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PubMed2002

Involvement of MyD88 in host defense and the down-regulation of anti-heat shock protein 70 autoantibody formation by MyD88 in Toxoplasma gondii-infected mice.

This study investigated the influence of TLR (toll-like receptor)4, TLR2, and MyD88 in Toxoplasma gondii-infected wild-type (WT) mice and TLR4-, TLR2-, and MyD88-deficient mice. Ninety-five percent of MyD88-deficient mice died 10-16 days after intraperitoneal infection with 100 cysts of T. gondii Fukaya strain, whereas 95-100% of TLR4- and TLR2-deficient mice and WT C57BL/6 (B6) mice survived for more than 7 wk after T. gondii infection. The distribution of T. gondii in various organs of TLR4-, TLR2-, and MyD88-deficient mice and WT B6 mice was assessed 2 wk after T. gondii intraperitoneal infection using quantitative competitive polymerase chain reaction. In MyD88-deficient mice, high levels of T. gondii load were observed in the brain, tongue, heart, lungs, spleen, liver, mesenteric lymph node, and kidneys after infection. The T. gondii load was significantly increased in the lungs in both TLR4- and TLR2-deficient mice compared with WT B6 mice. High levels of anti-mouse heat shock protein (mHSP)70 autoantibody and anti-T. gondii HSP70 antibody production were detected in the sera from MyD88-deficient mice.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Lipopolysaccharide transport system across colonic epithelial cells in normal and infective rat.

To clarify whether lipopolysaccharide (LPS) is transported in rat intestinal epithelial cells, the transport of FITC-LPS across colonic epithelial cells in normal and LPS-exposured rats using a diffusion chamber was examined. The expression of CD14 and Toll-like receptor 4 (TLR4) was also examined. Rats were given 10 mg/kg LPS i.p. injection at 4 hr prior to the isolation of colonic epithelial tissues. The permeation rate across colonic mucosa by FITC-LPS was several times greater in the mucosal to serosal (M to S) direction than in the opposite direction in both normal and LPS-exposured rats. Increased M to S permeation by FITC-LPS was evident at 37 degrees C, but not at 4 degrees C. The permeability of FITC-LPS in both the M to S and S to M directions was inhibited by unlabeled LPS, anti-CD14 antibody or anti-TRL4 antibody in normal rat. In LPS-exposured rat, the inhibition in the M to S direction was observed by anti-TLR4 antibody, but not by unlabeled LPS and anti- CD14 antibody. In contrast, the permeability in the S to M direction was decreased only by unlabeled LPS in LPS-exposured rat. In normal rat, the expression of CD14 and TLR4 was found in the mucosal and serosal sides. In LPS-exposured rat, the expression of CD14 was not observed in the mucosal side. The electrophysiological parameters by LPS exposure remain unchanged. These findings suggest the possibility that colonic epithelial cells contain specific transport systems for LPS, one of which shows some degree of substrate specificity with the interaction of CD14 and/or that of TLR4.

Animals↗
PubMed2006

Association of toll-like receptor 4 polymorphisms with somatic cell score and lactation persistency in Holstein bulls.

Mastitis, an inflammatory disease of the mammary gland generally caused by intramammary infections, is the most frequently occurring disease in the North American dairy industry. Reduced milk yield, milk quality, and lactation persistency as well as early culling contribute to the economic losses associated with this disease. During intramammary infections, cells of the innate immune system become activated through pattern recognition receptors that recognize conserved molecular signatures associated with the invading pathogen. The quality, timing, and intensity of the host inflammatory and subsequent immune response determine the fate of this disease. Toll-like receptor 4 (TLR4) is an important pattern recognition receptor that recognizes endotoxins associated with gram-negative bacterial infections. Its role in pathogen recognition and subsequent initiation of the inflammatory and immune response makes it a suitable candidate gene for enhancing disease resistance in Canadian Holsteins. In this study, polymorphisms in the TLR4 gene were identified in the Canadian Holstein bull population. Genotypes and haplotypes were constructed, and their associations with somatic cell score and lactation persistency were determined. Sequencing of selective DNA pools was used to reveal polymorphisms in TLR4. Two DNA pools were constituted based on high and low estimated breeding values for somatic cell scores. A total of 3 single nucleotide polymorphisms (SNP), including 1 SNP in a putative promoter region (P-226) and 2 SNP in exon3 (E3+1656 and E3+2021) of TLR4 were detected. A total of 388 bulls were genotyped for the SNP, haplotypes were reconstructed, and their frequencies were obtained. Polymorphisms in these regions were found to be associated with estimated breeding values for lactation persistency, and somatic cell scores in the Canadian Holstein bull population. The unfavorable alleles at P-226 and E3+1656 were found at a frequency of 40 and 37%, respectively; hence, selection against these alleles is promising in Canadian Holsteins. Selection against the unfavorable allele, T at E3+2021, is limited because of its low frequency (7%). Two frequently occurring haplotypes (GCC and CTC) occurred in 86% of the Canadian Holstein bull population chosen for genotyping. The most frequent haplotype (GCC; 54%) was found to be associated with higher lactation persistency and lower somatic cell scores. The transversion SNP in the putative promoter region (P-226) was in a potential DNA binding site.

