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PubMed2006

C-reactive protein is expressed and secreted by peripheral blood mononuclear cells.

C-reactive protein (CRP) protects against bacterial pathogens and is a predictor of cardiovascular events. CRP is produced by vascular and organ-specific cells but the generation of CRP from peripheral blood mononuclear cells (PBMC) is poorly established. In a randomized, double-blind, placebo-controlled, two-way cross-over trial six healthy volunteers received a bolus infusion of 20 IU/kg Escherichia coli endotoxin [lipopolysaccharide (LPS)] or placebo. Intracellular CRP protein and CRP secretion of peripheral blood mononuclear cells (PBMC) was measured at baseline and 6 h after LPS by flow cytometry and enzyme-linked immubosorbent assay (ELISA), respectively. CRP mRNA expression was determined by real-time polymerase chain reaction (PCR). Regulation of the expression pathway was assessed using specific inhibitors in vitro. Small amounts of CRP protein and mRNA were detectable in PBMC, which were up-regulated between two- and eightfold by endotoxaemia in vivo. Augmented expression and release of CRP by LPS was consistent in PBMC cell culture experiments. LPS, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha increased and IL-10 reduced CRP expression in PBMC. Toll-like receptor (TLR)-4, nuclear factor (NF)-kappaB and protein kinase C (PKC) activation were identified as intracellular signal transduction pathways of LPS-induced CRP expression. Constitutive CRP expression and release in PBMC is enhanced by inflammatory stimuli in vivo and in vitro. LPS might induce CRP generation via activation of TLR-4, NF-kappaB and PKC.

Adult↗
PubMed2004

CD14 and toll-like receptor 4: a link between infection and acute coronary events?

The CD14 receptor is a pattern recognition molecule in the innate immune response against microorganisms and other exogenous and endogenous stress factors. The most important CD14 signalling co-receptor is toll-like receptor 4 (TLR4), which activates, among others, the nuclear factor kappaB (NF-kappaB) inflammatory pathway. Besides its role in innate immunity and host defence, the proinflammatory cytokines expressed upon TLR4/NF-kappaB pathway activation exert proatherogenic effects. The CD14 C(-260)T promoter and TLR4 Asp299Gly functional polymorphisms have been recently implicated in the development of cardiovascular events, suggesting that the genetically determined inflammatory response against pathogens or their antigens may have a major role in atherogenesis and subsequent acute events. Is the association of these polymorphisms with cardiovascular disease more evidence for the implication of infection, especially by Gram negative bacteria, in the development of acute coronary events? This article reviews the molecular basis, biological functions, and clinical implications of the CD14/TLR4 polymorphisms in the development of cardiovascular events.

Cell Communication↗
PubMed2006

Toll-like receptor signaling and atherosclerosis.

PURPOSE OF REVIEW: Chronic inflammation and disordered lipid metabolism represent hallmarks of atherosclerosis. Considerable evidence has accumulated to suggest that innate immune defense mechanisms might interact with proinflammatory pathways and exacerbate or perhaps even initiate development of arterial plaques. Until recently the preponderance of such evidence has been indirectly emerging from clinical and epidemiologic studies, with some support from experimental animal models of atherosclerosis. RECENT FINDINGS: Recent data now directly implicate signaling by toll-like receptor 4 and the common adaptor molecule MyD88 in the pathogenesis of atherosclerosis, establishing a key link between atherosclerosis and defense against both foreign pathogens and endogenously generated inflammatory ligands. SUMMARY: Here we briefly review these and closely related studies, highlighting areas that should provide fertile ground for future studies aimed at a more comprehensive understanding of the interplay between innate immune defense mechanisms, atherosclerosis and related vascular disorders.

Animals↗
PubMed2003

Synaptic activity modifies the levels of Dorsal and Cactus at the neuromuscular junction of Drosophila.

