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Divisions of
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Pediatric Infectious Diseases and
Pediatric Intensive Care, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, CA 90048; and
Department of Immunology, Mayo Clinic, Rochester, MN 55905
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B and HIV-LTR activation in HMEC
through IL-1 signaling molecules, namely myeloid differentiation
protein, IL-1R-associated kinase, TNFR-associated factor, and
NF-B-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase
and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates
LPS-induced HIV transcription as does the use of dominant-negative
mutants of the IL-1 signaling molecules. Transfection of HMEC with an
HIV-LTR-mutant that lacks the NF-B binding site or pretreatment of
cells with chemical inhibitors of the NF-B pathway also blocked
LPS-induced HIV-LTR transactivation. These data support the conclusion
that TLR4 mediates enterobacterial LPS-induced HIV transcription via
IL-1 signaling molecules and NF-B activation plays an important role
in HIV-LTR transactivation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
(3, 4, 5, 6, 7). The initiation of the cellular responses to LPS
has been shown recently to involve a human homologue of the
Drosophila Toll receptor, termed Toll-like receptor 4
(TLR4)3 (reviewed
in Ref. 8). Studies conducted over the past several years
have demonstrated that the Toll family of signaling receptors play a
crucial role in both Drosophila and mammalian innate immune
responses to microbial Ags (8, 9, 10). Genetic studies using
the mutant LPS-hyporesponsive C3H/HeJ and LPS nonresponsive
C57BL/10ScCr mouse strains have revealed that TLR4 functions as the
long sought signaling receptor that mediates enteric LPS-induced
cellular activation (reviewed in Ref. 10).
We have recently shown that endothelial cells and macrophages express
the TLR4 LPS receptor and respond to LPS through this membrane receptor
by induction of NF-B activation via IL-1R-associated signaling
molecules, including myeloid differentiation protein (MyD88),
IL-1R-activated kinase (IRAK), TNFR-associated factor-6 (TRAF6), and
NF-B-inducing kinase (NIK) (11). The nuclear
transcription factor NF-B, which has for many years been recognized
as a critical cytoplasmic target in LPS-initiated cell activation, is
also thought to play a major role in the regulation of HIV-1 gene
expression (12). Although the HIV long terminal repeat
(LTR) alone can serve as its own promoter, early mRNA transcription
appears to rely primarily on binding of cellular transcription factors,
including NF-B, to the LTR (13). The activation of
cytoplasmic NF-B by various stimuli, such as cytokines (e.g., IL-2,
IL-6, and TNF-
) or after infection with other viruses induces HIV
replication (14, 15, 16, 17, 18, 19). Microbes responsible for several
sexually transmitted diseases, opportunistic infections with
Gram-negative organisms such as Hemophilus influenza, and
coliform bacteria that cause enteritis are common in AIDS patients and
lead to increases in local and circulating levels of biologically
active LPS. Recently, virus levels in HIV-infected individuals were
reported to be higher in the genital-tract sheddings of patients
coinfected with sexually transmitted diseases such as Neisseria
gonorrhea and Chlamydia trachomatis (20).
These findings suggest increased rates of HIV replication in these
patients, most likely through NF-B-mediated regulation of the
HIV-LTR. Although activation of NF-B has been implicated in
LPS-induced enhancement of HIV replication, the receptor(s) and the
signaling mechanism involved have not to date been clearly defined.
In the studies reported here, we have examined the mechanism(s) of
LPS-mediated stimulation of HIV-1 replication in human dermal
endothelial cells (HMEC) transfected with an HIV-1- LTR luciferase gene
construct. We have determined the contribution of membrane TLR4 in LPS
induction of HIV-LTR transactivation, as well as the molecular
signaling mechanisms involved. Our results support the conclusion that
TLR4 mediates LPS-induced transactivation of HIV-LTR in HMEC via the
IL-1R-associated signaling molecules MyD88, IRAK, TRAF6, and NIK.
