Department of Immunology, The Scripps Research Institute, La Jolla, California
Correspondence: Richard J. Ulevitch, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: ulevitch{at}scripps.edu
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: intracellular signaling • interleukin-1 • transforming growth factor ß-activated kinase-1
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B kinases, and PKB/Akt. These
effectors control proliferative and/or apoptotic changes depending on
the stimulus and cell type. Although a number of key upstream molecules
in these signaling pathways have been identified, there are still
substantial gaps in our knowledge, including the identity(ies) of
members of the MAP kinase kinase kinase family (MAPKKK).
Transforming growth factor (TGF) ß-activated kinase 1 (TAK1), a
member of the MAPKKK family, was first reported as a regulator of MAP
kinase signaling induced by TGF-ß [1
, 2
].
TAK1 was also shown to be involved in BMP signaling in early
Xenopus development [3
] and in Wnt signaling
in Drosophila [4
]. Most recently, TAK1 was
reported to be activated by stress signals as well as proinflammatory
cytokines [5
], including the IL-1 signaling pathway
[6
]. TAK1 has also been reported to play a role in
LPS-induced NF-B activation [7
].
We demonstrate that TAK1 plays a central and essential role in
LPS-induced activation of p38, c-Jun amino terminal kinase (JNK), and
I-B kinase (IKK) in pre-B and myeloid lineage cell lines. However,
TAK1 is not essential for LPS-induced activation of ERK1/ERK2 or for
stress kinase activation induced by hyperosmolarity. Surprisingly, we
also found that TAK1 also plays a role in LPS-induced PKB/Akt
activation. Finally, in at least one cell line, TAK1 is involved in
intracellular signaling pathways leading to cell survival that may be
mediated by PKB/Akt.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TNF-) and IL-1ß were purchased from Endogen. Wortmannin,
LY294002, Z-VAD, Ac-DEVD, PD98059, SB20358, okadaic acid, and
insulin-like growth factor 1 (IGF-1) were all obtained from Calbiochem.
Prostaglandin A1 (PGA1) was from Sigma.
Cell culture
70Z/3 and THP-1 cells were grown in RPMI supplemented with 10%
fetal bovine serum (Hyclone Laboratories), 2 mM glutamine, 50 µM
ß-mercaptoethanol, and 100 µg/mL streptomycin. 293-HEK cells were
maintained in Dulbecco’s modified Eagle’s medium supplemented with
10% fetal bovine serum (Hyclone Laboratories), 2 mM glutamine, and 100
µg/mL streptomycin.
Expression constructs
HA-tagged TAK1 (WT) and TAK1 (K63W) [2
]
were cloned by polymerase chain reaction (PCR) into the retroviral
vector pBMN-Z-I-Blasto (a gift from G. P. Nolan, Stanford
University) by introducing Bam HI site at the 5’-end and Eco RI at the
3’-end. p85-
iSH2-N (p85) was directly cloned into the Eco RI
site of pBMN-Z-I-Blasto. The preparation and use of retrovirus is as
described [9
].
Establishment of stable transfectants
70Z/3 and THP-1 cells were infected with
pBMN-TAK1(WT)-I-Blasto, pBMN-TAK1(K63W)-I-Blasto, or
pBMN-p85-I-Blasto as described [9
], and infected
cells were selected by growth in the presence of 10 µg/mL of
blasticidine S (Calbiochem). 293-Human embryonic kidney cells were
transfected with pBMN-Z-I-Blasto or pBMN-TAK1(K63W)-I-Blasto by the
calcium phosphate precipitation method and selected in the medium
containing blasticidine S (10 µg/mL).
Apoptosis assay
70Z/3 cells expressing LacZ, TAK1 (WT), or TAK1 (K63W) were
treated with 1 ng of LPS for 4 h, and the amount of programmed
cell death was monitored by TUNEL (TdT-mediated UTP nick-end labeling)
assay according to the manufacturer’s instructions (Boehringer
Mannheim).
