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,
Departments of
*
Pharmacology,
Pediatrics, and
Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, and IRAK-deficient mice withstand
the lethal effects of LPS. These findings, coupled with the critical
role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the
importance of this kinase and the IL-1/Toll signaling cassette in
sensing and responding to Gram-negative
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1. Purified
TNF- can recapitulate aspects of LPS-induced shock in vivo
(2), and IL-1 potentiates these actions of TNF-
(3). Furthermore, passive immunization against TNF-
protects animals from the lethal effects of LPS (4) and
IL-1 antagonism improves survival in some models of Gram-negative
septic shock (5).
LPS induces cytokine secretion by binding CD14, which in turn triggers
intracellular signal transduction cascades in many different cell types
(reviewed in Ref. 6). LPS-mediated TNF- production is
subject to both transcriptional and posttranscriptional controls and
requires intact signaling through at least three of these pathways.
LPS-induced TNF- transcription depends on NF-
B pathway activation
(7, 8), while the Jun N-terminal kinase
(JNK)4/stress-activated
protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK)
pathways regulate TNF mRNA translation (9, 10).
Furthermore, recent positional cloning of the murine Lps
locus and demonstration that Lpsd alleles
that cause impaired LPS responsiveness are mutant forms of the
Toll-like receptor 4 (Tlr4) gene have begun to clarify the
molecular basis for LPS signal transmission to the cell interior
(11).
TLR4 belongs to the Toll/IL-1R family. Members share a conserved cytoplasmic domain required for signal transduction to the cell interior (12, 13). Receptors for IL-1 and IL-18 activate a common intracellular pathway composed of the IL-1R-associated kinase (IRAK), MyD88, and TNF receptor-associated factor 6 (TRAF6) (14, 15, 16, 17, 18). Identification of TLR4 as the murine LPS signal transducer prompted us to ask whether LPS activated IRAK in relevant immune effector cells and to determine the role of this kinase in cellular and in vivo responses to LPS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IRAK-deficient mice were generated as described
(19). Sib-sib intercrosses between hybrid 129/B6 animals
produced wild-type mice. LPS from Escherichia coli K-12
(LCD25, from Robert Munford, University of Texas Southwestern Medical
Center) was used for in vitro experiments and from E. coli
O111:B4 (Sigma, St. Louis, MO) for in vivo challenges. Polyclonal
anti-IRAK antiserum (from Zhaodan Cao, Tularik, South San
Francisco, CA) was generated as described (16). Abs
recognizing extracellular signal-regulated kinase 2 (ERK2), p38, and
JNK/SAPK were previously described (9, 20). Anti-IB
kinase (IKK) Abs were purchased from Santa Cruz Biotechnology (Santa
Cruz, CA).
Macrophage isolation and stimulation
Thioglycollate-elicited macrophages were obtained as described
(21). LPS stock solution was thawed, sonicated, and
diluted to appropriate concentrations in medium. For TNF- production
experiments, macrophages were stimulated with the indicated
concentrations of LPS for 20 h before harvesting supernatants. For
in vitro kinase and EMSA studies, macrophages were treated with LPS (10
ng/ml) for different time periods.
In vitro kinase assays
Endogenous IKK-, IKK-ß, JNK/SAPK, and p38 were
immunoprecipitated from LPS-stimulated macrophages, and assays
determining kinase activity were performed as described (8, 9). For IRAK and ERK2, LPS-treated wild-type (WT) or knockout
(KO) macrophages were lysed and cleared by centrifugation. IRAK or ERK2
was immunoprecipitated using polyclonal rabbit sera. After washing,
immunoprecipitated IRAK or ERK2 was incubated in kinase buffer
containing myelin basic protein (MBP) (0.3 mg/ml) and
[
-32P]ATP (
10 µCi/sample) for 45 min.
Supernatants containing substrate were removed, added to SDS-loading
dye, boiled, and fractionated using SDS-PAGE. Once completed, gels were
processed and analyzed as previously described (8, 9).