The Drosophila Rel transcription factor Dorsal and its inhibitor Cactus participate in a signal transduction pathway involved in several biologic processes, including embryonic pattern formation, immunity, and muscle development. In contrast with embryonic muscle, where Dorsal is reportedly absent, this protein and Cactus accumulates in the neuromuscular junctions in the muscle of both larvae and adults. The phenotype of homozygous dorsal mutant larvae suggested that Dorsal and Cactus maybe necessary for normal function and maintenance of the neuromuscular system. Here we investigate if these proteins can respond to synaptic activity. Using larval body wall preparations and antibodies specific for Dorsal or Cactus we show that the amount of these proteins at the neuromuscular junction is substantially decreased after electrical stimulation of the nerves or incubation in glutamate, the principal transmitter in this type of synapse. The specificity of the response was tested with a glutamate receptor antagonist (argiotoxin 636). Because the effect can be reproduced using a calcium ionophore (ionomycin treatment) as well as blocked by the inhibition of the muscle ryanodine receptor (tetracaine treatment), the involvement of calcium in this process seems likely. We also observed that the inhibition of the calcium dependent protein phosphatase calcineurin prevents the effect of glutamate on the fluorescence for Dorsal and Cactus, suggesting its participation in a signal transduction cascade that may activate Dorsal in the muscle independently of Toll. Our results are consistent with a novel function of the Rel factor Dorsal in a molecular pathway turned on by neural activity and/or contractile activity.

Anesthetics, Local↗
PubMed2003

Toll-like receptors: networking for success.

The innate immune system is essential for host defense and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells such as macrophages and dendritic cells, diverse signaling pathways are activated that combine to define inflammatory responses that direct sterilization of the threat and/or orchestrate development of the adaptive immune response. Innate immune signaling must be carefully controlled, and regulation comes in part from interactions between activating and inhibiting signaling receptors. Toll-like receptors (TLR) have recently emerged as key receptors responsible for recognizing specific conserved components of microbes including lipopolysaccharides from Gram-negative bacteria, CpG DNA, and flagellin. Full activation of inflammatory responses by TLR may require the assembly of receptor signaling complexes including other transmembrane proteins that may influence signal transduction. In addition to TLR, many additional receptors participate in innate recognition of microbes, and recent studies demonstrate strong interactions between signaling through these receptors and signaling through TLR. Useful models for these interacting signaling pathways are now emerging and should pave the way for understanding the molecular mechanisms that drive the rich diversity of inflammatory responses.

Carrier Proteins↗
PubMed2001

Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation.

An early component of atherogenesis is abnormal vascular smooth muscle cell (VSMC) proliferation. The presence of Chlamydia pneumoniae in many atherosclerotic lesions raises the possibility that this organism plays a causal role in atherogenesis. In this study, C pneumoniae elementary bodies (EBs) rapidly activated p44/p42 mitogen-activated protein kinases (MAPKs) and stimulated proliferation of VSMCs in vitro. Exposure of VSMCs derived from human saphenous vein to C pneumoniae EBs (3x10(7) inclusion forming units/mL) enhanced bromodeoxyuridine (BrdU) incorporation 12+/-3-fold. UV- and heat-inactivated C pneumoniae EBs also stimulated VSMC proliferation, indicating a role of direct stimulation by chlamydial antigens. However, the mitogenic activity of C pneumoniae was heat-labile, thus excluding a role of lipopolysaccharide. Chlamydial hsp60 (25 microg/mL) replicated the effect of C pneumoniae, stimulating BrdU incorporation 7+/-3-fold. Exposure to C pneumoniae or chlamydial hsp60 rapidly activated p44/p42 MAPK, within 5 to 10 minutes of exposure. In addition, PD98059 and U0126, which are two distinct inhibitors of upstream MAPK kinase 1/2 (MEK1/2), abolished the mitogenic effect of C pneumoniae and chlamydial hsp60. Toll-like receptors (TLRs) act as sensors for microbial antigens and can signal via the p44/p42 MAPK pathway. Human VSMCs were shown to express TLR4 mRNA and protein, and a TLR4 antagonist abolished chlamydial hsp60-induced VSMC proliferation and attenuated C pneumoniae-induced MAPK activation and VSMC proliferation. Together these results indicate that C pneumoniae and chlamydial hsp60 are potent inducers of human VSMC proliferation and that these effects are mediated, at least in part, by rapid TLR4-mediated activation of p44/p42 MAPK.