In vitro kinase assays
After stimulation as noted in the figure legends, cells
were lysed (lysis buffer: 20 mM Tris, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1
mM EGTA, 1% Triton X-100, 1 mM glycerophosphate, 2.5 mM sodium
pyrophosphate, 1 mM sodium orthovanadate, 2 µg/mL aprotinin, 1 mM
phenylmethylsulfonyl fluoride). The kinase to be studied was
immunoprecipitated and the immune complexes were washed successively in
lysis buffer containing 0.5 M NaCl and kinase buffer (25 mM Tris, pH
7.5, 10 mM MgCl2, 2 mM EGTA, 1 mM dithiothreitol, and 1 mM
sodium orthovandate). The properties of anti-p38 monoclonal
antibody are described elsewhere [10
]; antibody to JNK
and antibody to ERK1/2 were purchased from Santa Cruz Biotechnology.
p38 and JNK kinase activity were measured with a nonradioactive method
(New England Biolabs) using phosphospecific antibodies against ATF-2 or
c-Jun, respectively. Kinase reactions were carried out at 37°C for 20
min. In some specified experiments activation of p38 was measured with
anti-phospho-p38 antibodies (New England Biolabs). ERK1 and TAK1 kinase
activity were measured in a 20-min assay through the use of MBP or MKK3
as the substrate, respectively. Kinase reaction for IKKß was
performed as described [11
]. The fold activation of
kinase activity was quantified either with a densitometer for
nonradioactive assays or with a PhosphorImager (Molecular Dynamics) for
radioactive assays. Activation of PKB/Akt was monitored with
anti-phospho-Akt antibodies (New England Biolabs).
NF-B activation
An electrophoretic mobility shift assay was used to determine
the presence of NF-B in nuclear extracts as described
[12
].
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 View larger version (14K): [in a new window] |
Figure 1. (A) TAK1 is activated by LPS. 70Z/3-hCD14 cells (1 x
105 cells/sample) were stimulated with LPS (Re595, 1 µg)
for indicated periods and endogenous TAK1 was immunoprecipitated with
anti-TAK1 antibodies (Santa Cruz Biotech); the kinase activity was
measured using recombinant MKK3 as a substrate. (B) Expression of TAK1
(WT) and TAK1 (K63W) in 70Z/3 or THP-1 cells was confirmed by
immunoblotting with anti-HA antibodies (Boehringer Mannheim). Note that
TAK1 (K63W) migrates faster than TAK1 (WT) on SDS-PAGE.
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B pathway. The experiments shown
in Figure 2 A-D
, are performed with 70Z/3-hCD14 cells expressing
either TAK1 (WT) or TAK1 (K63W) as noted. After stimulation with LPS or
IL-1, endogenous p38 or JNK was immunoprecipitated and in
vitro kinase assays were used to assess enzyme activity.
Expression of TAK1 (K63W) in 70Z/3 cells prevented activation of the
two stress MAP kinases (Fig. 2A)
. In studies not shown we determined
that this effect of TAK1 (K63W) was observed over a wide range of
agonist concentrations. The effect of TAK1 (K63W) on stress kinase
activation does not reflect a general disablement of these pathways
because exposure of cells to hyperosmolar sorbitol leads to p38
activation when TAK1 (K63W) is expressed in 70Z/3 (Fig. 2B)
or THP-1 cell line (data not shown). Thus TAK1 is an important upstream
component of the stress kinase pathways leading to p38 and JNK
activation by some pro-inflammatory stimuli like LPS or IL-1. However,
as shown here, other stimuli such as hyperosmolarity activate the MAP
kinases by a TAK1-independent pathway.
 View larger version (39K): [in a new window] |
Figure 2. TAK1 mediates p38, JNK, and IKKß activation by LPS or IL-1 in
70Z/3 cells. (A) Endogenous p38 and JNK were recovered from LPS-treated
70Z/3-hCD14 cells [TAK1 (WT) or TAK1 (K63W)] by immunoprecipitation
with specific antibody as described in Materials and Methods after
various times as noted; the kinase activity in the immunoprecipitates
was measured with a nonradioactive kinase assay method (New England
Biolabs). (B) p38 activation by hyperosmolarity is independent of TAK1.