Animals↗
PubMed2000

Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex.

Human heat shock protein 60 (hsp60) elicits a potent proinflammatory response in cells of the innate immune system and therefore has been proposed as a danger signal of stressed or damaged cells. We report here that macrophages of C3H/HeJ mice, carrying a mutant Toll-like-receptor (Tlr) 4 are nonresponsive to hsp60. Both the induction of TNF-alpha and NO formation were found dependent on a functional Tlr4 whereas stimulation of macrophages by CpG DNA was Tlr4 independent. We conclude that Tlr4 mediates hsp60 signaling. This is the first report of a putative endogenous ligand of the Tlr4 complex.

Animals↗
PubMed2000

Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression.

Monocytes/macrophages exposed to LPS show reduced responses to second stimulation with LPS, which is termed LPS tolerance. In this study, we investigated molecular mechanism of LPS tolerance in macrophages. Mouse peritoneal macrophages pre-exposed to LPS exhibited reduced production of inflammatory cytokines in a time- and dose-dependent manner. Activation of neither IL-1 receptor-associated kinase nor NF-kappaB was observed in macrophages that became tolerant by LPS pretreatment, indicating that the proximal event in Toll-like receptor 4 (TLR4)-MyD88-dependent signaling is affected in tolerant macrophages. Although TLR4 mRNA expression significantly decreased within a few hours of LPS pretreatment and returned to the original level at 24 h, the surface TLR4 expression began to decrease within 1 h, with a gradual decrease after that, and remained suppressed over 24 h. A decrease in inflammatory cytokine production in tolerant macrophages well correlates with down-regulation of the surface TLR4 expression, which may explain one of the mechanisms for LPS tolerance.

Animals↗
PubMed2000

Regulation of toll-like receptor 2 expression by macrophages following Mycobacterium avium infection.

Recent studies have implicated Toll-like receptors (TLR), especially TLR2 and TLR4, as sentinel receptors that signal the interaction of macrophages with bacterial pathogens via a NF-kappaB-mediated pathway. The regulation of TLR gene expression, however, has not been intensively studied. Here, we report that TLR2 mRNA was induced following infection of murine macrophages with Mycobacterium avium. The changes in TLR2 mRNA correlated with an increase in TLR2 surface expression. Infection with M. avium resulted in a concomitant decrease in TLR4 mRNA. The effect of M. avium infection on TLR2 mRNA appeared to be mediated, in part, by TLR2 because the induction of the mRNA was partially blocked by preincubation of the macrophages with an anti-human TLR2 Ab. In contrast, the effect of LPS stimulation was mediated via TLR4 because infection of macrophages from LPS(d) mice, which do not express active TLR4, resulted in an increase in TLR2 mRNA, while treatment of macrophages from these mice with LPS failed to induce TLR2 mRNA. Several cytokines, including TNF-alpha, IL-1alpha, and GM-CSF, but not IFN-gamma, induced TLR2 mRNA. M. avium infection resulted in the induction of TLR2 mRNA by macrophages from both TNFRI knockout and NF-kappaB p50 knockout mice.

Animals↗
PubMed2001

Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo.