Furthermore, our findings indicate that LPS-induced transactivation of
HIV-LTR-luciferase is dependent on NF-B activation in this
experimental system and is modulated by both the p38 mitogen-activated
protein kinase (MAPK) and phosphatidylinositol 3 (PI3) kinase pathways.
A more complete understanding of the molecular mechanism(s) of
LPS-induced HIV replication is expected to have potential therapeutic
implications, as concurrent and opportunistic infections such as
sexually transmitted diseases in HIV-infected patients are known to be
associated with an increase in plasma HIV RNA (17).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The immortalized HMEC (a generous gift of Dr. F. J. Candal,
Centers for Disease Control and Prevention, Atlanta, GA.)
(21) were cultured in MCDB-131 medium supplemented with
10% heat-inactivated FBS, 2 mM glutamine, and 100 µg/ml penicillin
and streptomycin in 24-well plates. The cells were routinely used
between passages 10 and 14 as described earlier (11).
Tissue culture reagents were purchased from Life Technologies
(Rockville, MD). The NF-B proteasome inhibitor I was purchased from
Calbiochem (San Diego, CA),
15-Deoxy-
12,14-PGJ2
(15d-PGJ2) was purchased from Cayman Chemical
(Ann Arbor, MI), and PI3 kinase inhibitor LY294002 was obtained from
Biomol (Plymouth Meeting, PA). Highly purified, phenol-water-extracted
Escherichia coli K235 LPS (<0.008% protein), which was
prepared according to the method of McIntyre et al. (22),
was generously provided by Dr. Stefanie Vogel (Uniformed Services
University of Health Sciences, Bethesda, MD). All reagents were
verified to be LPS-free by the Limulus amebocyte lysate
assay (<0.03 endotoxin U/ml; Pyrotell; Associates of Cape Cod, Woods
Hole, MA).
Expression vectors
Dominant-negative cDNA constructs of MyD88, IRAK, TRAF6, and NIK
have been characterized and described earlier (11, 23, 24, 25); C3H/HeJ TLR4 cDNA (0.5 µg) was a generous gift from
Dr. Bruce Beutler (University of Texas Southwestern Medical Center,
Dallas, TX); dominant-negative IKK
was a kind gift from Dr. Michael
Karin (University of California, San Diego, CA). The HIV-LTRwt-Luc and
a mutant lacking the NF-B binding site (HIV-LTRB-Luc)
expression vectors have been described previously (26).
Briefly, they carry U2 + R regions of the HIV-LTR (laboratory adapted
xytropic HIV-1 isolate (LAI) strain) from nucleoside -644
(XhoI) to +78 (HindIII), except
that the tandem B-responsive elements were deleted in
HIV-LTRB-Luc and replaced by the consensus sequence for
BclI (27). Endothelial leukocyte adhesion
molecule (ELAM)-NF-B-luciferase and pCMV--galactosidase vectors
were used as described previously (11).
Transfection of HMEC
HMEC were plated at a concentration of 50,000 cells/well in
24-well plates and cultured overnight in MCDB-131 with 10% serum as
described above. Cells were cotransfected the following day with FuGene
6 transfection reagent (Boehringer Mannheim, Indianapolis, IN)
according to the manufacturer’s instructions. The reporter genes
pCMV--galactosidase (0.1 µg), HIV-LTRwt-Luc (0.5 µg), or
HIV-LTRB-Luc expression vectors (0.5 µg), as well as
dominant-negative mutants of MyD88, IRAK, TRAF6, or NIK (0.5 µg
each), were transfected into HMEC as reported previously
(28). Reporter genes pCMV--galactosidase (0.1 µg) and
C3H/HeJ TLR4 (0.5 µg) were cotransfected with either HIV-LTR
wild-type (0.5 µg) or HIV-LTR-B luciferase construct (0.5
µg). pCMV--galactosidase was transfected to normalize the results
for transfection efficiency as described earlier (11).