Northern analysis
Total RNA was isolated from thioglycollate-elicited macrophages
stimulated with LPS (1 ng/ml) for indicated times. One microgram of
total RNA was fractionated, blotted, and probed with a radiolabeled
murine TNF- cDNA (from Bruce Beutler, University of Texas
Southwestern Medical Center), according to standard procedures. The
membrane was stripped and reprobed with a rat GAPDH cDNA (from Brett
Giroir, University of Texas Southwestern Medical Center) to control for
RNA loading.
EMSA
Nuclear extracts were prepared from saline- and LPS-treated
macrophages at different times following LPS stimulation as previously
described (22). After determination of total protein, 2.5
µg of extract protein was incubated for 30 min with a
32P-labeled double-stranded oligonucleotide probe
containing the NF-B binding site from the murine Ig -chain
promoter. Samples were then electrophoresed on a 5% acrylamide/0.5x
TBE nondenaturing gel. The gel was dried and autoradiography
performed.
In vivo LPS challenge
Statistical power analysis indicated a requirement for 45 animals per test group to detect a 25% mortality difference with 80% probability. Accordingly, 48 WT and 48 KO mice were injected with 500 µg/25 g body weight LPS. Animals were observed throughout the 7-day test period. Mortality and time of death were recorded.
Statistics
Two-way ANOVA followed by Bonferroni-corrected t
tests were used to determine significant differences in TNF-
production between WT and KO macrophages at each dose. Mortality from
in vivo LPS challenges was analyzed using a two-tailed Fisher’s
exact test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To demonstrate that LPS activates IRAK, we stimulated WT
thioglycollate-elicited macrophages with LPS, immunoprecipitated
endogenous IRAK, and measured IRAK catalytic activity. Although
physiologic IRAK substrates are unknown, the activated kinase can
phosphorylate permissive substrates such as MBP (23). As
shown in Fig. 1
, LPS activates IRAK in
macrophages. Activation occurs rapidly: it is detectable within 7.5 min
and reaches maximum activity by 15 min after LPS stimulation. Catalytic
activity declines quickly thereafter. LPS also triggers IRAK activity
in the murine macrophage cell line RAW 264.7, eliciting a catalytic
profile similar to that seen in primary macrophages (data not shown).
We also performed similar immunoprecipitation (IP)- kinase reactions in
LPS-treated KO macrophages. Anti-IRAK antiserum also precipitated a
weaker, signal-dependent kinase activity in cells lacking IRAK (Fig. 1). This catalytic activity peaked at 15 min after LPS stimulation,
exhibiting a 2-fold induction over baseline (compared with 4- to 5-fold
seen in WT macrophages). Nonimmune serum does not precipitate kinase
activity in this assay (data not shown).
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B pathway activation
We then wished to learn whether IRAK influenced LPS-triggered
downstream signaling cascades. We first examined signal transduction in
the pathway leading to NF-B activation, a critical event in the
initial host response to infection. NF-B activation occurs following
signal-dependent serine phosphorylation of the inhibitor proteins,
IB- and IB-ß by the IKKs, IKK- and IKK-ß
(24, 25, 26, 27, 28). Therefore, we tested the capacity of LPS to
activate IKK- and IKK-ß in IRAK-deficient and WT macrophages.
LPS-triggered IKK- activity is unaffected in KO macrophages (Fig. 2A). In contrast, IRAK exerts
a striking effect on LPS-mediated IKK-ß activity. IKK-ß reaches
peak catalytic activity more slowly in IRAK-deficient macrophages: 30
min vs 7.5 min in WT cells (Fig. 2B). Furthermore, in
IRAK-deficient cells, maximal LPS-induced IKK-ß activity is reduced
compared with WT macrophages. The differences in maximal catalytic
activity cannot be explained by reduced IKK concentrations in KO
macrophages, as both WT and IRAK-deficient cells contain equivalent
amounts of immunoreactive proteins (data not shown).