The adaptive immune system has evolved distinct responses against different pathogens, but the mechanism(s) by which a particular response is initiated is poorly understood. In this study, we investigated the type of Ag-specific CD4(+) Th and CD8(+) T cell responses elicited in vivo, in response to soluble OVA, coinjected with LPS from two different pathogens. We used Escherichia coli LPS, which signals through Toll-like receptor 4 (TLR4) and LPS from the oral pathogen Porphyromonas gingivalis, which does not appear to require TLR4 for signaling. Coinjections of E. coli LPS + OVA or P. gingivalis LPS + OVA induced similar clonal expansions of OVA-specific CD4(+) and CD8(+) T cells, but strikingly different cytokine profiles. E. coli LPS induced a Th1-like response with abundant IFN-gamma, but little or no IL-4, IL-13, and IL-5. In contrast, P. gingivalis LPS induced Th and T cell responses characterized by significant levels of IL-13, IL-5, and IL-10, but lower levels of IFN-gamma. Consistent with these results, E. coli LPS induced IL-12(p70) in the CD8alpha(+) dendritic cell (DC) subset, while P. gingivalis LPS did not. Both LPS, however, activated the two DC subsets to up-regulate costimulatory molecules and produce IL-6 and TNF-alpha. Interestingly, these LPS appeared to have differences in their ability to signal through TLR4; proliferation of splenocytes and cytokine secretion by splenocytes or DCs from TLR4-deficient C3H/HeJ mice were greatly impaired in response to E. coli LPS, but not P. gingivalis LPS. Therefore, LPS from different bacteria activate DC subsets to produce different cytokines, and induce distinct types of adaptive immunity in vivo.

Animals↗
PubMed2003

Cumulative Toll-like receptor activation in human macrophages treated with whole bacteria.

Purified components from bacteria selectively activate Toll-like receptors (TLR), leading to shared and unique responses in innate immune cells. Whole bacteria contain agonists for multiple TLR and induce a common macrophage activation program of transcription. It is not known, however, whether the stimulation of specific TLR by whole bacteria results in differential activation of the innate immune system. We evaluated gene expression data from human macrophages and found a unique gene expression profile induced by Gram-negative bacteria. In contrast, Gram-positive bacteria evoked few specific alterations in gene expression. LPS, a TLR4-specific ligand, was sufficient to elicit the distinct expression profile observed with Gram-negative bacteria. TLR4 activation regulated gene expression by both an IFN-dependent and an IFN-independent mechanism, illustrated by I-TAC and IL-12 p70, respectively. IL-12 p70 was produced by cells in whole blood exposed to Gram-negative bacteria, demonstrating faithful reproduction of the macrophage response in mixed populations of cells and identifying a potential diagnostic marker of infection. Our results show that the macrophage response to bacteria is dominated by the accumulated input from multiple TLR. For macrophages exposed to Gram-negative bacteria, gene expression changes encompass those induced by Gram-positive bacteria plus a distinct TLR4 response. This distinct TLR4 response may provide the basis to diagnose clinical Gram-negative infections.

Cells, Cultured↗
PubMed2003

Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology.

Signaling through Toll-like receptors (TLR) activates dendritic cell (DC) maturation and IL-12 production, which directs the induction of Th1 cells. We found that the production of IL-10, in addition to inflammatory cytokines and chemokines, was significantly reduced in DCs from TLR4-defective C3H/HeJ mice in response to Bordetella pertussis. TLR4 was also required for B. pertussis LPS-induced maturation of DCs, but other B. pertussis components stimulated DC maturation independently of TLR4. The course of B. pertussis infection was more severe in C3H/HeJ than in C3H/HeN mice. Surprisingly, Ab- and Ag-specific IFN-gamma responses were enhanced at the peak of infection, whereas Ag-specific IL-10-producing T cells were significantly reduced in C3H/HeJ mice. This was associated with enhanced inflammatory cytokine production, cellular infiltration, and severe pathological changes in the lungs of TLR4-defective mice. Our findings suggest that TLR-4 signaling activates innate IL-10 production in response to B. pertussis, which both directly, and by promoting the induction of IL-10-secreting type 1 regulatory T cells, may inhibit Th1 responses and limit inflammatory pathology in the lungs during infection with B. pertussis.

Administration, Inhalation↗
PubMed2004

Intracellular bacterial infection-induced IFN-gamma is critically but not solely dependent on Toll-like receptor 4-myeloid differentiation factor 88-IFN-alpha beta-STAT1 signaling.