70Z/3-hCD14 cells expressing TAK1 (WT) or TAK1 (K63W) were stimulated
for 30 min with the indicated amount of LPS or 0.5 M sorbitol (S), and
after recovery of endogenous p38 by immunoprecipitation the kinase
activity was measured as above. (C) IKKß activation by LPS or IL-1 is
dependent on TAK1. Cells were stimulated with LPS (100 ng) or IL-1 (1
ng) for the indicated periods, and IKKß activities were measured as
described in Materials and Methods. (D) Translocation of NF-B to
nucleus by LPS stimulation was not significantly affected in TAK1
(K63W) cells. 70Z/3 cells were stimulated 1 h with the indicated
amount of LPS, and EMSA was performed as described in Materials and
Methods. (E) LPS activates ERK1 in a TAK1-independent manner.
Endogenous ERK1 was immunoprecipitated after exposure to LPS for 30
min; the kinase activity was measured using myelin basic protein (MBP)
as substrate as described in Materials and Methods.
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B is a hallmark of stimulation by LPS and IL-1.
Thus we next asked whether TAK1 is upstream of the NF-B pathway. To
do this we immunoprecipitated the NF-B activation complex containing
the IKKß at various times after the addition of LPS or IL-1. The
immunoprecipitates were used to measure the kinase activity of the
endogenous IKKß in unstimulated or stimulated control or TAK1 (K63W)
cell lines. IKKß activation by LPS or IL-1 was prevented by
expression of TAK1 (K63W) (Fig. 2C)
. However, we did not observe any
significant inhibition in LPS-induced NF-B translocation to nucleus
in TAK1 (K63W) cells (Fig. 2D)
. Treatment of 70Z/3-hCD14 cells with LPS
also leads to an increase in the activity of ERK1/ERK2; in marked
contrast to the effects on the stress-activated kinases, expression of
TAK1 (K63W) failed to inhibit ERK activation (Fig. 2E) .
We obtained a similar set of data with THP-1 cells; p38 and IKK
activation by LPS or IL-1 was dependent on TAK1 activity (Fig. 3 A
and C
). As a distinction, p38 and IKKß
activation induced by TNF- of THP1-hCD14 cells was independent of
TAK1 (Fig. 3B
and 3C
, respectively). In totality these data show that
TAK1 is a central and essential component of signaling pathways
activated by LPS and IL-1.
 View larger version (40K): [in a new window] |
Figure 3. TAK1 mediates activation of p38 and IKKß by LPS or IL-1 in THP-1
cells. (A) LPS or IL-1 activates p38 in a TAK1-dependent manner. Cells
were stimulated for 30 min with the indicated amount of stimuli and p38
was immunoprecipitated with monoclonal anti-p38 antibodies for
kinase assay. (B) Activation of p38 by TNF- is independent of TAK1.
Kinase activities were measured as above after stimulation with 20 ng
of TNF- for the indicated time periods. (C) LPS but not TNF-
activates IKKß in a TAK1-dependent fashion. LPS (100 ng) or TNF-
(20 ng) was used to stimulate cells and IKKß activities were measured
in vitro with GST-IB as a substrate.
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 View larger version (31K): [in a new window] |
Figure 4. (A) 70Z/3-hCD14 cells expressing TAK1 (K63W) undergo apoptosis upon LPS
stimulation. 70Z/3-hCD14 cells expressing with LacZ, TAK1 (WT), or TAK1
(K63W) were treated with 1 ng of LPS for 4 h; a TUNEL assay was
performed as described by the manufacturer (Boehringer Mannheim). (B)
LPS-induced apoptosis is abolished by anti-CD14 antibodies (28C5, 1
µg/mL) or caspase inhibitors, 1 µM Z-VAD or 10 µM Ac-DEVD.
