml fibrinogen
stimulated MCP-1 secretion >100-fold. PEC and RAW264.7 cells also
secreted MIP-1 protein in response to fibrinogen (data not
shown). Fibrinogen stimulates chemokine secretion from activated or differentiated human monocytic cells
Having established that murine macrophages secrete chemokines in
response to fibrinogen, we sought to extend our findings to human
cells. Initial studies revealed that freshly harvested human PBMC as
well as THP-1 and U937 monocytic cell lines failed to significantly
up-regulate MCP-1 secretion in response to fibrinogen. However, when we
preactivated U937 with 500 U/ml IFN- for 24 h, fibrinogen then
stimulated >20-fold increases in MCP-1 production (Fig. 3A). Unlike U937 cells, THP-1
cells did not acquire fibrinogen responsiveness when pretreated with
IFN-. However, when THP-1 cells were cultured with vitamin
D3, which promotes differentiation to a more
macrophage-like phenotype (23), they then became
fibrinogen responsive (Fig. 3B). The failure of fibrinogen
to up-regulate MCP-1 production from unprimed/undifferentiated
U937/THP-1 cells suggests that fibrinogen-induced chemokine secretion
may predominantly be a characteristic of activated macrophages.
Accordingly, resting vascular monocytes may be unresponsive to
circulating fibrinogen, while activated monocytes and tissue
macrophages may promptly secrete chemokines in response to extravasated
fibrin(ogen).
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We next evaluated the specificity of fibrinogen-induced chemokine
secretion. Adhesion alone was clearly insufficient to stimulate
chemokine secretion, as the cells in our control and
fibrinogen-stimulated cultures were both adherent to plastic culture
dishes. Fibrin(ogen) is a ligand for the macrophage-expressed integrins
CD11b/CD18, CD11c/CD18, and CD51/CD61
(v3) (8, 9, 10, 11, 12, 13, 14, 15, 16, 24). To evaluate whether all ligands for macrophage integrins
stimulate MCP-1 secretion, we cultured RAW264.7 cells with fibronectin,
another CD51/CD61 ligand (24). In contrast to fibrinogen,
fibronectin did not stimulate macrophage MCP-1 secretion (Fig. 4). Thus, integrin-mediated adhesion is
not sufficient to activate chemokine secretion.
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). Thus, fibrinogen-stimulated chemokine
expression does not require the conversion of fibrinogen to fibrin. Fibrinogen-stimulated macrophage chemokine secretion is LPS independent
LPS is a potent activator of macrophage activities. Indeed, like
fibrinogen, LPS up-regulates macrophage expression of mRNA encoding
MIP-1, MIP-1, MIP-2, and MCP-1 (data not shown) and secretion of
MCP-1 (Fig. 5). To establish that
fibrinogen-induced chemokine secretion could not be explained by LPS
contamination, we supplemented cultures with polymyxin B, a
well-characterized pharmacologic LPS antagonist. Although polymyxin B
did not significantly affect fibrinogen-induced MCP-1 secretion by PEC
(Fig. 5A), it clearly suppressed LPS-stimulated MCP-1
secretion (Fig. 5B). We obtained similar results with
RAW264.7 cells (Fig. 5, C and D) and
IFN--primed U937 cells (data not shown). Polymyxin B also failed to
suppress fibrinogen-stimulated increases in MIP-1, MIP-1, MIP-2,
and MCP-1 mRNA (data not shown). Although published studies routinely
use 10 µg/ml polymyxin B to antagonize LPS, polymyxin B did not
significantly affect fibrinogen-induced chemokine secretion even at 25
µg/ml; higher concentrations were toxic to macrophage cultures.
Control experiments using suboptimal doses of fibrinogen supplemented
with stimulating doses of LPS established that fibrinogen does not
prevent polymyxin B from inactivating contaminating LPS (data not
shown).
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C). In
contrast, boiled LPS remained active (Fig. 5D). Together,
the temperature-sensitive nature of the stimuli and the failure of
polymyxin B to inhibit the response indicate that fibrinogen-induced
macrophage MCP-1 secretion is LPS independent. Fibrinogen-stimulated macrophage chemokine secretion is TLR4 dependent
As fibrinogen and LPS both transmit signals prompting macrophage
chemokine secretion, we evaluated whether they function through similar
pathways. TLR4 was recently implicated in responses to LPS
(26, 27, 28). As C3H/HeJ mice express mutant TLR4 (26, 27), we analyzed fibrinogen-induced chemokine production from
C3H/HeJ macrophages. In comparison to genetically similar, but
TLR4-sufficient, PEC from C3H/HeOuJ mice, fibrinogen failed to
stimulate MCP-1 secretion from C3H/HeJ PEC (Fig. 6). Again, this result could not be
explained by LPS contamination, as polymyxin B suppressed LPS-induced,
but not fibrinogen-induced, MCP-1 secretion by C3H/HeOuJ PEC (Fig. 6).
