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At least 703 records · Page 39Linked to original sources
PubMed2002

Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages.

Treatment of macrophages with lipopolysaccharide (LPS) from Gram-negative bacteria or peptidoglycan (PGN) from Gram-positive bacteria activates multiple intracellular signaling pathways and a large, diverse group of nuclear transcription factors. The signaling receptors for PGN and LPS are now known to be the Toll-like receptors 2 and 4 (TLR2 and -4, respectively). While a large body of literature indicates that the members of the TLR family activate nearly identical cytoplasmic signaling programs, several recent reports have suggested that the functional outcomes of signaling via TLR2 or TLR4 are not equivalent. In the current studies, we compared the responses of the secretory IL-1 receptor antagonist (sIL-1Ra) gene to both LPS and PGN. Both LPS and PGN induced IL-1Ra gene expression; however, the combination of both stimuli synergistically increased sIL-1Ra mRNA expression and promoter activity, suggesting that the signals induced by PGN and LPS are not equivalent. While both LPS and PGN utilized the PU.1-binding sites in the proximal sIL-1Ra promoter region to generate a full response, additional distinct promoter elements were utilized by LPS or PGN. Activation of p38 stress-activated protein kinase was required for LPS- or PGN-induced IL-1Ra gene expression, but the p38-responsive promoter elements localized to distinct regions of the sIL-1Ra gene. Additionally, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. Collectively, these data indicated that while some of the intracellular signaling events by TLR2 and TLR4 agonists are similar, there are clearly distinct differences in the responses elicited by these two bacterial products.

Animals↗
PubMed2006

Toll-like receptors and innate antiviral immunity.

Viral infections are first detected by a set of innate immunity receptors that detect primary infections by pathogens, and trigger a transcriptional response. Among the induced target genes, type I interferons (IFNs) are central to the antiviral response of the host. The receptors and signaling pathways that mediate the strong induction of the synthesis of these cytokines have long remained elusive. In the past few years, Toll-like receptors (TLRs) emerged as important sensors of infections. Several TLRs participate in the recognition of virus infection, interacting in particular with viral nucleic acids. Upon activation, TLRs interact with different cytosolic adapter molecules and activate transcription factors of the nuclear factor-kappaB and IFN regulatory factor families that concur to mediate induction of IFN-alpha/beta and other inflammatory cytokines. In addition to the transmembrane TLRs, cytosolic helicases also detect viral nucleic acids, and trigger type I IFN synthesis.

Animals↗
PubMed2005

C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways.

alpha1-Antitrypsin (AAT), a major endogenous inhibitor of serine proteases, plays an important role in minimizing proteolytic injury to host tissue at sites of infection and inflammation. There is now increasing evidence that AAT undergoes post-translational modifications to yield by-products with novel biological activity. One such molecule, the C-terminal fragment of AAT, corresponding to residues 359-394 (C-36 peptide) has been reported to stimulate significant pro-inflammatory activity in monocytes and neutrophils in vitro. In this study we showed that C-36 peptide is present in human lung tissue and mimics the effects of lipopolysaccharide (LPS), albeit with lower magnitude, by inducing monocyte cytokine (TNFalpha, IL-1beta) and chemokine (IL-8) release in conjunction with the activation of nuclear factor-kappaB (NF-kappaB). Using receptor blocking antibodies and protein kinase inhibitors, we further demonstrated that C-36, like LPS, utilizes CD14 and Toll-like receptor 4 (TLR4) receptors and enzymes of the mitogen-activated protein kinase (MAPK) signaling pathways to stimulate monocyte TNFalpha release. The specificity of C-36 effects were demonstrated by failure of a shorter peptide (C-20) to elicit biological activity and the failure of C-36 to inhibit CD3/CD28-stimulated IL-2 receptor expression or proliferation in T-cells which lack TLR4 and CD14. We suggest that C-36 mediates its effects though the activation of LPS signaling pathways.

Cells, Cultured↗
PubMed2005

Achieving stability of lipopolysaccharide-induced NF-kappaB activation.

The activation dynamics of the transcription factor NF-kappaB exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor-alpha (TNFalpha) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-kappaB that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early anti-phase activation of NF-kappaB by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3-dependent expression of TNFalpha to activate NF-kappaB, and the time required for TNFalpha synthesis established the delay.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Diesel exhaust particles suppress in vivo IFN-gamma production by inhibiting cytokine effects on NK and NKT cells.