Bacterial Proteins↗
PubMed2006

Toll-like receptor (TLR) response tolerance: a key physiological "damage limitation" effect and an important potential opportunity for therapy.

Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in pro-inflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or "re-booting" the immune system may be a useful therapeutic target in the post-septic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLR-ligands such as the gut and liver.

Humans↗
PubMed2005

Chemokines and Toll-like receptors in Lyme disease pathogenesis.

Lyme disease is a tick-transmitted inflammatory disorder, caused by the spirochete Borrelia burgdorferi (Bb). Recent discoveries cast new light on Bb dissemination and the ensuing pathogenesis of inflammation. Although the strong proinflammatory Bb lipoproteins have been implicated in the induction of inflammation, they do not seem to act exclusively through Toll-like receptor (TLR) engagement. In fact, mice that are deficient for MyD88, a component of the TLR signaling pathway, manifest similar or increased recruitment of cells into Bb-infected tissues. By contrast, the absence of the chemokine receptor CXCR2 results in reduced inflammation. Overall, these findings highlight the complexity of Lyme disease pathogenesis and identify chemokine pathways as novel therapeutic targets for the control of Bb-induced inflammation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The transforming growth factor-beta-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual mechanism involving functional cooperation with NF-kappaB and MAPK phosphatase 1-dependent negative cross-talk with p38 MAPK.

The transforming growth factor beta (TGF-beta) pathway represents an important signaling pathway involved in the regulation of diverse biological processes, including cell proliferation, differentiation, and apoptosis. Despite the known role of TGF-betaR-mediated signaling in suppressing immune response, its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here, we show for the first time that TGF-betaR-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacterium nontypeable Hemophilus influenzae (NTHi) in vitro and in vivo. The positive regulation of TLR2 induction by TGF-betaR is mediated via a dual mechanism involving distinct signaling pathways. One mechanism involves functional cooperation between the TGF-betaR-Smad3/4 pathway and NF-kappaB pathway. Another involves MAP kinase phosphatase 1 (MKP-1)-dependent inhibition of p38 MAPK, a known negative regulator for TLR2 induction. Moreover, we showed that TbetaR-mediated signaling is probably activated by NTHi-derived TGF-beta mimicry molecule via an autocrine-independent mechanism. Thus, our study provides new insights into the role of TGF-beta signaling in positively regulating host defense response by tightly controlling the expression level of TLR2 during bacterial infections and may lead to new therapeutic strategies for modulating host defense and inflammatory response.

Bacteria↗
PubMed2006

Centaurin beta1 down-regulates nucleotide-binding oligomerization domains 1- and 2-dependent NF-kappaB activation.

Centaurin beta1 (CENTB1), a GTPase-activating protein, is a member of the ADP-ribosylation factor family encoded by a gene located on the short arm of human chromosome 17. A yeast two-hybrid screen first suggested a direct interaction between CENTB1 and NOD2. Co-immunoprecipitation experiments confirmed direct interaction between CENTB1 and NOD2 and demonstrated similar interaction between CENTB1 and NOD1. We also demonstrate that endogenous CENTB1 interacts with endogenous NOD2 and NOD1 in SW480 and HT-29 intestinal epithelial cells. CENTB1 partially co-localized with NOD2 and NOD1 proteins in the cytoplasm of mammalian cells. CENTB1 expression in epithelial cells was highly induced by tumor necrosis factor alpha, interleukin 1beta, and the NOD1 and NOD2 ligands (gamma-d-glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively). In addition, CENTB1 mRNA level is increased in the inflamed mucosa of patients with inflammatory bowel disease. Functionally, CENTB1 overexpression inhibited NOD1- and NOD2-dependent activation of NF-kappaB, whereas small inhibitory RNA against CENTB1 increased NF-kappaB activation following NOD1- or NOD2-mediated recognition of the bacterial components gamma-d-glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively. In contrast, CENTB1 had no effect on NF-kappaB activation induced by Toll-like receptors. In conclusion, CENTB1 selectively down-regulates NF-kappaB activation via NODs pathways, creating a "feedback" loop and suggesting a novel role of CENTB1 in innate immune responses to bacteria and inflammatory responses.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Type I interferons (alpha/beta) in immunity and autoimmunity.