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B degradation and NF-B nuclear
translocation, promoter binding, and transcriptional up-regulation of
responsive genes, we tested whether LPS-induced NF-B DNA binding was
altered in IRAK-deficient macrophages. LPS-treated KO macrophages
exhibit reduced NF-B DNA binding activity compared with their
WT counterparts at each time point assayed (Fig. 2
C),
although binding activity at later time points in KO cells approaches
that seen in WT cells at earlier time points. This attenuation
parallels the retardation of peak IKK-ß activity in LPS-treated KO
macrophages. Thus, the decrease in IKK activity in KO cells results in
defective NF-B function. Therefore, IRAK optimizes LPS-triggered
signaling to NF-B activation through its effect on both timing and
maximal activation of downstream pathway members. Optimal LPS-induced activation of multiple MAPK pathways is IRAK dependent
LPS activates several MAPK pathways, at least two of which
directly regulate macrophage production of TNF- (8, 9, 29), an early mediator of the innate immune response to
Gram-negative infection. We examined IRAK’s influence on LPS-induced
MAPK signaling by stimulating WT and IRAK-deficient macrophages with
LPS and assessing the catalytic function of endogenous JNK/SAPK,
p38, and ERK2. As shown in Fig. 3,
A and B, activation of JNK/SAPK and p38 is
delayed in KO cells. Peak SAPK and p38 kinase activities are also
decreased in KO macrophages (Fig. 3, A and B).
Furthermore, LPS-dependent ERK2 activity is attenuated in macrophages
without IRAK (Fig. 3C). The differences in maximal catalytic
activity are not due to reduced SAPK, p38, or ERK2 concentrations in
IRAK-deficient macrophages, as both WT and KO cells contain similar
quantities of immunoreactive proteins (data not shown). Thus, IRAK is
required for appropriate timing of downstream kinase activity in two
MAPK pathways and maximal catalytic function in all three cascades.
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production
Demonstration of a requirement for IRAK in optimal
LPS-induced signaling to NF-B and the MAPK pathways led us to ask
whether this kinase mediated a relevant biologic response to LPS.
Because NF-B, JNK/SAPK, and p38 MAPK activation regulate TNF-
biosynthesis (8, 9, 10), we tested whether IRAK regulated
LPS-induced TNF- production. We first examined TNF- mRNA in
macrophages at different times after LPS treatment and saw no
discernible difference in net accumulation and decay between WT and KO
cells (Fig. 4A). We then
examined secretion of TNF- protein. Macrophages lacking IRAK exhibit
significant impairment in LPS-induced TNF- production at 0.1 ng/ml,
0.5 ng/ml, and 1 ng/ml (Fig. 4B). This reduction in TNF-
secretion is not due to IL-1ß secreted into the medium, as this
latter cytokine was undetectable at these LPS doses (data not shown).
The difference in TNF- secretion between WT and IRAK-deficient
macrophages persists at LPS concentrations up to 1.6 ng/ml (data not
shown). Higher LPS doses (>2 ng/ml) overcome the effect of IRAK
deletion on TNF- production (Fig. 4B and data not shown),
even though defective signaling still occurs at 10 ng/ml (see above).
Thus, IRAK mediates optimal LPS-stimulated macrophage TNF-
production, a critical host response to Gram-negative infection through
mechanisms independent of net mRNA accumulation.
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Having established the insensitivity of IRAK-deficient macrophages
to LPS and linked diminished TNF- production to disrupted
LPS-induced signal transduction, we then asked if IRAK-deficient mice
were resistant to the lethal effects of endotoxin. As seen in Fig. 5, 19 of 48 (40%) WT mice died when administered 500 µg/25 g body
weight, whereas only nine of 48 (19%) IRAK-deficient mice succumbed to
the same LPS dose. Thus, IRAK also participates in the response to
acute lethal endotoxemia.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B DNA binding,
both of which are required for signal-dependent NF-B transcriptional
activation (8). Macrophages lacking IRAK also exhibit
defective LPS-induced activation of three MAPK pathways. IRAK appears
to exert two major functions on the activity of these downstream
pathways. First, it enhances the kinetics of subsequent kinase cascade
activation. Second, it boosts peak catalytic activity of these kinases.
This dual effect on downstream kinase activation is also seen in
MyD88-deficient macrophages (30). Macrophages without IRAK
produce less TNF- in response to LPS than WT cells. The reduction in
TNF- may be related to a selective IRAK effect on translation of
TNF- mRNA, a process regulated by SAPK/JNK and p38 (9, 10, 31), as elimination of IRAK has no effect on the net
accumulation and decay of TNF- message. The diminished production of
this key proinflammatory cytokine persists over a >10-fold dose range.