Thus, macrophage responses to both LPS and fibrinogen require
functional TLR4.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neutrophils, monocytes/macrophages, and subsets of dendritic, NK, and T cells express the fibrin(ogen)-binding integrins CD11b/CD18 (Mac-1) and CD11c/CD18 (p150/95) (8, 9, 10, 11, 12, 13, 14, 15, 16), further suggesting that fibrin(ogen) functions in inflammation/immunity. Given that these integrins are physiologic adhesion molecules (17, 18), it is easily conceivable that fibrin acts as an inducible matrix supporting leukocyte accumulation at sites of inflammation.
Here we demonstrated that fibrin(ogen) stimulates macrophage chemokine
secretion. Specifically, we found that primary macrophages and
activated/differentiated monocytic cell lines exposed to fibrinogen
up-regulate the expression of MIP-1, MIP-1, MIP-2, and MCP-1.
Several prior reports had suggested that CD11b/CD18 contributes to
fibrin(ogen)-stimulated NF-B activation and gene expression
(20, 21, 29). To assess roles for the fibrinogen-binding
CD18 integrins in macrophage chemokine secretion, we supplemented
cultures with peptides and mAbs known to inhibit CD11b/CD18- and
CD11c/CD18-fibrinogen interactions (8, 9, 10, 11, 12, 15, 20). None
of those agents reduced fibrinogen-stimulated chemokine or IL-1
secretion (data not shown). Thus, in our studies, fibrinogen-induced
macrophage gene expression did not appear to involve the known
fibrinogen-binding leukocyte integrins.
Several prior studies clearly established that cross-linking CD11b/CD18
or CD11c/CD18 can stimulate cellular activities (22, 29, 30, 31, 32), and some of those activities could also be stimulated
by fibrinogen (22, 29, 30). However, the evidence that
CD11b/CD18 mediates fibrinogen-stimulated signaling was less decisive.
Fan and Edgington reported that monocyte TNF- secretion upon
adhesion to endothelial cells was inhibited by CD11b/CD18-specific mAb,
although fibrinogen-stimulated TNF- secretion was not, consistent
with our findings (22). Subsequently, Perez and Roman
demonstrated that preincubation with 100 µg/ml of one anti-CD11b
mAb partially reduced fibrin-stimulated IL-1 secretion, although in
that same study a second anti-CD11b mAb known to inhibit fibrinogen
binding (clone M1/70) (9) was not suppressive
(21). Likewise, the semiquantitative gel shift studies by
Sitrin et al. (20) suggested roles for CD11b/CD18 in
NF-B activation, but actually demonstrated only partial inhibition
by CD11b/CD18-specific mAb, and that inhibition required pretreatment
of cells with high concentrations of the Abs. Finally, Walzog et al.
(29) recently implicated CD18 in fibrinogen-stimulated
chemokine secretion by neutrophils, demonstrating that neutrophils from
CD18-deficient mice exhibit reduced up-regulation of MIP-2 mRNA levels
upon culture with fibrinogen. However, their data clearly show that
basal levels of MIP-2 mRNA were greatly reduced in CD18-deficient
neutrophils, and when re-evaluated in that context, the fold increase
in MIP-2 expression upon stimulation with fibrinogen may not be reduced
in CD18-deficient neutrophils. In fact, the data presented by Walzog et
al. (29) establish that fibrinogen can stimulate chemokine
secretion in the absence of CD18. Thus, prior studies have not
decisively demonstrated direct roles for CD18 integrins in
fibrinogen-mediated signaling, consistent with our inability to
demonstrate inhibition of fibrinogen-stimulated chemokine secretion by
CD18, CD11b, and CD11c antagonists.
Recently, fibrinogen was also shown to stimulate chemokine secretion by endothelial cells (33, 34, 35, 36) and fibroblasts (37), which do not express CD18 integrins. However, these cells express CD54 (ICAM-1), which can also bind fibrinogen (38), and could thus potentially contribute to fibrinogen-mediated chemokine secretion. Harley and Powell explicitly addressed this possibility, but they were unable to demonstrate roles for ICAM-1 in fibrinogen-stimulated chemokine secretion by endothelial cells (36). Thus, despite extensive evidence that CD11b/CD18, CD11c/CD18, and CD54 can bind fibrinogen (8, 9, 10, 11, 12, 13, 14, 15, 16, 38), prior studies have failed to clearly establish roles for any of these surface receptors in stimulating fibrin(ogen)-mediated gene expression.