Diesel exhaust particles (DEP) have strong, selective Th2 adjuvant activity when inhaled with conventional Ags. We used a novel technique for measuring in vivo cytokine production to investigate possible mechanisms by which DEP might promote a Th2 response. Injection of DEP i.p. stimulated IL-6 secretion, but failed to increase IL-4, IL-10, or TNF-alpha secretion, and decreased basal levels of IFN-gamma. When injected with or before LPS, DEP had little effect on the LPS-induced TNF-alpha responses, but partially inhibited the LPS-induced IL-10 response and strongly inhibited the LPS-induced IFN-gamma response. DEP also inhibited the IFN-gamma responses to IL-12, IL-12 plus IL-18, IL-2, and poly(I.C). DEP treatment had little effect on the percentages of NK and NKT cells in the spleen, but inhibited LPS-induced IFN-gamma production by splenic NK and NKT cells. In contrast, DEP failed to inhibit the IFN-gamma response by anti-CD3 mAb-activated NKT cells. Taken together, these observations suggest that DEP inhibit Toll-like receptor ligand-induced IFN-gamma responses by interfering with cytokine signaling pathways that stimulate NK and NKT cells to produce IFN-gamma. Our observations also suggest that DEP may promote a Th2 response by stimulating production of inflammatory cytokines while simultaneously inhibiting production of IFN-gamma, and raise the possibility that the same mechanisms contribute to the association between DEP exposure and asthma.

Adjuvants, Immunologic↗
PubMed2004

Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4.

An understanding of lipopolysaccharide (LPS) signal transduction is a key goal in the effort to provide a molecular basis for the lethal effect of LPS during septic shock and point the way to novel therapies. Rapid progress in this field during the last 6 years has resulted in the discovery of not only the receptor for LPS - Toll-like receptor 4 (TLR4) - but also in a better appreciation of the complexity of the signalling pathways activated by LPS. Soon after the discovery of TLR4, the formation of a receptor complex in response to LPS, consisting of dimerized TLR4 and MD-2, was described. Intracellular events following the formation of this receptor complex depend on different sets of adapters. An early response, which is dependent on MyD88 and MyD88-like adapter (Mal), leads to the activation of nuclear factor-kappaB (NF-kappaB). A later response to LPS makes use of TIR-domain-containing adapter-inducing interferon-beta (TRIF) and TRIF-related adapter molecule (TRAM), and leads to the late activation of NF-kappaB and IRF3, and to the induction of cytokines, chemokines, and other transcription factors. As LPS signal transduction is an area of intense research and rapid progress, this review is intended to sum up our present understanding of the events following LPS binding to TLR4, and we also attempt to create a model of the signalling pathways activated by LPS.

Acute-Phase Proteins↗
PubMed2003

IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.

The transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB are required for the expression of many genes involved in the innate immune response. Viral infection, or the binding of double-stranded RNA to Toll-like receptor 3, results in the coordinate activation of IRF3 and NF-kappaB. Activation of IRF3 requires signal-dependent phosphorylation, but little is known about the signaling pathway or kinases involved. Here we report that the noncanonical IkappaB kinase homologs, IkappaB kinase-epsilon (IKKepsilon) and TANK-binding kinase-1 (TBK1), which were previously implicated in NF-kappaB activation, are also essential components of the IRF3 signaling pathway. Thus, IKKepsilon and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Analysis of genes induced by Sendai virus infection of mutant cell lines reveals essential roles of interferon regulatory factor 3, NF-kappaB, and interferon but not toll-like receptor 3.

Sendai virus (SeV) infection causes the transcriptional induction of many cellular genes that are also induced by interferon (IFN) or double-stranded RNA (dsRNA). We took advantage of various mutant cell lines to investigate the putative roles of the components of the IFN and dsRNA signaling pathways in the induction of those genes by SeV. Profiling the patterns of gene expression in SeV-infected cells demonstrated that Toll-like receptor 3, although essential for gene induction by dsRNA, was dispensable for gene induction by SeV. In contrast, Jak1, which mediates IFN signaling, was required for the induction of a small subset of genes by SeV. NF-kappaB and interferon regulatory factor 3 (IRF-3), the two major transcription factors activated by virus infection, were essential for the induction of two sets of genes by SeV. As expected, some of the IRF-3-dependent genes, such as ISG56, were more strongly induced by SeV in IRF-3-overexpressing cells. Surprisingly, in those cells, a number of NF-kappaB-dependent genes, such as the A20 gene, were induced poorly. Using a series of cell lines expressing increasing levels of IRF-3, we demonstrated that the degree of induction of A20 mRNA, upon SeV infection, was inversely proportional to the cellular level of IRF-3, whereas that of ISG56 mRNA was directly proportional. Thus, IRF-3 can suppress the expression of NF-kappaB-dependent genes in SeV-infected cells.

Cell Line↗
PubMed2026

A Cooperative Release of Mitochondrial DNA From Platelets and Neutrophils Drives an Interferon Signature in Systemic Sclerosis.