Cells were transfected for 24 h and then stimulated for 6 h
with 50 ng/ml LPS suspended in growth medium or with recombinant human
TNF- (20 ng/ml; Genzyme, Cambridge, MA). Cells then were lysed and
luciferase activity was measured with a Promega kit (Promega, Madison,
WI) and a luminometer. -galactosidase activity was determined by
calorimetric method as described earlier (11). For
experiments using chemical inhibitors, the overnight-transfected HMEC
were pretreated for 1 h with chemical inhibitors of various
signaling molecules, including 15d-PGJ2 (10
µM), which has been found to block NF-B activation via specific
inhibition of inhibitory B (IB) kinase (IKK)
(29), PI3 kinase inhibitor LY294002 (20 µM), proteasome
inhibitor (100 µM), or p38 MAPK inhibitor SB203580 (20 µM). The
cells then were stimulated with either LPS (50 ng/ml) or human TNF-
(20 ng/ml) for 6 h. These inhibitors did not affect the viability
of HMEC at the concentrations used, as assessed by trypan blue staining
(data not shown).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In HIV-infected patients, opportunistic infections, including
Gram-negative bacterial infections, lead to an increase in plasma HIV
RNA levels, suggesting an induction of virus replication
(16, 17, 18, 19). To assess possible mechanisms that might be
responsible for these observations, we evaluated the role of the
Gram-negative bacterial cell wall component LPS on HIV replication by
investigating LPS-stimulated HIV-LTR transactivation in vitro. Because
we have shown previously that LPS can activate human endothelial cells
through a mechanism involving activation of the transcription factor
NF-B via TLR4 (28), we used HMEC for the
HIV-LTR-luciferase transfection experiments. In HMEC previously
transfected with HIV-LTR-luciferase construct, the addition of LPS
efficiently transactivates HIV-LTR in a dose-dependent manner (Fig. 1
). However, under otherwise identical
experimental conditions, LPS was unable to induce transactivation of
HIV-LTR-B, which lacks the NF-B binding site (Fig. 1). These
results indicate that LPS stimulates HMEC activation of intracellular
signaling pathways, which leads to enhancement of HIV-1 LTR
transactivation, and that NF-B activation is important in this
event.
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Because enterobacterial LPS activates HMEC through TLR4
(28), we undertook experiments to investigate the
functional role of TLR4 in LPS-induced HIV-LTR transactivation in HMEC.
For these studies, HMEC were transiently cotransfected with C3H/HeJ
TLR4 cDNA. In C3H/HeJ mice, a missense mutation in the cytoplasmic
domain of TLR4 allows this mutant TLR4 to act as a dominant-negative
molecule, most likely by sequestering the downstream adapter and
signaling molecules (e.g., MyD88 and IRAK1), thus preventing
LPS-induced signaling and NF-B activation (30, 31, 32).
Cells were also transfected with the HIV-LTR-dependent luciferase gene
and then tested for their responses to LPS by measuring the luciferase
activity. In the absence of C3H/HeJ TLR4 cDNA, LPS induces a high level
of luciferase activity. However, transient transfection of the C3H/HeJ
TLR4 cDNA construct blocked the LPS-induced HIV-LTR activation in a
dose-dependent manner (Fig. 2). As
anticipated, the C3H/HeJ TLR4 cDNA was without significant effect on
TNF--induced HIV-LTR transactivation (data not shown). These
findings suggest that the functional TLR4 expressed on HMEC and the
associated TLR4-mediated signaling pathway play important roles in
LPS-mediated HIV-1-LTR-dependent transcription.
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The IL-1 signaling pathway in mammals is strikingly similar to the
Toll-signaling pathway in Drosophila (33, 34, 35, 36).
LPS activates NF-B through IL-1R-associated signaling molecules in
human endothelial cells, namely adapter protein MyD88, IRAK, TRAF6, and
the protein kinase NIK (11). Therefore, we examined
whether similar or identical signaling mechanisms were involved in
LPS-induced HIV-LTR transactivation. For these studies, HMEC were
transiently cotransfected with the HIV-LTR-luciferase construct and
dominant-negative mutants of the IL-1R-associated signaling elements.