Infection of murine bone marrow-derived macrophages (BMMphi) with Chlamydia pneumoniae induces IFN-alphabeta-dependent IFN-gamma secretion that leads to control of the intracellular bacterial growth. Enhanced growth of C. pneumoniae in Toll-like receptor (TLR) 4(-/-) and myeloid differentiation factor (MyD) 88(-/-) (but not TLR2(-/-), TLR6(-/-), or TLR9(-/-)) BMMphi is shown in this study. Reduced accumulation of IFN-alpha and IFN-gamma mRNA was also observed in TLR4(-/-)- and MyD88(-/-)-infected cells. IL-1R and IL-18R signaling did not account for differences between MyD88(-/-) and wild-type BMMphi. Surprisingly, infection-induced NF-kappaB activation as well as TNF-alpha, IL-1, or IL-6 mRNA expression were all normal in TLR4(-/-) and MyD88(-/-) cells. Phosphorylation of the transcription factor STAT1 during bacterial infection is IFN-alphabeta dependent, and necessary for increased IFN-gamma mRNA accumulation and chlamydial growth control. Signaling through common cytokine receptor gamma-chain and RNA-dependent protein kinase both mediated IFN-alphabeta-dependent enhancement of IFN-gamma mRNA levels. Accumulation of IFN-gamma mRNA and control of C. pneumoniae growth required NF-kappaB activation. Such NF-kappaB activation was independent of IFN-alphabeta, STAT1, and RNA-dependent protein kinase. In summary, C. pneumoniae-induced IFN-gamma expression in BMMphi is controlled by a TLR4-MyD88-IFN-alphabeta-STAT1-dependent pathway, as well as by a TLR4-independent pathway leading to NF-kappaB activation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B.

Although oxidative stress has been thought to play a general role in the activation of NF-kappaB, the involvement of reactive oxygen species (ROS) in facilitating nuclear translocation of NF-kappaB in neutrophils has not been described. In addition, the mechanisms by which ROS modulate the transcriptional activity of NF-kappaB in response to Toll-like receptor 4 (TLR4)-dependent signaling are not well characterized. To examine these issues, oxidant-dependent signaling events downstream of TLR4 were investigated in neutrophils stimulated with LPS. Pretreatment of neutrophils with the antioxidants N-acetylcysteine or alpha-tocopherol prevented LPS-induced nuclear translocation of NF-kappaB. Antioxidant treatment of LPS-stimulated neutrophils also inhibited the production of proinflammatory cytokines (TNF-alpha, macrophage inflammatory protein-2, and IL-1beta), as well as activation of the kinases IkappaB kinase alpha, IkappaB kinase beta, p38, Akt, and extracellular receptor-activated kinases 1 and 2. The decrease in cytoplasmic levels of IkappaBalpha produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or alpha-tocopherol. Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants. These results demonstrate that proximal events in TLR4 signaling, at or antecedent to IRAK-1 and IRAK-4 activation, are oxidant dependent and indicate that ROS can modulate NF-kappaB-dependent transcription through their involvement in early TLR4-mediated cellular responses.

Acetylcysteine↗
PubMed2004

Role of Toll-like receptor 4 in endotoxin-induced acute renal failure.

Toll-like receptor 4 (TLR4) is present on monocytes and other cell types, and mediates inflammatory events such as the release of TNF after exposure to LPS. C3H/HeJ mice are resistant to LPS-induced mortality, due to a naturally occurring mutation in TLR4. We therefore hypothesized that LPS-induced acute renal failure (ARF) requires systemic TNF release triggered by LPS acting on extrarenal TLR4. We injected C3H/HeJ mice and C3H/HeOuJ controls with 0.25 mg of LPS, and sacrificed them 6 h later for analysis of blood urea nitrogen (BUN) and kidney tissue (n = 8 per group). In contrast to C3H/HeOuJ controls, C3H/HeJ mice were completely resistant to LPS-induced ARF (6-h BUN of 32.3 +/- 1.1 vs 61.7 +/- 5.6 mg/dl). C3H/HeJ mice released no TNF into the circulation at 2 h (0.00 vs 1.24 +/- 0.16 ng/ml), had less renal neutrophil infiltration (6.4 +/- 1.0 vs 11.4 +/- 1.3 neutrophils per high power field), and less renal apoptosis, as assessed by DNA laddering. Transplant studies showed that C3H/HeJ recipients of wild-type kidneys (n = 9) were protected from LPS-induced ARF, while wild-type recipients of C3H/HeJ kidneys (n = 11) developed severe LPS-induced ARF (24-h BUN 44.0 +/- 4.1 vs 112.1 +/- 20.0 mg/dl). These experiments support our hypothesis that LPS acts on extrarenal TLR4, thereby leading to systemic TNF release and subsequent ARF. Renal neutrophil infiltration and renal cell apoptosis are potential mechanisms by which endotoxemia leads to functional ARF.