Antibodies were added 30 min before LPS stimulation and inhibitors at
the time of stimulation. Apoptosis was measured with TUNEL assay. (C)
LPS activates PKB/Akt but not IL-1 in 70Z/3 cells; phosphorylation of
PKB/Akt on Ser473 in total cell extracts was detected by
antibodies specific for phospho-PKB/Akt (New England Biolabs). (D)
LPS-induced activation of PKB/Akt is dependent on TAK1. 70Z/3-hCD14
cells expressing TAK1 (WT) or TAK1 (K63W) were stimulated with 100 ng
of LPS for the indicated time period or 1 µM okadaic acid (OA) for 30
min.
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We next sought to determine what other kinases might be involved in LPS-induced PKB activation. Pretreatment of 70Z/3 cells with PI3-K inhibitors, wortmannin (WM) or LY294002 (LY), prevented LPS-induced PKB/Akt activation (Fig. 5A ). Others have suggested a role of the p38 pathway in PKB/Akt activation [23 , 24 ]. However, the p38 inhibitor, SB20358, did not prevent LPS-induced PKB/Akt activation at the concentrations that p38 activation is inhibited (Fig. 5B and 5C .) LPS-induced activation of IKK was also independent of PI3-K (Fig. 5D) . In contrast, inclusion of PGA1, an inhibitor of IKKß [25 ], did prevent LPS-induced IKKß activation. We also asked whether TAK1 is upstream of PKB when other activators are used. Expression of TAK1 (K63W) in 293-HEK cells (Fig. 5E) failed to block PKB/Akt activation by IGF-1 or H2O2 (Fig. 5F) .
 View larger version (20K): [in a new window] |
Figure 5. LPS activates PKB/Akt in 70Z/3-hCD14 cells in a PI3-K-dependent
manner. (A) Activation of PKB/Akt by LPS is dependent on PI3-kinase.
70Z/3-CD14 cells were preincubated with 100 nM wortmannin (WM) or 10
µM LY294002 (LY) for 30 min before 30 min stimulation with 100 ng of
LPS. (B) Activation of PKB/Akt by LPS is independent of p38.
70Z/3-hCD14 cells were preincubated with SB20358 (SB) for 30 min before
LPS stimulation. (C) LPS-induced activation of p38 is independent of
PI3-K. 70Z/3 cells were preincubated with SB or LY for 30 min before
LPS stimulation for 30 min, and activation of p38 was measured with
anti-phospho-p38 antibodies (New England Biolabs). (D) LPS activates
IKKß independently of PI3-K. 70Z/3 cells were preincubated with LY or
PGA1 (prostaglandin A1) for 30 min before LPS
stimulation. (E) Expression of TAK1 (K63W) in 293-HEK cells detected
with anti-HA antibodies. Note that there are two nonspecific bands
detected by anti-HA antibodies, one above and one below the HA-TAK1
band. HEK 293 cells were stably transfected using a LacZ control vector
or one containing TAK1 (K63W). (F) Activation of PKB/Akt by
H2O2 or IGF-1 is independent of TAK1 in 293-HEK
cells. Cells were incubated in serum-free DMEM for 4 h before
stimulation, and total cell lysates were subject to SDS-PAGE followed
by immunoblotting with anti-phospho-Akt antibodies.
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iSH2-N
or p85) [26
] was expressed in 70Z/3 cells. Expression
of p85 leads to inhibition of LPS-induced PKB/Akt activation without
affecting activation of p38 or JNK by LPS (Fig. 6A
). Furthermore the presence of p85-iSH2-N results in
LPS-induced apoptosis (Fig. 6B) . PI3-K inhibitors (LY294002 or
wortmannin) sensitized cells to LPS-induced apoptosis while inhibitors
of either the p38 (SB20358) or the classical ERK pathway (PD98059)
failed to do so (data not shown). Thus both TAK1 and PI3-K play
essential roles in transducing information from stress signals like LPS
to the PKB/Akt pathway. In contrast TAK1, but not PI3-K, is involved in
steps leading to p38, JNK, and IKK activation.