During the course of our studies we noted that LPS and fibrinogen
stimulate the expression of the same cytokines and chemokines in
macrophages. LPS contamination could not account for fibrinogen-induced
chemokine secretion, as the pharmacologic LPS antagonist polymyxin B
did not suppress fibrinogen-induced MCP-1 secretion (Figs. 5 and 6) or
fibrinogen-induced increases in mRNA encoding MIP-1, MIP-1,
MIP-2, and MCP-1 (data not shown). Moreover, heat denaturation
inhibited the chemokine-stimulating activity of fibrinogen, but not
that of LPS (Fig. 5). Although these data indicate that
fibrinogen-stimulated chemokine secretion is not due to contaminating
LPS, at this time we cannot rule out the possibility that some
heat-sensitive, polymyxin B-resistant contaminant accounts for the
stimulatory activities of fibrinogen. Notably, we recently determined
that chemokine production can be fibrinogen dependent in vivo using
gene-targeted fibrinogen-deficient mice (39), strongly
supporting the idea that the in vitro chemokine responses reported here
are either directly stimulated by fibrinogen itself or by a copurifying
contaminant that requires fibrinogen for activity in vivo (S. T.
Smiley, manuscript in preparation).
Given the similarity between genes induced by LPS and fibrinogen, we
evaluated whether similar signaling pathways are involved. Recent
studies have implicated TLR in signaling processes triggered by
pathogens (40, 41), and TLR critical for signaling the
presence of LPS have been identified in mice, humans and
Drosophila (26, 27, 28, 41, 42, 43). C3H/HeJ mice
express mutant TLR4 and thus respond poorly to LPS (26, 27). We found that C3H/HeJ PEC also respond poorly to fibrinogen
(Fig. 6), suggesting that fibrinogen and LPS signaling converge at
TLR4. Indeed, all previously identified fibrinogen-inducible genes are
also inducible by LPS.
As fibroblasts and endothelial cells can express TLR4
(44, 45, 46, 47), we suspect that fibrinogen-stimulated chemokine
secretion by those cells is also TLR4 dependent. Likewise, we predict
that fibrinogen-induced leukocyte NF-B activation (20)
and expression of TNF- (22) and IL-1
(21) are TLR4 dependent. Notably, under certain
experimental conditions, full leukocyte responses to LPS require the
expression of both TLR4 and CD11b/CD18 (48). Thus,
associations between TLR4 and CD11b may account for the prior studies
suggesting roles for CD11b in some fibrinogen-stimulated responses
(20, 21, 29). We hypothesize that integrin-mediated
binding may sometimes help to initiate fibrinogen-stimulated responses,
but that signal propagation will proceed through TLR4.
Formally, we have yet to demonstrate that fibrinogen signals directly through TLR4. Rather, we found that C3H/HeJ macrophages, which express mutant TLR4, fail to respond to fibrinogen. It is conceivable that the expression of TLR4 may enable fibrinogen responsiveness indirectly, perhaps by affecting the priming or differentiation of macrophages. Indeed, TLR4 apparently regulates aspects of macrophage priming/differentiation, as C3H/HeJ macrophages express altered basal levels of IFN regulatory factors (49). Although future studies will be required to distinguish direct and indirect roles for TLR4 in fibrinogen signaling, our data clearly establish that macrophage chemokine secretion in response to fibrinogen requires the expression of functional TLR4.
Medzhitov and Janeway (50, 51) recently demonstrated
striking evolutionary conservation in Toll pathways.
Drosophila and mammals not only possess homologous TLR, but
also express conserved downstream adapter molecules, kinases, and
transcription factors (reviewed in Ref. 52). In
Drosophila, TLR function in both host defense and embryonic
development. In the developmental pathway, Toll functions downstream of
a serine protease cascade that prompts cleavage-induced multimerization
of Spatzle (reviewed in Ref. 53) (Fig. 7). In the host defense pathway, Spatzle
and an as yet to be defined protease(s) also function upstream of Toll
(54, 55) (Fig. 7). Notably, despite extensive downstream
conservation, upstream homologues have yet to be defined in mammalian
TLR-dependent responses.
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), a reaction that is the basis of the
widely used Limulus assay for endotoxin
(58, 59, 60). Thus, in flies and crabs pathogens trigger
serine protease cascades prompting multimerization of structurally
homologous targets, Spatzle and coagulogen. We note that in mammals, an
upstream serine protease cascade prompts cleavage of fibrinogen,
resulting in its multimerization and deposition as fibrin. Thus,
fibrinogen, Spatzle, and coagulogen are functional homologues, each
polymerizing upon activation of an upstream serine protease cascade
(Fig. 7). These remarkable interspecies homologies suggest that
fibrinogen-activated TLR-dependent mammalian responses may have evolved
from Spatzle-activated Drosophila responses. To facilitate sterilizing immunity, the host must recognize the presence of danger and then attract and activate effector leukocytes (61, 62). When danger takes the form of infectious microbes, detection may proceed through host receptors that recognize characteristic pathogen-associated molecular patterns. The ensuing response to "non-self" promptly signals the production of chemokines and cytokines, stimulating immune cell accumulation and activation, respectively.