Dominant-negative constructs for MyD88 (MyD88), IRAK (IRAK),
TRAF-6 (TRAF6), and NIK (NIK) all significantly inhibited
LPS-mediated HIV-LTR-dependent reporter gene expression (Fig. 3). Overexpression of the empty vector
had no detectable effect on LPS-induced HIV-LTR transactivation.
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B is important for induction of HIV-LTR
transactivation
Potent activators of NF-B, such as IL-1, TNF-, or LPS,
induce rapid phosphorylation of the IKK complex (e.g., IKK, IKK,
IKK
) (37, 38, 39). Phosphorylated IB is then
polyubiquitinylated and targeted for rapid degradation by the 26S
proteasome, thus allowing the liberation and translocation of NF-B
into the nucleus. Inhibition of the activity of 26S proteasome by
proteasome inhibitor I has been shown to block the degradation of
IB and block the activation, the nuclear translocation, and DNA
binding of NF-B (40). To investigate further the
participation of NF-B in LPS-induced HIV-LTR transactivation, HMEC
were transfected with a dominant-negative construct of IKK
(IKK) along with HIV-LTR-dependent reporter gene, and luciferase
activity was measured after 5 h of LPS stimulation. In separate
experiments, HMEC were pretreated with the proteasome inhibitor I (100
µM) for 1 h, and the HIV-LTR-luciferase activity was then
assessed after LPS stimulation. The inhibition of NF-B activation by
transient transfection of IKK (Fig. 3
) or by preincubating the
cells with proteasome inhibitor I (Fig. 4) prevented LPS-induced HIV-LTR
transactivation. These observations, together with our findings that
LPS is unable to induce transactivation of HIV-LTR-B, support the
conclusion that LPS-TLR4-induced NF-B activation is required for HIV
replication in the experimental system that we used.
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Cyclopentene PGs (cyPGs) have been reported to exert
anti-inflammatory activity through the activation of peroxisome
proliferator-activated receptor-
(PPAR-) (41, 42, 43, 44, 45).
The bioactive cyPG, 15d-PGJ2, which is
physiologically formed by dehydration and isomerization of
cyclooxygenase metabolite PGD2, can activate
PPAR-, a nuclear receptor that interferes with NF-B
transcriptional activity (41, 43). A recent study has
demonstrated a novel mechanism of the anti-inflammatory activity of
cyPGs that appears to be PPAR- independent and is based upon a
direct inhibition and modification of the IKK subunit of IKKs
(29), resulting in blocking of NF-B DNA binding. To
investigate the potential role of 15d-PGJ2 on
LPS-induced HIV-LTR transcription, we pretreated HIV-LTRwt-luciferase
transfected-HMEC with 15d-PGJ2 (10 µM) for
1 h before LPS stimulation. 15d-PGJ2 also
completely blocked the LPS-induced HIV-LTR-luciferase activity (Fig. 4), as well as NF-B activation (data not shown). These findings
further support the important role of NF-B activation in LPS-induced
HIV-LTR transactivation. Our observations also suggest that bioactive
cyPGs, such as 15d-PGJ2, and possibly more potent
derivatives, may potentially be useful for down-modulating LPS-induced
HIV replication.
Role of PI3 kinase on LPS-induced HIV-LTR transactivation
PI3 kinase has been shown previously to be activated rapidly after
LPS stimulation (46). PI3 kinase regulates the activation
of p65/RelA by phosphorylation and transactivation of p65/RelA
(47). PI3 kinase is also involved in TNF--mediated
activation of NF-B-dependent genes; the inhibition of PI3 kinase
activity by wortmannin or LY294002 has been reported to greatly
potentiate TNF--induced apoptosis (48). However, the
interaction between the PI3 kinase pathway and the LPS-TLR4-mediated
NF-B signaling pathway is not well understood. To study the role of
the PI3 kinase pathway in LPS-induced HIV-LTR transcription, we
pretreated HMEC with the PI3 kinase inhibitor LY294002 (20 µM) for
1 h before LPS stimulation. Pretreatment of HMEC with LY294002
significantly blocked LPS-induced HIV-LTR-dependent reporter gene
activation (Fig. 4). These findings suggest that PI3 kinase plays a
role in LPS-TLR4-mediated NF-B activation and HIV-LTR transcription.