OBJECTIVE: Mitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release. METHODS: Total DNA was isolated from the plasma of healthy controls (HCs) and patients with SSc. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by quantitative real-time polymerase chain reaction. mtDNA was isolated from HCs and patients with SSc. Neutrophils and platelets were incubated with the plasma and mtDNA of patients with SSc, and neutrophil extracellular trap (NET) formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG enzyme-linked immunosorbent assay (ELISA) of patient plasma. Plasma interferon (IFN) type 1 and chemokine (C-X-C motif) ligand 4 (CXCL4) were measured by ELISA. IFN signaling activation capacity was evaluated using THP-1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis. RESULTS: Median plasma mtDNA levels were 152-fold higher in patients with SSc compared with HCs, whereas nuclear DNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in the neutrophils of patients with SSc and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in the blood of patients with SSc, and SSc blood exhibited elevated IFN-stimulated gene expression. SSc plasma-derived mtDNA-induced IFN signaling and NET formation via endosomal Toll-like receptors, cyclic GMP-AMP synthase/stimulator of IFN genes, and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release because IFN receptor and JAK inhibition antagonized the proNETotic effects of IFN. CONCLUSION: SSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.

Humans↗
PubMed2000

Tlr4: central component of the sole mammalian LPS sensor.

Mutations of the mouse Lps locus abolish responses to lipopolysaccharide (LPS). Positional cloning work has revealed that Lps encodes the Toll-like receptor 4 (Tlr4), which functions as the transmembrane component of the LPS receptor complex, an unduplicated pathway for the detection of endotoxin. The structurally related protein Tlr2 makes no contribution to LPS signal transduction.

Alleles↗
PubMed2005

Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway.

Myeloid differentiation factor MyD88 is the essential adaptor protein that integrates and transduces intracellular signals generated by multiple Toll-like receptors including receptor complex for interleukin (IL) 1beta, a key inflammatory cytokine. IL1beta receptor complex interacts with MyD88 via the Toll/IL1 receptor (TIR) domain. Here we report structure-function studies that help define the MyD88 TIR domain binding sites involved in IL1beta-induced protein-protein interactions. The MyD88 TIR domain, employed as a dominant negative inhibitor of IL1beta signaling to screen MyD88 TIR mutants, lost its suppressing activity upon truncation of its Box 3. Accordingly, mutations of Box 3 residues 285-286 reversed the dominant negative effect of the MyD88 TIR domain on IL1beta-induced and NFkappaB-dependent reporter gene activity and IL6 production. Moreover, mutations of residues 171 in helix alphaA, 195-197 in Box 2, and 275 in betaE-strand had similar functional effects. Strikingly, only mutations of residues 195-197 eliminated the TIR-TIR interaction of MyD88 and IL1 receptor accessory protein (IL1RAcP), whereas substitution of neighboring canonical Pro200 by His was without effect. Mutations in Box 2 and 3 prevented homotypic MyD88 oligomerization via TIR domain. Based on this structure-function analysis, a three-dimensional docking model of TIR-TIR interaction between MyD88 and IL1RAcP was developed.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Topical application of a novel immunomodulatory peptide, RDP58, reduces skin inflammation in the phorbol ester-induced dermatitis model.

RDP58 is the first lead compound in a series of immunomodulating decapeptides discovered through activity-based screening and computer-aided, rational design. RDP58 disrupts cellular responses signaled through the Toll-like and tumor necrosis factor (TNF) receptor families and occludes important signal transduction pathways involved in inflammation, inhibiting the production of tumor necrosis factor alpha (TNFalpha), interferon-gamma, interleukin (IL)-2, IL-6, and IL-12. These pro-inflammatory cytokines are thought to be involved in the pathogenesis of several inflammatory and autoimmune diseases, including atopic dermatitis and psoriasis. The goal of this study was to determine the ability of RDP58 to inhibit skin inflammation following exposure to the well-characterized protein kinase C activator and tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of RDP58 to the epidermis following TPA treatment resulted in the amelioration of the phorbol ester-induced irritant contact dermatitis. Substantial reductions were observed in skin thickness and tissue weight, neutrophil-mediated myeloperoxidase activity, inflammatory cytokine production, and various histopathological indicators. We also found RDP58 to be effective in reducing the compounding inflammatory damage brought on by chronic TPA exposure, and that it is capable of targeting inflammatory mediators specifically in the keratinocyte. These results demonstrate that topically applied RDP58 is an effective anti-inflammatory treatment in the phorbol ester-induced dermatitis model, and suggest that it may have therapeutic potential in a variety of immune-related cutaneous diseases.

Administration, Topical↗
PubMed2006

The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation.