ADP-Ribosylation Factor 6↗
PubMed2004

Aberrant Toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-beta 1 signaling pathway.

TGF-beta1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-beta1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-alpha and IL-1beta, as well as inducible NO synthase, each regulated by NF-kappaB. Treatment with the proteasome inhibitor MG132 to prevent NF-kappaB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-kappaB activation in the TGF-beta1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-beta1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-kappaB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-beta1 null mice as well as in mice lacking the TGF-beta transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-beta1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-beta suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.

Animals↗
PubMed2004

The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages.

Fc gamma R clustering in macrophages activates signaling events that result in phagocytosis. Phagocytosis is accompanied by the generation harmful byproducts such as reactive oxygen radicals and production of inflammatory cytokines, which mandate that the phagocytic process be subject to a tight regulation. The molecular mechanisms involved in this regulation are not fully understood. In this study, we have examined the role of the inositol 3-phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in Fc gamma R-induced macrophage function. We demonstrate that in ex vivo murine peritoneal macrophages that are deficient in PTEN expression, Fc gamma R-induced Akt and extracellular signal-regulated kinase phosphorylation are enhanced. Notably, PTEN(-/-) macrophages showed constitutively high phosphorylation of Akt. However, PTEN did not seem to influence tyrosine phosphorylation events induced by Fc gamma R clustering. Furthermore, PTEN(-/-) macrophages displayed enhanced phagocytic ability. Likewise, Fc gamma R-induced production of TNF-alpha, IL-6, and IL-10 was significantly elevated in PTEN(-/-) macrophages. Surprisingly, LPS-induced TNF-alpha production was down-regulated in PTEN(-/-) macrophages. Analyzing the molecular events leading to PTEN influence on LPS/Toll-like receptor 4 (TLR4) signaling, we found that LPS-induced activation of mitogen-activated protein kinases is suppressed in PTEN(-/-) cells. Previous reports indicated that LPS-induced mitogen-activated protein kinase activation is down-regulated by phosphatidylinositol 3-kinase through the activation of Akt. Our observation that Akt activation is basally enhanced in PTEN(-/-) cells suggests that PTEN supports TLR4-induced inflammatory responses by suppressing the activation of Akt. Thus, we conclude that PTEN is a negative regulator of Fc gamma R signaling, but a positive regulator of TLR4 signaling. These findings are the first to demonstrate a role for PTEN in Fc gamma R- and TLR4-mediated macrophage inflammatory response.

Animals↗
PubMed2004

Signaling of apoptosis through TLRs critically involves toll/IL-1 receptor domain-containing adapter inducing IFN-beta, but not MyD88, in bacteria-infected murine macrophages.

TLRs are important sensors of the innate immune system that serve to identify conserved microbial components to mount a protective immune response. They furthermore control the survival of the challenged cell by governing the induction of pro- and antiapoptotic signaling pathways. Pathogenic Yersinia spp. uncouple the balance of life and death signals in infected macrophages, which compels the macrophage to undergo apoptosis. The initiation of apoptosis by Yersinia infection specifically involves TLR4 signaling, although Yersinia can activate TLR2 and TLR4. In this study we characterized the roles of downstream TLR adapter proteins in the induction of TLR-responsive apoptosis. Experiments using murine macrophages defective for MyD88 or Toll/IL-1R domain-containing adapter inducing IFN-beta (TRIF) revealed that deficiency of TRIF, but not of MyD88, provides protection against Yersinia-mediated cell death. Similarly, apoptosis provoked by treatment of macrophages with the TLR4 agonist LPS in the presence of a proteasome inhibitor was inhibited in TRIF-defective, but not in MyD88-negative, cells. The transfection of macrophages with TRIF furthermore potently promoted macrophage apoptosis, a process that involved activation of a Fas-associated death domain- and caspase-8-dependent apoptotic pathway. These data indicate a crucial function of TRIF as proapoptotic signal transducer in bacteria-infected murine macrophages, an activity that is not prominent for MyD88. The ability to elicit TRIF-dependent apoptosis was not restricted to TLR4 activation, but was also demonstrated for TLR3 agonists. Together, these results argue for a specific proapoptotic activity of TRIF as part of the host innate immune response to bacterial or viral infection.