Although signaling danger in response to non-self is an attractive means to initiate microbe-specific immunity, pathogens may circumvent this mode of recognition through evolution. Presumably to combat such scenarios, mammals also evolved mechanisms that facilitate indirect recognition of infectious agents: T cells perceive altered self (i.e., self MHC molecules that adopt non-self structures upon binding foreign peptides), NK cells respond to missing self (i.e., altered or down-regulated self MHC molecules), and macrophages and dendritic cells respond to stressed self (i.e., self heat shock proteins released from necrotic cells (63, 64). Notably, responses to heat shock proteins are also TLR4 dependent (65).
Here we propose another reliable means for host cells to detect danger:
innate recognition of relocated self (i.e., host proteins that have
been relocated in response to tissue damage). Fibrinogen is normally
confined to the vasculature, but at sites of inflammation increased
vascular permeability allows plasma extravasation. Relocated
fibrin(ogen) may then stimulate macrophage secretion of MIP-1,
MIP-1, MIP-2, and MCP-1, chemokines that attract T cells,
neutrophils, and macrophages. As these cells also express
fibrin(ogen)-binding integrins, extravasated fibrin(ogen) probably
stimulates both leukocyte recruitment to and retention at sites of
inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stephen T. Smiley, Trudeau Institute, 100 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: ssmiley{at}trudeauinstitute.org
3 Abbreviations used in this paper: TLR, Toll-like receptor; PEC, peritoneal exudate cells; MIP-1, macrophage inflammatory protein-1; MCP-1, monocyte chemoattractant protein-1.
Received for publication February 15, 2001. Accepted for publication June 27, 2001.
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 D. Yang, Q. Chen, S. B. Su, P. Zhang, K. Kurosaka, R. R. Caspi, S. M. Michalek, H. F. Rosenberg, N. Zhang, and J. J. Oppenheim Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses J. Exp. Med., January 21, 2008; 205(1): 79 - 90. [Abstract] [Full Text] [PDF]
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K. P. Mollen, R. M. Levy, J. M. Prince, R. A. Hoffman, M. J. Scott, D. J. Kaczorowski, R. Vallabhaneni, Y. Vodovotz, and T. R. Billiar Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells J. Leukoc. Biol., January 1, 2008; 83(1): 80 - 88. [Abstract] [Full Text] [PDF]
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M. H. Hoffmann, J. Tuncel, K. Skriner, M. Tohidast-Akrad, B. Turk, S. Pinol-Roma, G. Serre, G. Schett, J. S. Smolen, R. Holmdahl, et al. The Rheumatoid Arthritis-Associated Autoantigen hnRNP-A2 (RA33) Is a Major Stimulator of Autoimmunity in Rats with Pristane-Induced Arthritis J. Immunol., December 1, 2007; 179(11): 7568 - 7576. [Abstract] [Full Text] [PDF]
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C. Marik, P. A. Felts, J. Bauer, H. Lassmann, and K. J. Smith Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain, November 1, 2007; 130(11): 2800 - 2815. [Abstract] [Full Text] [PDF]
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 V. Andreani, G. Gatti, L. Simonella, V. Rivero, and M. Maccioni Activation of Toll-like Receptor 4 on Tumor Cells In vitro Inhibits Subsequent Tumor Growth In vivo Cancer Res., November 1, 2007; 67(21): 10519 - 10527. [Abstract] [Full Text] [PDF]
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 A. S. Williams, S.-Y. Leung, P. Nath, N. M. Khorasani, P. Bhavsar, R. Issa, J. A. Mitchell, I. M. Adcock, and K. F. Chung Role of TLR2, TLR4, and MyD88 in murine ozone-induced airway hyperresponsiveness and neutrophilia J Appl Physiol, October 1, 2007; 103(4): 1189 - 1195. [Abstract] [Full Text] [PDF]
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 J. Mu, D. Qu, A. Bartczak, M. J. Phillips, J. Manuel, W. He, C. Koscik, M. Mendicino, L. Zhang, D. A. Clark, et al. Fgl2 deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice Physiol Genomics, September 11, 2007; 31(1): 53 - 62. [Abstract] [Full Text] [PDF]
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E. A. Lefevre, W. R. Hein, Z. Stamataki, L. S. Brackenbury, E. A. Supple, L. G. Hunt, P. Monaghan, G. Borhis, Y. Richard, and B. Charleston Fibrinogen is localized on dark zone follicular dendritic cells in vivo and enhances the proliferation and survival of a centroblastic cell line in vitro J. Leukoc. Biol., September 1, 2007; 82(3): 666 - 677. [Abstract] [Full Text] [PDF]