Furthermore, mice without IRAK respond abnormally to high doses of LPS,
dying at a lower frequency than their WT counterparts. This difference
is detectable despite the engagement of multiple mechanisms to
compensate for genetic deletion of IRAK.
LPS-activated TLR4 may recruit MyD88 and IRAK to the activated receptor
complex, as occurs with the IL-1R1 (14, 15) (see Fig. 6).
Several lines of evidence support this notion. First, the cytoplasmic
domain of TLR4 conserves residues from the IL-1R1 required in
IL-1-mediated IRAK and NF-B activation and IL-8 gene expression
(12, 32). Second, macrophages from C3H/HeJ mice, which
express a mutant form of TLR4 but retain a WT Toll/IL-1R1 homology
domain (11), still respond to LPS with NF-B activation
(33). Third, cells from MyD88-deficient macrophages and
mice are hyporesponsive to LPS, exhibiting a more pronounced resistance
to LPS than IRAK-deficient cells and animals (30).
Furthermore, dominant negative versions of MyD88, IRAK, and TRAF6 also
inhibit NF-B activity triggered by a constitutively activated human
TLR4 (34, 35). Finally, in a single case report, cells
from a patient with multiple life-threatening Gram-negative and
Gram-positive bacterial infections exhibit discrete hyporesponsiveness
to LPS and IL-1 (36). Therefore, TLR4 may engage many of
the same signaling components as the IL-1R1, but documentation of a
signal-dependent interaction between TLR4, MyD88, and IRAK awaits
confirmation.
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B in one
IRAK-deficient cell line, supporting the notion that they may
substitute for IRAK in KO cells and mice (39). A second
possible explanation for residual signal transduction could be that
optimal LPS-induced signal transduction requires that the activities of
two or more proximal signaling molecules be detected by their
downstream targets. As our results indicate, IRAK may be required for
proper kinetics of kinase activation or assembly of signaling
molecules. Thus, in cells lacking IRAK, exposure to endotoxin leads to
suboptimal downstream effector activation.
Differences in TNF- production between WT and KO macrophages are
greatest at the lower end of the dose range tested (0.1–1 ng/ml),
whereas the distinction disappears at doses higher than 5 ng/ml.
Clinical studies suggest that the concentration range in which IRAK
functions is physiologically relevant. Patients with meningococcal
sepsis—a disease caused by the Gram-negative bacterium Neisseria
meningiditis and characterized by severe septic shock and
coagulation abnormalities—had serum LPS levels that ranged from 10 to
970 pg/ml in one study (40) and from 800 pg/ml to 300
ng/ml in another series with sicker patients (41). In the
second study, patients with serum LPS concentrations >3.8 ng/ml died
within minutes or hours of hospital admission, their normal host
defenses already overwhelmed by the infection. Although conclusions
from these clinical data must be tempered by several caveats
(bioactivity of LPS not determined, serum is not usual compartment
where LPS/bacteria and innate immune cells interact, and so forth),
these studies suggest that 1 ng/ml represents the upper limits of
"normal" LPS concentrations at the site of Gram-negative infection.
If this is indeed the case, IRAK clearly plays a critical role in
transducing the LPS signals that result in TNF- production, one of
the earliest and most important host responses to Gram-negative
infection.
IRAK may be an important target for treatment of severe Gram-negative infections, because even complete inhibition (or genetic deletion) of IRAK down-regulates, but does not obliterate, the host response to endotoxin. Complete blockade of endotoxin responsiveness is undesirable. Maintenance of immune competence is critical to contain and eliminate invasive bacteria. This point is highlighted by the finding that the recent increase in human sepsis-related mortality in the U.S. is due to the increasing numbers of immunodeficient patients (1). Thus, inhibiting IRAK activity could moderate an overexuberant inflammatory response, as occurs in septic shock, while retaining the host’s ability to fight infection. IRAK could also represent an attractive therapeutic target because its participation in at least three different steps in the response to Gram-negative infection. Inhibiting IRAK activity could temper the host response to Gram-negative infection at three sequential control points, obviating the need for three different extracellular agents—against LPS, IL-1, and IL-18—to accomplish a similar goal.