The significance of type I interferons (IFN-alpha/beta) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-alpha/beta, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.

Adaptation, Physiological↗
PubMed2003

IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity.

Infections often precede the development of autoimmunity. Correlation between infection with a specific pathogen and a particular autoimmune disease ranges from moderately strong to quite weak. This lack of correspondence suggests that autoimmunity may result from microbial activation of a generic, as opposed to pathogen-specific host-defense response. The Toll-like receptors, essential to host recognition of microbial invasion, signal through a common, highly conserved pathway, activate innate immunity, and control adaptive immune responses. To determine the influence of Toll/IL-1 signaling on the development of autoimmunity, the responses of wild-type (WT) mice and IL-1R-associated kinase 1 (IRAK1)-deficient mice to induction of experimental autoimmune encephalomyelitis were compared. C57BL/6 and B6.IRAK1-deficient mice were immunized with MOG 35-55/CFA or MOG 35-55/CpG DNA/IFA. WT animals developed severe disease, whereas IRAK1-deficient mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation. IRAK1-deficient T cells also displayed impaired Th1 development, particularly during disease induction, despite normal TCR signaling. These results suggest that IRAK1 and the Toll/IL-1 pathway play an essential role in T cell priming, and demonstrate one means through which innate immunity can control subsequent development of autoimmunity. These findings may also help explain the association between antecedent infection and the development or exacerbations of some autoimmune diseases.

Adjuvants, Immunologic↗
PubMed2005

Enhanced TLR4 reactivity following injury is mediated by increased p38 activation.

Severe injury primes the innate-immune system for increased Toll-like receptor 4 (TLR4)-induced proinflammatory cytokine production by macrophages. In this study, we examined changes in TLR4 signaling pathways in splenic macrophages from burn-injured or sham mice to determine the molecular mechanism(s) responsible for the increased TLR4 responsiveness. Using flow cytometry and specific antibodies, we first looked for injury-induced changes in the expression levels of several TLR-associated signaling molecules. We found similar levels of myeloid differentiation primary-response protein 88 (MyD88) and interleukin-1 receptor-associated kinase-M (IRAK-M) and somewhat lower levels of total p38, extracellular signal-regulated kinase (ERK), and stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in burn compared with sham macrophages. However, with the use of antibodies specific for the phosphorylated (activated) forms of the three MAPKs, we found that macrophages from burn mice showed a twofold increase in purified lipopolysaccharide (LPS)-stimulated p38 activation as compared with cells from sham mice on days 1 and 7 post-injury, whereas ERK and SAPK/JNK activation was increased by burn injury only on day 1. Using the specific p38 inhibitor (SB203580), we confirmed that the increase in tumor necrosis factor alpha production by LPS-stimulated burn macrophages requires p38 activation. Although we demonstrated that injury increases macrophage TLR4 mRNA expression and intracellular expression of TLR4-myeloid differentiation protein-2 (MD-2) protein, macrophage cell-surface expression of TLR4-MD-2 was not changed by burn injury. Our results suggest that the injury-induced increase in TLR4 reactivity is mediated, at least in part, by enhanced activation of the p38 signaling pathway.

Animals↗
PubMed2006

Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells.

Engaging mammalian Toll-like receptors (TLRs) activate both the NF-kappaB and mitogen-activated protein kinase signaling pathways. Here we establish that mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands. Despite rescuing TLR-dependent ERK activation in nfkb1(-/-) bone marrow-derived macrophages by using an estrogen receptor-regulated version of the mitogen-activated protein 3 kinase, c-Raf (Raf:ER), CpG or LPS induction of IL-10 was only partially restored in nfkb1(-/-) cells expressing Raf:ER, a finding consistent with NF-kappaB1 regulating IL-10 by a combination of ERK-independent and -dependent mechanisms. Collectively, our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells.

Animals↗
PubMed2006

Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease.