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S. Divanovic, A. Trompette, L. K. Petiniot, J. L. Allen, L. M. Flick, Y. Belkaid, R. Madan, J. J. Haky, and C. L. Karp Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105 J. Leukoc. Biol., August 1, 2007; 82(2): 265 - 271. [Abstract] [Full Text] [PDF]
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 R. T. Figueiredo, P. L. Fernandez, D. S. Mourao-Sa, B. N. Porto, F. F. Dutra, L. S. Alves, M. F. Oliveira, P. L. Oliveira, A. V. Graca-Souza, and M. T. Bozza Characterization of Heme as Activator of Toll-like Receptor 4 J. Biol. Chem., July 13, 2007; 282(28): 20221 - 20229. [Abstract] [Full Text] [PDF]
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 U. Koedel, U. M. Merbt, C. Schmidt, B. Angele, B. Popp, H. Wagner, H.-W. Pfister, and C. J. Kirschning Acute Brain Injury Triggers MyD88-Dependent, TLR2/4-Independent Inflammatory Responses Am. J. Pathol., July 1, 2007; 171(1): 200 - 213. [Abstract] [Full Text] [PDF]
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A. A. Shigeoka, T. D. Holscher, A. J. King, F. W. Hall, W. B. Kiosses, P. S. Tobias, N. Mackman, and D. B. McKay TLR2 Is Constitutively Expressed within the Kidney and Participates in Ischemic Renal Injury through Both MyD88-Dependent and -Independent Pathways J. Immunol., May 15, 2007; 178(10): 6252 - 6258. [Abstract] [Full Text] [PDF]
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J. Fan, Y. Li, R. M. Levy, J. J. Fan, D. J. Hackam, Y. Vodovotz, H. Yang, K. J. Tracey, T. R. Billiar, and M. A. Wilson Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling J. Immunol., May 15, 2007; 178(10): 6573 - 6580. [Abstract] [Full Text] [PDF]
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 J. R. Caso, J. M. Pradillo, O. Hurtado, P. Lorenzo, M. A. Moro, and I. Lizasoain Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke Circulation, March 27, 2007; 115(12): 1599 - 1608. [Abstract] [Full Text] [PDF]
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 P L E M van Lent, A B Blom, L Grevers, A Sloetjes, and W B van den Berg Toll-like receptor 4 induced Fc{gamma}R expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates Fc{gamma}R expression by interleukin 10 Ann Rheum Dis, March 1, 2007; 66(3): 334 - 340. [Abstract] [Full Text] [PDF]
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A. Tsung, N. Zheng, G. Jeyabalan, K. Izuishi, J. R. Klune, D. A. Geller, M. T. Lotze, L. Lu, and T. R. Billiar Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury J. Leukoc. Biol., January 1, 2007; 81(1): 119 - 128. [Abstract] [Full Text] [PDF]
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 A. Shimamoto, T. H. Pohlman, S. Shomura, T. Tarukawa, M. Takao, and H. Shimpo Toll-Like Receptor 4 Mediates Lung Ischemia-Reperfusion Injury Ann. Thorac. Surg., December 1, 2006; 82(6): 2017 - 2023. [Abstract] [Full Text] [PDF]
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A. C. Aplin, M. Gelati, E. Fogel, E. Carnevale, and R. F. Nicosia Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis Physiol Genomics, October 3, 2006; 27(1): 20 - 28. [Abstract] [Full Text] [PDF]
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 G. E. Morris, L. C. Parker, J. R. Ward, E. C. Jones, M. K. B. Whyte, C. E. Brightling, P. Bradding, S. K. Dower, and I. Sabroe Cooperative molecular and cellular networks regulate Toll-like receptor-dependent inflammatory responses FASEB J, October 1, 2006; 20(12): 2153 - 2155. [Abstract] [Full Text] [PDF]
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 Z. Wang, L. Xiang, J. Shao, and Z. Yuan The 3' CCACCA Sequence of tRNAAla(UGC) Is the Motif That Is Important in Inducing Th1-Like Immune Response, and This Motif Can Be Recognized by Toll-Like Receptor 3. Clin. Vaccine Immunol., July 1, 2006; 13(7): 733 - 739. [Abstract] [Full Text] [PDF]
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P. Rallabhandi, J. Bell, M. S. Boukhvalova, A. Medvedev, E. Lorenz, M. Arditi, V. G. Hemming, J. C. G. Blanco, D. M. Segal, and S. N. Vogel Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling J. Immunol., July 1, 2006; 177(1): 322 - 332. [Abstract] [Full Text] [PDF]