PI3 kinase inhibitors strongly block NF-B p65 phosphorylation and
inhibit both PI3 kinase and NF-B transactivation and
NF-B-dependent gene expression but have no effect on degradation of
IB, nuclear translocation, or the ability of NF-B to bind DNA
(47).
Role of p38 MAPK activation on LPS-induced HIV-LTR transactivation
The cytoplasmic enzyme p38 MAPK present in monocytes and
endothelial cells is activated by a variety of environmental stresses,
as well as UV light, LPS, and inflammatory cytokines (49, 50). In monocytes, inhibition of the p38 MAPK pathway blocks the
LPS-induced production of IL-1 and TNF- (51, 52). In T
lymphocytes, p38 MAPK contributes to HIV-LTR activation by IL-1,
TNF-, UV light, and osmotic stress, which can be blocked by the p38
MAPK inhibitor SB203580 (53). The NF-B sites in
HIV-1-LTR are required for p38 MAPK-mediated responses to cytokines
(53), and a recent study showed that p38 MAPK pathway is
required for NF-B activation (54). We next investigated
the role of p38 MAPK pathway in LPS-TLR4-induced HIV-1-LTR
transactivation. HMEC transfected with HIV-LTRwt-luciferase construct
were preincubated with the specific p38 MAPK inhibitor (SB203580) for
60 min and stimulated with LPS for 5 h. Pretreatment of cells with
SB203580 inhibited the LPS-induced HIV-LTR-dependent luciferase
activity (Fig. 4), as well as NF-B-luciferase activity (data not
shown). The inhibition was 
50%, which is consistent with a previous
report showing a similar degree of inhibition of TNF--induced
HIV-LTR activation by the p38 MAPK inhibitor SB203580
(55). These observations support the concept that, in
addition to PI3 kinase, the p38 MAPK pathway also contributes to
LPS-induced NF-B activation and HIV-LTR transactivation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B through TLR4 and IL-1 signaling molecules,
namely MyD88, IRAK, TRAF6, and NIK. The activation of NF-B is
important and required for LPS-induced HIV-1 transcription in
endothelial cell system that we used because an
HIV-LTRB-luciferase construct lacking the NF-B binding site
could not be activated by LPS. However, our data were obtained in an
endothelial cell system, and HIV-LTR expression can be differentially
regulated on different cell types. Indeed, in HIV-susceptible monocytic
cell lines, LPS-induced HIV-LTR transactivation was shown to be
mediated by transcription factor PU.1, which is specifically expressed
in monocytes in addition to NF-B (56). Furthermore, we
have shown that p38 MAPK and PI3 kinase are also involved in LPS
induction of HIV-1 LTR. Thus, we conclude that the innate immune
receptor TLR4 mediates enterobacterial LPS-induced HIV-LTR
transactivation via IL-1R-associated signaling molecules and that
LPS-mediated HIV transcription is dependent on the activation of
NF-B and modulated by the p38 MAPK and the PI3 kinase pathways.