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Acknowledgments |
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Footnotes |
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2 Current address: Inflammation Therapeutics, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48105.
3 Address correspondence and reprint requests to Dr. James A. Thomas, Departments of Pediatrics and Molecular Biology, Room NA5.320A, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9148.
4 Abbreviations used in this paper: JNK, Jun N-terminal kinase; SAPK, stress-activated protein kinase; MAPK, mitogen-activated protein kinase; TLR4, Toll-like receptor 4; IRAK, IL-1R-associated kinase; TRAK6, TNF receptor-associated factor 6; ERK2, extracellular signal-regulated kinase 2; IKK, IB kinase; WT, wild type; KO, knockout; MBP, myelin basic protein; IP, immunoprecipitation.
Received for publication October 5, 1999. Accepted for publication February 7, 2000.
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Y. Huang, T. Li, D. C. Sane, and L. Li IRAK1 Serves as a Novel Regulator Essential for Lipopolysaccharide-induced Interleukin-10 Gene Expression J. Biol. Chem., December 3, 2004; 279(49): 51697 - 51703. [Abstract] [Full Text] [PDF]
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 J. W. Horton, J. Tan, D. J. White, D. L. Maass, and J. A. Thomas Selective decontamination of the digestive tract attenuated the myocardial inflammation and dysfunction that occur with burn injury Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2241 - H2251. [Abstract] [Full Text] [PDF]
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 D. D. Bannerman, K. T. Eiting, R. K. Winn, and J. M. Harlan FLICE-Like Inhibitory Protein (FLIP) Protects Against Apoptosis and Suppresses NF-{kappa}B Activation Induced by Bacterial Lipopolysaccharide Am. J. Pathol., October 1, 2004; 165(4): 1423 - 1431. [Abstract] [Full Text] [PDF]
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S. B. Pruett, C. Schwab, Q. Zheng, and R. Fan Suppression of Innate Immunity by Acute Ethanol Administration: A Global Perspective and a New Mechanism Beginning with Inhibition of Signaling through TLR3 J. Immunol., August 15, 2004; 173(4): 2715 - 2724. [Abstract] [Full Text] [PDF]
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S. Noubir, Z. Hmama, and N. E. Reiner Dual Receptors and Distinct Pathways Mediate Interleukin-1 Receptor-associated Kinase Degradation in Response to Lipopolysaccharide: INVOLVEMENT OF CD14/TLR4, CR3, AND PHOSPHATIDYLINOSITOL 3-KINASE J. Biol. Chem., June 11, 2004; 279(24): 25189 - 25195. [Abstract] [Full Text] [PDF]
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 D. S. Wheeler, J. D. Catravas, K. Odoms, A. Denenberg, V. Malhotra, and H. R. Wong Epigallocatechin-3-gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1{beta}-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells J. Nutr., May 1, 2004; 134(5): 1039 - 1044. [Abstract] [Full Text] [PDF]
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 Hongkuan Fan and J. A. Cook Review: Molecular mechanisms of endotoxin tolerance Innate Immunity, April 1, 2004; 10(2): 71 - 84. [Abstract] [PDF]
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H. Xiong, C. Zhu, F. Li, R. Hegazi, K. He, M. Babyatsky, A. J. Bauer, and S. E. Plevy Inhibition of Interleukin-12 p40 Transcription and NF-{kappa}B Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells J. Biol. Chem., March 12, 2004; 279(11): 10776 - 10783. [Abstract] [Full Text] [PDF]
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K. S. Kobayashi and R. A. Flavell Shielding the double-edged sword: negative regulation of the innate immune system J. Leukoc. Biol., March 1, 2004; 75(3): 428 - 433. [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. Suzuki, S. Suzuki, U. Eriksson, H. Hara, C. Mirtosis, N.-J. Chen, T. Wada, D. Bouchard, I. Hwang, K. Takeda, et al. IL-1R-Associated Kinase 4 Is Required for Lipopolysaccharide- Induced Activation of APC J. Immunol., December 1, 2003; 171(11): 6065 - 6071. [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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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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J. A. Thomas, S. B. Haudek, T. Koroglu, M. F. Tsen, D. D. Bryant, D. J. White, D. F. Kusewitt, J. W. Horton, and B. P. Giroir IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2003; 285(2): H597 - H606. [Abstract] [Full Text] [PDF]