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K. Izuishi, A. Tsung, G. Jeyabalan, N. D. Critchlow, J. Li, K. J. Tracey, R. A. Demarco, M. T. Lotze, M. P. Fink, D. A. Geller, et al. Cutting Edge: High-Mobility Group Box 1 Preconditioning Protects against Liver Ischemia-Reperfusion Injury. J. Immunol., June 15, 2006; 176(12): 7154 - 7158. [Abstract] [Full Text] [PDF]
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G. Wolf, J. Bohlender, T. Bondeva, T. Roger, F. Thaiss, and U. O. Wenzel Angiotensin II Upregulates Toll-Like Receptor 4 on Mesangial Cells J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1585 - 1593. [Abstract] [Full Text] [PDF]
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I. Jou, J. H. Lee, S. Y. Park, H. J. Yoon, E.-H. Joe, and E. J. Park Gangliosides Trigger Inflammatory Responses via TLR4 in Brain Glia Am. J. Pathol., May 1, 2006; 168(5): 1619 - 1630. [Abstract] [Full Text] [PDF]
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S. T. Qureshi, X. Zhang, E. Aberg, N. Bousette, A. Giaid, P. Shan, R. M. Medzhitov, and P. J. Lee Inducible Activation of TLR4 Confers Resistance to Hyperoxia-Induced Pulmonary Apoptosis. J. Immunol., April 15, 2006; 176(8): 4950 - 4958. [Abstract] [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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E. F. Cohn, C. Nathan, D. Radzioch, H. Yu, Z. Xiang, and A. Ding Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli J. Immunol., January 15, 2006; 176(2): 1185 - 1194. [Abstract] [Full Text] [PDF]
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A. Tsung, R. A. Hoffman, K. Izuishi, N. D. Critchlow, A. Nakao, M. H. Chan, M. T. Lotze, D. A. Geller, and T. R. Billiar Hepatic Ischemia/Reperfusion Injury Involves Functional TLR4 Signaling in Nonparenchymal Cells J. Immunol., December 1, 2005; 175(11): 7661 - 7668. [Abstract] [Full Text] [PDF]
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F. J. Barrat, T. Meeker, J. Gregorio, J. H. Chan, S. Uematsu, S. Akira, B. Chang, O. Duramad, and R. L. Coffman Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus J. Exp. Med., October 17, 2005; 202(8): 1131 - 1139. [Abstract] [Full Text] [PDF]
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E. East, D. Baker, G. Pryce, H. R. Lijnen, M. L. Cuzner, and D. Gveric A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2005; 167(2): 545 - 554. [Abstract] [Full Text] [PDF]
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M. Mendicino, M. Liu, A. Ghanekar, W. He, C. Koscik, I. Shalev, M. Javadi, J. Turnbull, W. Chen, L. Fung, et al. Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts Circulation, July 12, 2005; 112(2): 248 - 256. [Abstract] [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Weis, M. Nabauer, and J. Koglin Expansion of Circulating Toll-Like Receptor 4-Positive Monocytes in Patients With Acute Coronary Syndrome Circulation, May 24, 2005; 111(20): 2654 - 2661. [Abstract] [Full Text] [PDF]
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F. Geisler, H. Algul, M. Riemann, and R. M. Schmid Questioning Current Concepts in Acute Pancreatitis: Endotoxin Contamination of Porcine Pancreatic Elastase Is Responsible for Experimental Pancreatitis-Associated Distant Organ Failure J. Immunol., May 15, 2005; 174(10): 6431 - 6439. [Abstract] [Full Text] [PDF]
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B. Valentinis, A. Bianchi, D. Zhou, A. Cipponi, F. Catalanotti, V. Russo, and C. Traversari Direct Effects of Polymyxin B on Human Dendritic Cells Maturation: THE ROLE OF I{kappa}B-{alpha}/NF-{kappa}B AND ERK1/2 PATHWAYS AND ADHESION J. Biol. Chem., April 8, 2005; 280(14): 14264 - 14271. [Abstract] [Full Text] [PDF]
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A. Tsung, R. Sahai, H. Tanaka, A. Nakao, M. P. Fink, M. T. Lotze, H. Yang, J. Li, K. J. Tracey, D. A. Geller, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion J. Exp. Med., April 4, 2005; 201(7): 1135 - 1143. [Abstract] [Full Text] [PDF]
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D. De Nardo, P. Masendycz, S. Ho, M. Cross, A. J. Fleetwood, E. C. Reynolds, J. A. Hamilton, and G. M. Scholz A Central Role for the Hsp90{middle dot}Cdc37 Molecular Chaperone Module in Interleukin-1 Receptor-associated-kinase-dependent Signaling by Toll-like Receptors J. Biol. Chem., March 18, 2005; 280(11): 9813 - 9822. [Abstract] [Full Text] [PDF]
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 E.-K. Lee, S.-M. Kang, D.-J. Paik, J. M. Kim, and J. Youn Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS Int. Immunol., March 1, 2005; 17(3): 325 - 333. [Abstract] [Full Text] [PDF]