 View larger version (25K): [in a new window] |
Figure 6. (A) Expression of p85 (dominant-negative) leads to inhibition of
LPS-induced activation of PKB/Akt but not p38 and JNK. 70Z/3 cells
expressing LacZ or p85 were stimulated with the indicated amount of
LPS for 30 min and activation of Akt, p38, or JNK from total cell
extracts was monitored with phospho-specific antibody to Akt, p38, or
JNK (Santa Cruz Biotech), respectively. Expression of p85 was
detected with anti-p85 antibodies (Upstate Biotechnology) and p85
overlaps p85-WT on Western blot. (B) LPS induces apoptosis in 70Z/3
cells expressing p85 in a similar manner seen in 70Z/3-TAK1 (K63W)
cells. Cells were stimulated for 4 h with LPS (1 ng) before
apoptosis assay.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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First we showed that endogenous TAK1 is activated by LPS using
recombinant MKK3 as substrate. In studies not shown here we also
determined that LPS induced incorporation of 32P into TAK1
protein. Whether this results from an autophosphorylation or from the
effects of an upstream kinase is under investigation. To determine
whether TAK1 controls downstream events after LPS stimulation we used
retroviral infection to establish stable cell lines expressing either
wild-type or kinase-inactive TAK1. In these studies we used two cells
lines developed in our laboratory where we have expressed human CD14;
both the 70Z/3-hCD14 and THP1-hCD14 cell lines demonstrate marked
increased sensitivity to LPS and retain responsiveness to other stimuli
[13
, 14
]. In both cell lines we observed a
selective blockade of LPS-induced activation of the stress kinases p38
and JNK but not of ERK. Similar findings were obtained using IL-1 as a
stimulus. In contrast, expression of TAK1 (K63W) did not prevent stress
kinase activation induced by hyperosmolar sorbitol. Furthermore
expression of TAK1 (K63W) failed to block TNF- stimulation of p38 in
THP1-hCD14 cells. Thus TAK1 has a selective function regulating
pathways leading to p38 and JNK activation.
We also show here that TAK1 is upstream of IKKß because expression of
TAK1 (K63W) blocks activation of this kinase in LPS-treated cells. In
contrast, IKKß activation by TNF is not prevented in cells
expressing the kinase-inactive TAK1. Our findings confirm and extend
the recently published report of Irie et al. [7
]. In
contrast to IKKß kinase activities, the induction of NF-B
translocation to nucleus by LPS or IL-1 was not significantly affected
in both 70Z/3 (Fig. 2D) and THP-1 (data not shown) cells expressing
TAK1 (K63W). Although the mechanism is not clear, it is possible that
the residual activity of IKK in TAK1 (K63W) cells is enough to induce
translation of NF-B.
To our surprise, 70Z/3 cells expressing TAK1 (K63W) undergo marked apoptosis after stimulation with LPS but not IL-1. In contrast a similar phenomenon was not observed in THP-1 cells expressing TAK1 (K63W). We considered the possibility that in the pre-B cell line LPS activates a survival signal downstream of TAK1. Others have noted that LPS activates PI3-K and PKB/Akt, both of which are linked to survival pathways. Here we provide data supporting the contention that in 70Z/3-hCD14 cells LPS, but not IL-1 activates PKB; this event is completely blocked in cells expressing TAK1 (K63W). LPS-induced PKB activation is also prevented by pharmacological inhibitors of PI3-K as well as by expression of a dominant-negative form of the p85 subunit of p85 [26 ]. Inhibition of LPS-induced activation of Akt/PKB with either PI3-K inhibitors or overexpression of a PI3-K dominant-negative mutant leads to apoptosis in 70Z/3 cells in the same manner seen in cells expressing TAK1 (K63W). These results indicate that LPS-induced PKB activation is dependent not only on PI3-K but TAK1 as well. In contrast, LPS-induced activation of p38, JNK, and IKK by LPS is not dependent on PI3-K because inhibitors of PI3-K did not prevent activation of these kinases. Finally, we show data supporting the contention that TAK1 is on an LPS pathway leading to PKB activation and that this is a relatively specific pathway. The growth factor IGF-1 or hydrogen peroxide treatment of 293-HEK cells leads to PKB activation; this occurs similarly in control and cell-expressing TAK1 (K63W). These data indicate that PKB is an effector of a LPS-driven survival pathway in pre-B cells and this signal is mediated by TAK1 in cooperation with PI3-K. The exact mechanism whereby TAK1 is involved in PKB activation is currently under investigation. Recently others have suggested an involvement of TAK1 in apoptosis in other experimental systems, including Drosophila [4 ] and BMP2-induced apoptosis [27 ].