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 D. D. Bannerman and S. E. Goldblum Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L899 - L914. [Abstract] [Full Text] [PDF]
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S. E. Doyle, R. O'Connell, S. A. Vaidya, E. K. Chow, K. Yee, and G. Cheng Toll-Like Receptor 3 Mediates a More Potent Antiviral Response Than Toll-Like Receptor 4 J. Immunol., April 1, 2003; 170(7): 3565 - 3571. [Abstract] [Full Text] [PDF]
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C. Deng, C. Radu, A. Diab, M. F. Tsen, R. Hussain, J. S. Cowdery, M. K. Racke, and J. A. Thomas IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity J. Immunol., March 15, 2003; 170(6): 2833 - 2842. [Abstract] [Full Text] [PDF]
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A. Dunne and L. A. J. O'Neill The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense Sci. Signal., February 25, 2003; 2003(171): re3 - re3. [Abstract] [Full Text] [PDF]
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Liwu Li, R. Jacinto, B. Yoza, and C. E. McCall Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes Innate Immunity, February 1, 2003; 9(1): 39 - 44. [Abstract] [PDF]
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K. Burns, S. Janssens, B. Brissoni, N. Olivos, R. Beyaert, and J. Tschopp Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4 J. Exp. Med., January 20, 2003; 197(2): 263 - 268. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, S.-C. Hong, and A.-K. Yi CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression J. Immunol., January 15, 2003; 170(2): 1052 - 1061. [Abstract] [Full Text] [PDF]
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S. Bozinovski, J. E. Jones, R. Vlahos, J. A. Hamilton, and G. P. Anderson Granulocyte/Macrophage-Colony-stimulating Factor (GM-CSF) Regulates Lung Innate Immunity to Lipopolysaccharide through Akt/Erk Activation of NFkappa B and AP-1 in Vivo J. Biol. Chem., November 1, 2002; 277(45): 42808 - 42814. [Abstract] [Full Text] [PDF]
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D. Haller, M. P. Russo, R. B. Sartor, and C. Jobin IKKbeta and Phosphatidylinositol 3-Kinase/Akt Participate in Non-pathogenic Gram-negative Enteric Bacteria-induced RelA Phosphorylation and NF-kappa B Activation in Both Primary and Intestinal Epithelial Cell Lines J. Biol. Chem., October 4, 2002; 277(41): 38168 - 38178. [Abstract] [Full Text] [PDF]
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 C. Schmitt, A. Humeny, C.-M. Becker, K. Brune, and A. Pahl Polymorphisms of TLR4: Rapid Genotyping and Reduced Response to Lipopolysaccharide of TLR4 Mutant Alleles Clin. Chem., October 1, 2002; 48(10): 1661 - 1667. [Abstract] [Full Text] [PDF]
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B. Billack, D. E. Heck, T. M. Mariano, C. R. Gardner, R. Sur, D. L. Laskin, and J. D. Laskin Induction of cyclooxygenase-2 by heat shock protein 60 in macrophages and endothelial cells Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1267 - C1277. [Abstract] [Full Text] [PDF]
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J. A. Thomas, M. F. Tsen, D. J. White, and J. W. Horton IRAK contributes to burn-triggered myocardial contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H829 - H836. [Abstract] [Full Text] [PDF]
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 M.M. Monick and G.W. Hunninghake Activation of second messenger pathways in alveolar macrophages by endotoxin Eur. Respir. J., July 1, 2002; 20(1): 210 - 222. [Abstract] [Full Text] [PDF]
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J. Radons, S. Gabler, H. Wesche, C. Korherr, R. Hofmeister, and W. Falk Identification of Essential Regions in the Cytoplasmic Tail of Interleukin-1 Receptor Accessory Protein Critical for Interleukin-1 Signaling J. Biol. Chem., May 3, 2002; 277(19): 16456 - 16463. [Abstract] [Full Text] [PDF]