Microarray--assisted gene--expression screens of human macrophages revealed WNT5A, a homolog of Wingless, a key regulator of Drosophila melanogaster embryonic segmentation and patterning, to be consistently up-regulated following stimulation with different mycobacterial species and conserved bacterial structures. The expression of WNT5A required Toll-like receptor signaling and NF-kappaB activation, which identifies a novel induction pathway for a Wingless homolog. We show that human peripheral-blood mononuclear cells express the WNT5A receptor Frizzled-5 (FZD5). Both WNT5A and FZD5 also were detected in granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected patients. Functional studies showed that WNT5A and FZD5 regulate the microbially induced interleukin-12 response of antigen-presenting cells and interferon-gamma production by mycobacterial antigen-stimulated T cells. Our findings implicate the evolutionarily conserved WNT/Frizzled signaling system in bridging innate and adaptive immunity to infections.

Antigen-Presenting Cells↗
PubMed2005

Situating stress: lessons from lay discourses on diabetes.

In response to the serious toll diabetes takes on health and resources, researchers increasingly are examining physical and psychological pathways that affect and are affected by diabetes, including stress. Although biomedical researchers and practitioners are beginning to recognize the association between stress and diabetes onset and management, laypersons have long-standing and extensive insights into the multiple ways in which stress is associated with the diabetes disease process. In this article, we examine lay perspectives on stress and diabetes among a multiethnic sample of 80 adults. Participants suggest varying arenas in which stress intersects with diabetes, including stress as implicated in the origin of diabetes, as a threat to maintaining glycemic control, as a challenge to self-management, and as a precursor to and a consequence of diabetes complications. An improved understanding of such perspectives may enhance appropriate disease management and develop a more valid conceptualization of stress in research efforts.

Black or African American↗
PubMed2001

Two receptor theory in innate immune activation: studies on the receptors for bacillus Culmet Guillen-cell wall skeleton.

Activation of the innate immune system is a prerequisite for the maturation of dendritic cells (DC) and macrophages (Mphi) followed by clonal expansion of the lymphocytes, targeting cells expressing "non-self' antigens. Microbes usually have a component competent to activate DC/Mphi for antigen presentation. This component has been called adjuvant, but recently renamed "pathogen-associated molecular pattern" (PAMP) or modulin based on its molecular identification. Here, we propose the hypothesis that DC/Mphi express two sorts of receptors for PAMP, whose signaling pathways lead to a sufficient antigen (Ag)-presenting state. In bacterial infection, a Toll-like receptor (TLR) and an uptake receptor participate in DC maturation and Mphi activation. Likewise, with a number of viruses, two of the receptors, with short consensus repeats (SCR), immunoglobulin-like domains or chemokine receptor-like motifs etc. induce functional modulation of DC/Mphi. In immune therapy for cancer, primary activation of the innate system would be essential for tumor Ag-specific T cell augmentation. Cancer cells express tumor-associated Ag but barely co-express PAMP, which situation does not allow for the activation of innate immune responses. Supplementing tumor-associated Ag with PAMP may be an effective therapy for patients with cancer. Here, we discuss the possibility of an innate immune therapy for cancer with reference to bacillus Culmet Guillen cell-wall skeleton (BCG-CWS).

Adjuvants, Immunologic↗
PubMed2006

Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance.

Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immuno-suppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined Talpha1 for possible induction of DC-dependent regulatory effects. Talpha1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by Talpha1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, Talpha1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory environment. Thus, instructive immunotherapy with Talpha1 targeting IDO-competent DCs could allow for a balanced control of inflammation and tolerance.

Adjuvants, Immunologic↗
PubMed2005

Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4.

Toll-like receptors (TLR) recognize pathogen-derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine-choline deficient (MCD) diet-induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2 mice had significantly higher levels of serum ALT and greater TNF-alpha levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL-6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet-fed TLR2 mice was associated with reduced baseline and LPS-induced NF-kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2-mediated signals in liver injury.

Animals↗
PubMed2006

IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation.

Toll-like receptor (TLR)-mediated immune responses are downregulated by several mechanisms that affect signaling pathways. However, it remains elusive how TLR-mediated gene expression is differentially modulated. Here, we show that IkappaBNS, a TLR-inducible nuclear IkappaB protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-kappaB activity. IkappaBNS-deficient macrophages and dendritic cells show increased TLR-mediated expression of genes such as IL-6 and IL-12p40, which are induced late after TLR stimulation. In contrast, IkappaBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of IkappaBNS-deficient macrophages prolonged NF-kappaB activity at the specific promoters, indicating that IkappaBNS mediates termination of NF-kappaB activity at selective gene promoters. Moreover, IkappaBNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, IkappaBNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-kappaB activity.

Animals↗