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Y. Zhai, X.-d. Shen, R. O'Connell, F. Gao, C. Lassman, R. W. Busuttil, G. Cheng, and J. W. Kupiec-Weglinski Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway J. Immunol., December 15, 2004; 173(12): 7115 - 7119. [Abstract] [Full Text] [PDF]
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 M. J. Flick, X. Du, and J. L. Degen Fibrin(ogen)-{alpha}M{beta}2 Interactions Regulate Leukocyte Function and Innate Immunity In Vivo Experimental Biology and Medicine, December 1, 2004; 229(11): 1105 - 1110. [Abstract] [Full Text] [PDF]
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M.-F. Tsan and B. Gao Endogenous ligands of Toll-like receptors J. Leukoc. Biol., September 1, 2004; 76(3): 514 - 519. [Abstract] [Full Text] [PDF]
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 K. A. Barsness, J. Arcaroli, A. H. Harken, E. Abraham, A. Banerjee, L. Reznikov, and R. C. McIntyre Hemorrhage-induced acute lung injury is TLR-4 dependent Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R592 - R599. [Abstract] [Full Text] [PDF]
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 A. J. Chong, A. Shimamoto, C. R. Hampton, H. Takayama, D. J. Spring, C. L. Rothnie, M. Yada, T. H. Pohlman, and E. D. Verrier Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 170 - 179. [Abstract] [Full Text] [PDF]
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 J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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M. Levi, T. van der Poll, and H. R. Buller Bidirectional Relation Between Inflammation and Coagulation Circulation, June 8, 2004; 109(22): 2698 - 2704. [Full Text] [PDF]
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 R. A. Adams, M. Passino, B. D. Sachs, T. Nuriel, and K. Akassoglou Fibrin Mechanisms and Functions in Nervous System Pathology Mol. Interv., June 1, 2004; 4(3): 163 - 176. [Abstract] [Full Text] [PDF]
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C. Farina, D. Theil, B. Semlinger, R. Hohlfeld, and E. Meinl Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines Int. Immunol., June 1, 2004; 16(6): 799 - 809. [Abstract] [Full Text] [PDF]
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S. Kato, Y. Yuzawa, N. Tsuboi, S. Maruyama, Y. Morita, T. Matsuguchi, and S. Matsuo Endotoxin-Induced Chemokine Expression in Murine Peritoneal Mesothelial Cells: The Role of Toll-Like Receptor 4 J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1289 - 1299. [Abstract] [Full Text] [PDF]
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 K. Akassoglou, R. A. Adams, J. Bauer, P. Mercado, V. Tseveleki, H. Lassmann, L. Probert, and S. Strickland Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis PNAS, April 27, 2004; 101(17): 6698 - 6703. [Abstract] [Full Text] [PDF]
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H.-J. Anders, B. Banas, and D. Schlondorff Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease J. Am. Soc. Nephrol., April 1, 2004; 15(4): 854 - 867. [Abstract] [Full Text] [PDF]
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D. A. Armstrong, J. A. Major, A. Chudyk, and T. A. Hamilton Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury J. Leukoc. Biol., April 1, 2004; 75(4): 641 - 648. [Abstract] [Full Text] [PDF]
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K. Kariko, H. Ni, J. Capodici, M. Lamphier, and D. Weissman mRNA Is an Endogenous Ligand for Toll-like Receptor 3 J. Biol. Chem., March 26, 2004; 279(13): 12542 - 12550. [Abstract] [Full Text] [PDF]
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T. J. Murphy, H. M. Paterson, J. A. Mannick, and J. A. Lederer Injury, sepsis, and the regulation of Toll-like receptor responses J. Leukoc. Biol., March 1, 2004; 75(3): 400 - 407. [Abstract] [Full Text] [PDF]
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S. C.G. Hollestelle, M. R. de Vries, J. K. van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. van Middelaar, G. Pasterkamp, P. H.A. Quax, and D. P.V. de Kleijn Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling Circulation, January 27, 2004; 109(3): 393 - 398. [Abstract] [Full Text] [PDF]