The expression of integrated HIV-1 is controlled at the level of
transcription by cellular factors and the viral transactivator Tat,
acting through the HIV-1-LTR (57, 58, 59). The HIV-1-LTR
contains cis acting elements required for
transcription initiation as well as binding sites for several
transcription factors, including NF-B. The activation of HIV-1 gene
expression by many extracellular stimuli is critically dependent on
activation of NF-B, which is known to bind to two B sites within
the HIV-1-LTR enhancer region (27, 60, 61). The
predominant complex binding to the LTR B sites in activated cells is
NF-B p50-p65 heterodimer. In unstimulated cells, NF-B is
restricted to the cytoplasm through its interaction with inhibitor
proteins belonging to IB family. Activation of NF-B occurs
through phosphorylation and proteolysis of the IB inhibitor, with
subsequent translocation of the active NF-B into the nucleus, where
it can bind to its cognate binding sites (62). Multiple
factors can induce translocation of NF-B into the nucleus, including
Gram-negative bacterial LPS. Although LPS is known to be a very potent
stimulator of HIV-1 replication in latently HIV-1-infected monocytic
cell line (U1 cells) through the activation of NF-B
(63), the cellular signaling mechanisms and the
receptor(s) involved in LPS induction of HIV replication have not been
fully defined. While CD14 was shown to play a role in LPS-induced HIV
replication (64), this GPI-linked receptor lacks an
intracytoplasmic tail and therefore is not capable of providing
intracellular signals. Recent studies have established that TLR4 is the
primary signaling receptor for enterobacterial LPS. TLR4 contains a
cytoplasmic domain that is homologous to the signaling domain of the
IL-1R and activation of TLR4 results in activation of NF-B via
IL-1R-associated signaling molecules (11). Our results
reported here suggest that TLR4 is responsible for LPS induction of
HIV-LTR transactivation. Because TLR4-induced NF-B activation
pathway shares IL-1R signaling molecules (11), it is of
interest to note that IL-1 has also been shown to induce HIV-LTR
transactivation and HIV replication (65). Furthermore,
IL-1 and TNF- concentrations were shown to be consistently elevated
in cervical secretions during bacterial vaginosis, which was recently
identified as a cofactor that promotes sexual transmission of HIV
(66).
In HIV-1-infected patients, concurrent infections with Gram-negative bacteria are associated with increased plasma HIV RNA levels, suggesting LPS-enhanced HIV replication in vivo. LPS also has been shown to enhance HIV replication in monocytic cell lines in vitro (63); however, several other in vitro studies reported that LPS induces resistance of macrophages to HIV infection (67, 68, 69). This apparent discrepancy was suggested to be the result of several potential factors, including the protective effect of LPS-induced cytokines/chemokines, the activation state of the cells, and induction of a negative regulatory factor that may have an inhibitory effects on HIV-LTR and viral expression (67, 68, 69, 70). One recent study reported a differential expression pattern of Toll receptors on human leukocytes and found that TLR4 is undetectable in resting or activated human T lymphocytes, although it is readily detectable in myelomonocytic cells (71). The exposure of human monocytes to bacterial products such as LPS or to proinflammatory cytokines increased TLR4 expression. Of potential importance, TLR4 expression by LPS was blocked after IL-10 treatment (71). These novel observations on differential expression patterns of Toll receptors on human leukocytes may also help explain the contradictory published findings regarding LPS effects on HIV replication in various cells.
Macrophages, which are thought to be the initial target cells of HIV infection and one of the major HIV reservoirs, play a crucial role in the overall host immune responses to HIV, especially in the polarization of Th cell responses to Th1 and Th2 cells through the production of IL-12 and IL-10 (72, 73, 74). We and others have recently shown a preferential replication pattern of chemokine receptors CCR5 and CXCR4 tropic primary HIV-1 isolates in Th1 and Th2 cells, respectively (75, 76). One well-characterized property of LPS is its ability to induce a low responsive state termed "LPS tolerance" in macrophages exposed to low levels of LPS priming (77). Furthermore, LPS "reprogramming" of macrophages have been shown to lead to up-regulation of IL-12 production and down-regulation of IL-10 production, which subsequently influences the Th1 and Th2 cell balance (78, 79). HIV-infected patients may be continuously exposed to low levels of LPS in vivo, during intercurrent infections, sexual intercourse, and i.v. drug use, which may lead to "reprogramming" of their macrophages and, as a consequence, significantly influence the cytokine environment. Reprogramming of macrophages may subsequently effect the susceptibility to HIV infection and efficiency of HIV replication. Therefore, understanding the molecular mechanisms and receptors involved in LPS induction of HIV replication may have important implications for the understanding of HIV immunopathogenesis.