Received May 13, 2000; revised July 25, 2000; accepted July 28, 2000.
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I. Sabroe, R. C. Read, M. K. B. Whyte, D. H. Dockrell, S. N. Vogel, and S. K. Dower Toll-Like Receptors in Health and Disease: Complex Questions Remain J. Immunol., August 15, 2003; 171(4): 1630 - 1635. [Full Text] [PDF]
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J. Lee, T.-H. Chuang, V. Redecke, L. She, P. M. Pitha, D. A. Carson, E. Raz, and H. B. Cottam Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7 PNAS, May 27, 2003; 100(11): 6646 - 6651. [Abstract] [Full Text] [PDF]
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M. D. Wheeler and R. G. Thurman Up-regulation of CD14 in Liver Caused by Acute Ethanol Involves Oxidant-dependent AP-1 Pathway J. Biol. Chem., February 28, 2003; 278(10): 8435 - 8441. [Abstract] [Full Text] [PDF]
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 M. A. E. Frevel, T. Bakheet, A. M. Silva, J. G. Hissong, K. S. A. Khabar, and B. R. G. Williams p38 Mitogen-Activated Protein Kinase-Dependent and -Independent Signaling of mRNA Stability of AU-Rich Element-Containing Transcripts Mol. Cell. Biol., January 15, 2003; 23(2): 425 - 436. [Abstract] [Full Text] [PDF]
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 K. Howe, J. Gauldie, and D. M. McKay TGF-beta effects on epithelial ion transport and barrier: reduced Cl- secretion blocked by a p38 MAPK inhibitor Am J Physiol Cell Physiol, December 1, 2002; 283(6): C1667 - C1674. [Abstract] [Full Text] [PDF]
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M. Guha and N. Mackman The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells J. Biol. Chem., August 23, 2002; 277(35): 32124 - 32132. [Abstract] [Full Text] [PDF]
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M. G. Sanna, J. da Silva Correia, Y. Luo, B. Chuang, L. M. Paulson, B. Nguyen, Q. L. Deveraux, and R. J. Ulevitch ILPIP, a Novel Anti-apoptotic Protein That Enhances XIAP-mediated Activation of JNK1 and Protection against Apoptosis J. Biol. Chem., August 16, 2002; 277(34): 30454 - 30462. [Abstract] [Full Text] [PDF]
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 R. M Smith, S. Lecour, and M. N Sack Innate immunity and cardiac preconditioning: a putative intrinsic cardioprotective program Cardiovasc Res, August 15, 2002; 55(3): 474 - 482. [Abstract] [Full Text] [PDF]
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Y. Qian, Z. Zhao, Z. Jiang, and X. Li Role of NFkappa B activator Act1 in CD40-mediated signaling in epithelial cells PNAS, July 9, 2002; 99(14): 9386 - 9391. [Abstract] [Full Text] [PDF]
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 M. R. Saban, N.-B. Nguyen, T. G. Hammond, and R. Saban Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation Am. J. Pathol., June 1, 2002; 160(6): 2095 - 2110. [Abstract] [Full Text] [PDF]
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H.-K. Lee, J. Lee, and P. S. Tobias Two Lipoproteins Extracted from Escherichia coli K-12 LCD25 Lipopolysaccharide Are the Major Components Responsible for Toll-Like Receptor 2-Mediated Signaling J. Immunol., April 15, 2002; 168(8): 4012 - 4017. [Abstract] [Full Text] [PDF]
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M. G. Sanna, J. d. S. Correia, O. Ducrey, J. Lee, K. Nomoto, N. Schrantz, Q. L. Deveraux, and R. J. Ulevitch IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition Mol. Cell. Biol., March 15, 2002; 22(6): 1754 - 1766. [Abstract] [Full Text] [PDF]
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