Many host cell types, including endothelial and epithelial cells, neutrophils, monocytes, natural killer cells, dendritic cells and macrophages, initiate the first line of defense against infection by sensing conserved microbial structures through Toll-like receptors (TLRs). Recognition of microbial ligands by TLRs induces their oligomerization and triggers intracellular signaling pathways, leading to production of pro- and anti-inflammatory cytokines. Dysregulation of the fine molecular mechanisms that tightly control TLR signaling may lead to hyperactivation of host cells by microbial products and septic shock. A prior exposure to bacterial products such as lipopolysaccharide (LPS) may result in a transient state of refractoriness to subsequent challenge that has been referred to as 'tolerance'. Tolerance has been postulated as a protective mechanism limiting excessive inflammation and preventing septic shock. However, tolerance may compromise the host's ability to counteract subsequent bacterial challenge since many septic patients exhibit an increased incidence of recurrent bacterial infection and suppressed monocyte responsiveness to LPS, closely resembling the tolerant phenotype. Thus, by studying mechanisms of microbial tolerance, we may gain insights into how normal regulatory mechanisms are dysregulated, leading ultimately to microbial hypo-responsiveness and life-threatening disease. In this review, we present current theories of the molecular mechanisms that underlie induction and maintenance of 'microbial tolerance', and discuss the possible relevance of tolerance to several infectious and non-infectious diseases.

Animals↗
PubMed2006

Signal integration between IFNgamma and TLR signalling pathways in macrophages.

Macrophages are major effector cells of the innate immune system, and appropriate regulation of macrophage function requires the integration of multiple signalling inputs derived from the recognition of host factors (e.g. interferon-gamma/IFNgamma) and pathogen products (e.g. toll-like receptor/TLR agonists). The profound effects of IFNgamma pre-treatment ("priming") on TLR-induced macrophage activation have long been recognised, but many of the mechanisms underlying the priming phenotype have only recently been identified. This review summarises the known mechanisms of integration between the IFNgamma and TLR signalling pathways. Synergy occurs at multiple levels, ranging from signal recognition to convergence of signals at the promoters of target genes. In particular, the cross-talk between the IFNgamma, and LPS and CpG DNA signalling pathways is discussed.

Animals↗
PubMed2001

LPS induction of gene expression in human monocytes.

Lipopolysaccharide (LPS [endotoxin]) is the principal component of the outer membrane of Gram-negative bacteria. Recent studies have elucidated how LPS is recognized by monocytes and macrophages of the innate immune system. Human monocytes are exquisitely sensitive to LPS and respond by expressing many inflammatory cytokines. LPS binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14. Next, LPS is transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2. LPS stimulation of human monocytes activates several intracellular signaling pathways that include the IkappaB kinase (IKK)-NF-kappaB pathway and three mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated kinases (ERK) 1 and 2, c-Jun N-terminal kinase (JNK) and p38. These signaling pathways in turn activate a variety of transcription factors that include NF-kappaB (p50/p65) and AP-1 (c-Fos/c-Jun), which coordinate the induction of many genes encoding inflammatory mediators.

Animals↗
PubMed2006

The intersubject variability of tissue factor mRNA production in human monocytes--relation with the toll-like receptor 4.

OBJECTIVE: Tissue factor (TF) is known as the primary initiator of blood coagulation. Previous studies have suggested a considerable variation in the monocytic lipopolysaccharide (LPS) stimulated TF antigen levels and procoagulant activities between different individuals. Our aim with the present study was to investigate the replicability of LPS induced TF mRNA production in a series of standardised experiments with the purpose to identify putative factors influencing the TF high and low response. RESULTS: A constant and reproducible production of LPS induced TF mRNA was identified in five high responders and three low responders (out of 42 individuals) and followed-up in three subsequent experiments performed over 2 years. The LPS induced TF mRNA production correlated with the corresponding expressions of interleukin-8, tumor necrosis factor-alfa and interleukin-1 beta, indicating a common pathway with the TF high and low response. A strong and significant correlation between the LPS induced TF and toll-like receptor 4 mRNA expressions was subsequently identified and replicated. CONCLUSIONS: We demonstrated a high and low responder phenomenon of LPS induced TF mRNA in human monocytes. The production of toll-like receptor 4 mRNA was significantly enhanced in TF high responders.

Follow-Up Studies↗