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J. Hu, R. Jacinto, C. McCall, and L. Li Regulation of IL-1 Receptor-Associated Kinases by Lipopolysaccharide J. Immunol., April 15, 2002; 168(8): 3910 - 3914. [Abstract] [Full Text] [PDF]
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 P.-L. Wang and K. Ohura PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE SIGNALING IN GINGIVAL FIBROBLASTS-CD14 AND TOLL-LIKE RECEPTORS Critical Reviews in Oral Biology & Medicine, March 1, 2002; 13(2): 132 - 142. [Abstract] [Full Text] [PDF]
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D. D. Bannerman, J. C. Tupper, R. D. Erwert, R. K. Winn, and J. M. Harlan Divergence of Bacterial Lipopolysaccharide Pro-apoptotic Signaling Downstream of IRAK-1 J. Biol. Chem., March 1, 2002; 277(10): 8048 - 8053. [Abstract] [Full Text] [PDF]
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G. Wright, I. S. Singh, J. D. Hasday, I. K. Farrance, G. Hall, A. S. Cross, and T. B. Rogers Endotoxin stress-response in cardiomyocytes: NF-kappa B activation and tumor necrosis factor-alpha expression Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H872 - H879. [Abstract] [Full Text] [PDF]
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 N. Silverman and T. Maniatis NF-{kappa}B signaling pathways in mammalian and insect innate immunity Genes & Dev., September 15, 2001; 15(18): 2321 - 2342. [Full Text] [PDF]
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A. E. Medvedev, P. Henneke, A. Schromm, E. Lien, R. Ingalls, M. J. Fenton, D. T. Golenbock, and S. N. Vogel Induction of Tolerance to Lipopolysaccharide and Mycobacterial Components in Chinese Hamster Ovary/CD14 Cells Is Not Affected by Overexpression of Toll-Like Receptors 2 or 4 J. Immunol., August 15, 2001; 167(4): 2257 - 2267. [Abstract] [Full Text] [PDF]
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 M. A. Moors, L. Li, and S. B. Mizel Activation of Interleukin-1 Receptor-Associated Kinase by Gram-Negative Flagellin Infect. Immun., July 1, 2001; 69(7): 4424 - 4429. [Abstract] [Full Text] [PDF]
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C. Alexander and E. Th. Rietschel Invited review: Bacterial lipopolysaccharides and innate immunity Innate Immunity, June 1, 2001; 7(3): 167 - 202. [Abstract] [PDF]
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T. Kaisho, O. Takeuchi, T. Kawai, K. Hoshino, and S. Akira Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells J. Immunol., May 1, 2001; 166(9): 5688 - 5694. [Abstract] [Full Text] [PDF]
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M. M. Monick, A. B. Carter, P. K. Robeff, D. M. Flaherty, M. W. Peterson, and G. W. Hunninghake Lipopolysaccharide Activates Akt in Human Alveolar Macrophages Resulting in Nuclear Accumulation and Transcriptional Activity of {{beta}}-Catenin J. Immunol., April 1, 2001; 166(7): 4713 - 4720. [Abstract] [Full Text] [PDF]
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S. B. Haudek, E. Spencer, D. D. Bryant, D. J. White, D. Maass, J. W. Horton, Z. J. Chen, and B. P. Giroir Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H962 - H968. [Abstract] [Full Text] [PDF]
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A. Schmidt, E. Caron, and A. Hall Lipopolysaccharide-Induced Activation of {beta}2-Integrin Function in Macrophages Requires Irak Kinase Activity, p38 Mitogen- Activated Protein Kinase, and the Rap1 GTPase Mol. Cell. Biol., January 15, 2001; 21(2): 438 - 448. [Abstract] [Full Text]
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A. Visintin, A. Mazzoni, J. H. Spitzer, D. H. Wyllie, S. K. Dower, and D. M. Segal Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells J. Immunol., January 1, 2001; 166(1): 249 - 255. [Abstract] [Full Text] [PDF]
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Guolong Zhang and S. Ghosh Molecular mechanisms of NF-{kappa}B activation induced by bacterial lipopolysaccharide through Toll-like receptors Innate Immunity, December 1, 2000; 6(6): 453 - 457. [Abstract] [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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