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J.-L. Imler and L. Zheng Biology of Toll receptors: lessons from insects and mammals J. Leukoc. Biol., January 1, 2004; 75(1): 18 - 26. [Abstract] [Full Text] [PDF]
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 N. Ameziane, T. Beillat, P. Verpillat, S. Chollet-Martin, M.-C. Aumont, P. Seknadji, M. Lamotte, D. Lebret, V. Ollivier, and D. de Prost Association of the Toll-Like Receptor 4 Gene Asp299Gly Polymorphism With Acute Coronary Events Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): e61 - e64. [Abstract] [Full Text] [PDF]
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J. M. Rothfork, S. Dessus-Babus, W. J. B. Van Wamel, A. L. Cheung, and H. D. Gresham Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation J. Immunol., November 15, 2003; 171(10): 5389 - 5395. [Abstract] [Full Text] [PDF]
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C. G. Feng, C. A. Scanga, C. M. Collazo-Custodio, A. W. Cheever, S. Hieny, P. Caspar, and A. Sher Mice Lacking Myeloid Differentiation Factor 88 Display Profound Defects in Host Resistance and Immune Responses to Mycobacterium avium Infection Not Exhibited by Toll-Like Receptor 2 (TLR2)- and TLR4-Deficient Animals J. Immunol., November 1, 2003; 171(9): 4758 - 4764. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, A. Lentschat, D. B. Kuhns, J. C.G. Blanco, C. Salkowski, S. Zhang, M. Arditi, J. I. Gallin, and S. N. Vogel Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections J. Exp. Med., August 18, 2003; 198(4): 521 - 531. [Abstract] [Full Text] [PDF]
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H. M. Paterson, T. J. Murphy, E. J. Purcell, O. Shelley, S. J. Kriynovich, E. Lien, J. A. Mannick, and J. A. Lederer Injury Primes the Innate Immune System for Enhanced Toll-Like Receptor Reactivity J. Immunol., August 1, 2003; 171(3): 1473 - 1483. [Abstract] [Full Text] [PDF]
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I. Sabroe, L. R. Prince, E. C. Jones, M. J. Horsburgh, S. J. Foster, S. N. Vogel, S. K. Dower, and M. K. B. Whyte Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span J. Immunol., May 15, 2003; 170(10): 5268 - 5275. [Abstract] [Full Text] [PDF]
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W. C. Aird The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome Blood, May 15, 2003; 101(10): 3765 - 3777. [Abstract] [Full Text] [PDF]
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E. T. Abrams, H. Brown, S. W. Chensue, G. D. H. Turner, E. Tadesse, V. M. Lema, M. E. Molyneux, R. Rochford, S. R. Meshnick, and S. J. Rogerson Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated {beta} Chemokine Expression J. Immunol., March 1, 2003; 170(5): 2759 - 2764. [Abstract] [Full Text] [PDF]
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J. S. Palumbo, J. M. Potter, L. S. Kaplan, K. Talmage, D. G. Jackson, and J. L. Degen Spontaneous Hematogenous and Lymphatic Metastasis, but not Primary Tumor Growth or Angiogenesis, Is Diminished in Fibrinogen-deficient Mice Cancer Res., December 1, 2002; 62(23): 6966 - 6972. [Abstract] [Full Text] [PDF]
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L. Guillot, V. Balloy, F. X. McCormack, D. T. Golenbock, M. Chignard, and M. Si-Tahar Cutting Edge: The Immunostimulatory Activity of the Lung Surfactant Protein-A Involves Toll-Like Receptor 4 J. Immunol., June 15, 2002; 168(12): 5989 - 5992. [Abstract] [Full Text] [PDF]
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K. Dabbagh, M. E. Dahl, P. Stepick-Biek, and D. B. Lewis Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4524 - 4530. [Abstract] [Full Text] [PDF]
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I. Sabroe, E. C. Jones, L. R. Usher, M. K. B. Whyte, and S. K. Dower Toll-Like Receptor (TLR)2 and TLR4 in Human Peripheral Blood Granulocytes: A Critical Role for Monocytes in Leukocyte Lipopolysaccharide Responses J. Immunol., May 1, 2002; 168(9): 4701 - 4710. [Abstract] [Full Text] [PDF]
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F. M. Szaba and S. T. Smiley Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo Blood, February 1, 2002; 99(3): 1053 - 1059. [Abstract] [Full Text] [PDF]
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G. Zhang and S. Ghosh Negative Regulation of Toll-like Receptor-mediated Signaling by Tollip J. Biol. Chem., February 22, 2002; 277(9): 7059 - 7065. [Abstract] [Full Text] [PDF]
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