Adaptor Proteins, Signal Transducing↗
PubMed2004

IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition.

The initial TLR-mediated interaction between Mycobacterium tuberculosis and dendritic cells is critical, since the cytokine production that ensues can greatly influence the class of adaptive immunity that is generated to the pathogen. In this study, we therefore determined the dependency on TLR2 and TLR4 for M. tuberculosis-induced cytokine production by murine dendritic cells. A key new finding of this study is that production of IL-6 and IL-10 from dendritic cells in response to M. tuberculosis is principally dependent on TLR2. The study also indicates that M. tuberculosis can induce IL-12 production in the absence of either TLR2 or TLR4, suggesting redundancy or possibly involvement of other receptors in IL-12 production. In addition, the data also reveal that lack of TLR2 or TLR4 does not impact on dendritic cell maturation or on their ability to influence the polarity of differentiating naive T cells. Collectively, data presented here provide a mechanistic insight for the contribution of TLR2 and TLR4 to tuberculosis disease progression and offer strategies for regulating IL-6 and IL-10 production in dendritic cell-based vaccine strategies.

Animals↗
PubMed2005

Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes.

Activated astroglial cells are implicated in neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators and cytokines have been proposed to play a key role in glial cell-related brain damage. Cytokine production seems to be initiated by signaling through TLR4/type I IL-1R (IL-1RI) in response to their ligands, LPS and IL-1beta, playing vital roles in innate host defense against infections, inflammation, injury, and stress. We have shown that glial cells are stimulated by ethanol, up-regulating cytokines and inflammatory mediators associated with TLR4 and IL-1RI signaling pathways in brain, suggesting that ethanol may contribute to brain damage via inflammation. We explore the possibility that ethanol, in the absence of LPS or IL-1beta, triggers signaling pathways and inflammatory mediators through TLR4 and/or IL-1RI activation in astrocytes. We show in this study that ethanol, at physiologically relevant concentrations, is capable of inducing rapid phosphorylation within 10 min of IL-1R-associated kinase, ERK1/2, stress-activated protein kinase/JNK, and p38 MAPK in astrocytes. Then an activation of NF-kappaB and AP-1 occurs after 30 min of ethanol treatment along with an up-regulation of inducible NO synthase and cyclooxygenase-2 expression. Finally, we note an increase in cell death after 3 h of treatment. Furthermore, by using either anti-TLR4- or anti-IL-1RI-neutralizing Abs, before and during ethanol treatment, we inhibit ethanol-induced signaling events, including NF-kappaB and AP-1 activation, inducible NO synthase, and cyclooxygenase-2 up-regulation and astrocyte death. In summary, these findings indicate that both TLR4 and IL-1RI activation occur upon ethanol treatment, and suggest that signaling through these receptors mediates ethanol-induced inflammatory events in astrocytes and brain.

Animals↗
PubMed2005

TLRs 2 and 4 are not involved in hypersusceptibility to acute Pseudomonas aeruginosa lung infections.

TLRs are implicated in defense against microorganisms. Animal models have demonstrated that the susceptibility to a number of Gram-negative pathogens is linked to TLR4, and thus LPS of many Gram-negative bacteria have been implicated as virulence factors. To assess the role of this pathogen-associated molecular pattern as it is exposed on intact Pseudomonas aeruginosa, the susceptibility of mice lacking TLR4 or both TLR2 and TLR4 was examined in a model of acute Pseudomonas pneumonia. These mutant mice were not hypersusceptible to the Pseudomonas challenge and mounted an effective innate response that cleared the organism despite low levels of TNF-alpha and KC in the airways. Bacterial and neutrophil counts in the lung were similar in control and TLR-deficient mice at 6 and 24 h after infection. MyD88(-/-) mice were, however, hypersusceptible, with 100% of mice dying within 48 h with a lower dose of P. aeruginosa. Of note there were normal levels of IL-6 and G-CSF in the airways of TLR mutant mice that were absent from the MyD88(-/-) mice. Thus, the susceptibility of mice to P. aeruginosa acute lung infection does not go through TLR2 or TLR4, implying that Pseudomonas LPS is not the most important virulence factor in acute pneumonia caused by this organism. Furthermore, G-CSF treatment of infected MyD88(-/-) mice results in improved clearance and survival. Thus, the resistance to infection in TLR2/TLR4(-/-) mice may be linked to G-CSF and possibly IL-6 production.

Acute Disease↗