In summary, our data indicate that TLR4 mediates the LPS induction of
NF-B activation and HIV-LTR transactivation through the
IL-1R-associated signaling molecules MyD88, IRAK, TRAF-6, as well as
p38 MAPK and PI3 kinase. To our knowledge, this is the first time that
LPS-TLR4 signaling and NF-B activation are being linked to increased
HIV replication via HIV-LTR transactivation and that the
LPS-TLR4-NF-B activation pathway is being tied to the PPAR- and
PI3 kinase pathways. Our results also suggest that the cyPG,
15d-PGJ2, and possibly more potent derivatives
may have potential therapeutic value in preventing LPS-mediated
enhancement of HIV replication during opportunistic bacterial
infections where suppression of NF-B activity may be desirable.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ozlem Equils, Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Shuman Trailer, Los Angeles, CA 90048.
3 Abbreviations used in this paper: TLR, Toll-like receptor; HMEC, human dermal microvessel endothelial cells; IRAK, IL-1R-associated kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation protein; NIK, NF-B-inducing kinase; TRAF, TNFR-associated factor; LTR, long terminal repeat; cyPg, cyclopentene PG; PI3, phosphatidylinositol 3; PPAR, peroxisome proliferator-activated receptor; IB, inhibitory B; IKK, IB kinase; 15d-PGJ2, 15-deoxy-12–14-PGJ2.
Received for publication August 25, 2000. Accepted for publication November 30, 2000.
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 X. Yang and D. L. Cox-Foster Impact of an ectoparasite on the immunity and pathology of an invertebrate: Evidence for host immunosuppression and viral amplification PNAS, May 24, 2005; 102(21): 7470 - 7475. [Abstract] [Full Text] [PDF]
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 O. Equils, A. Shapiro, Z. Madak, C. Liu, and D. Lu Human Immunodeficiency Virus Type 1 Protease Inhibitors Block Toll-Like Receptor 2 (TLR2)- and TLR4-Induced NF-{kappa}B Activation Antimicrob. Agents Chemother., October 1, 2004; 48(10): 3905 - 3911. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. Schito, D. Chaussabel, and A. Sher Influence of Coinfecting Pathogens on HIV Expression: Evidence for a Role of Toll-Like Receptors J. Immunol., June 15, 2004; 172(12): 7229 - 7234. [Abstract] [Full Text] [PDF]
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O. Equils, Z. Madak, C. Liu, K. S. Michelsen, Y. Bulut, and D. Lu Rac1 and Toll-IL-1 Receptor Domain-Containing Adapter Protein Mediate Toll-Like Receptor 4 Induction of HIV-Long Terminal Repeat J. Immunol., June 15, 2004; 172(12): 7642 - 7646. [Abstract] [Full Text] [PDF]
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J. B. Sundstrom, D. M. Little, F. Villinger, J. E. Ellis, and A. A. Ansari Signaling through Toll-Like Receptors Triggers HIV-1 Replication in Latently Infected Mast Cells J. Immunol., April 1, 2004; 172(7): 4391 - 4401. [Abstract] [Full Text] [PDF]
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 F. Sandor, E. Latz, F. Re, L. Mandell, G. Repik, D. T. Golenbock, T. Espevik, E. A. Kurt-Jones, and R. W. Finberg Importance of extra- and intracellular domains of TLR1 and TLR2 in NF{kappa}B signaling J. Cell Biol., September 15, 2003; 162(6): 1099 - 1110. [Abstract] [Full Text] [PDF]
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O. Equils, M. L. Schito, H. Karahashi, Z. Madak, A. Yarali, K. S. Michelsen, A. Sher, and M. Arditi Toll-Like Receptor 2 (TLR2) and TLR9 Signaling Results in HIV-Long Terminal Repeat Trans-Activation and HIV Replication in HIV-1 Transgenic Mouse Spleen Cells: Implications of Simultaneous Activation of TLRs on HIV Replication J. Immunol., May 15, 2003; 170(10): 5159 - 5164. [Abstract] [Full Text] [PDF]
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P. O. Neilsen, G. A. Zimmerman, and T. M. McIntyre Escherichia coli Braun Lipoprotein Induces a Lipopolysaccharide-Like Endotoxic Response from Primary Human Endothelial Cells J. Immunol., November 1, 2001; 167(9): 5231 - 5239. [Abstract] [Full Text] [PDF]
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