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PubMed2003

For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection.

The surveillance of the structural fidelity of the proteome is of utmost importance to all cells. The endoplasmic reticulum (ER) is the organelle responsible for proper folding and delivery of proteins to the secretory pathway. It contains a sophisticated protein proofreading and elimination mechanism. Failure of this machinery leads to disease and, finally, to cell death. Elimination of misfolded proteins requires retrograde transport across the ER membrane and depends on the central cytoplasmic proteolytic machinery involved in cellular regulation: the ubiquitin-proteasome system. The basics of this process as well as recent advances in the field are reviewed.

Endoplasmic Reticulum↗
PubMed2005

A central role for the Hsp90.Cdc37 molecular chaperone module in interleukin-1 receptor-associated-kinase-dependent signaling by toll-like receptors.

Toll-like receptors (TLRs) serve crucial roles in innate immunity by mediating the activation of macrophages by microbial pathogens. The protein kinase interleukin-1 receptor associated kinase (IRAK-1) is a key component of TLR signaling pathways via its interaction with TRAF6, which subsequently leads to the activation of MAP kinases and various transcription factors. IRAK-1 is degraded following TLR activation, and this has been proposed to contribute to tolerance in macrophages by limiting further TLR-mediated signaling. Using a mass spectrometric-based approach, we have identified a cohort of chaperones and co-chaperones including Hsp90 and Cdc37, which bind to IRAK-1 but not IRAK-4 in 293T cells. Pharmacologic inhibition of Hsp90 led to a rapid decline in the expression level of IRAK-1, whereas overexpression of Cdc37 enhanced the activation and oligomerization of IRAK-1 in 293T cells. Significantly, the inhibition of Hsp90 in macrophages resulted in the destabilization and degradation of IRAK-1 but not IRAK-4. Concomitant with the loss of IRAK-1 expression was a reduction in the activation of p38 MAP kinase and Erk1/2 following stimulation with the bacterially derived TLR ligands, lipopolysaccharide and CpG DNA. Moreover, TLR ligand-induced expression of proinflammatory cytokines was also reduced. Thus we conclude that the level of on-going support provided to IRAK-1 by the Hsp90-Cdc37 chaperone module directly influences the magnitude of TLR-mediated macrophage activation. In addition, because further TLR signaling depends on the synthesis of new IRAK-1, the Hsp90-Cdc37 chaperone module could also contribute to tolerance in macrophages by controlling the rate at which nascent IRAK-1 is folded into a functional conformation.

Benzoquinones↗
PubMed2001

Toll-like receptors: critical proteins linking innate and acquired immunity.

Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

Animals↗
PubMed2003

Phosphoinositide 3 kinase mediates Toll-like receptor 4-induced activation of NF-kappa B in endothelial cells.

Many of the proinflammatory effects of gram-negative bacteria are elicited by the interaction of bacterial lipopolysaccharide (LPS) with Toll-like receptor 4 (TLR4) expressed on host cells. TLR4 signaling leads to activation of NF-kappa B and transcription of many genes involved in the inflammatory response. In this study, we examined the signaling pathways involved in NF-kappa B activation by TLR4 signaling in human microvascular endothelial cells. Akt is a major downstream target of phosphoinositide 3 kinase (PI3-kinase), and PI3-kinase activation is necessary and sufficient for Akt phosphorylation. Consequently, Akt kinase activation was used as a measure of PI3-kinase activity. In a stable transfection system, dominant-negative mutants of myeloid differentiation factor 88 (MyD88) and interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK-1) (MyD88-TIR and IRAK-DD, respectively) blocked Akt kinase activity in response to LPS and IL-1 beta. A dominant-negative mutant (Mal-P/H) of MyD88 adapter-like protein (Mal), a protein with homology to MyD88, failed to inhibit LPS- or IL-1 beta-induced Akt activity. Moreover, a dominant-negative mutant of p85 (p85-DN) inhibited the NF-kappa B luciferase activity, IL-6 production, and I kappa B alpha degradation elicited by LPS and IL-1 beta but not that stimulated by tumor necrosis factor alpha. The dominant-negative mutant of Akt partially inhibited the NF-kappa B luciferase activity evoked by LPS and IL-1 beta. However, expression of a constitutively activated Akt failed to induce NF-kappa B luciferase activity. These findings indicate that TLR4- and IL-1R-induced PI3-kinase activity is mediated by the adapter proteins MyD88 and IRAK-1 but not Mal. Further, these studies suggest that PI3-kinase is an important mediator of LPS and IL-1 beta signaling leading to NF-kappa B activation in endothelial cells and that Akt is necessary but not sufficient for NF-kappa B activation by TLR4.

Cells, Cultured↗
PubMed2025

Interferon and TLR genes, but not endogenous bornavirus-like elements, limit BoDV1 replication after intracerebral infection.

Borna disease virus 1 (BoDV1) is a disease-causing agent in some livestock and, as has recently been shown, in humans. What constitutes a protective immune response to BoDV1 is unclear. Previous studies found that endogenous bornavirus-like nucleoprotein elements (EBLNs) present in mammalian genomes produce piRNAs antisense to BoDV1 nucleoprotein mRNAs. As a known function of piRNAs is to restrict transposons via RNA interference, it has been hypothesized that EBLN-derived piRNAs may restrict BoDV1. Here we used EBLN knockout (KO) and other KO mice to test genetic factors potentially involved in antiviral immunity to BoDV1. In previous reports, BoDV1 replication was higher in mice deficient in interferon gamma, and we confirmed a role for this cytokine in BoDV1 restriction at 12 weeks post infection using mice lacking its receptor. We show that BoDV1 replicates to higher levels in the brain of mice without Toll-like receptor 7 (TLR7), suggesting a role for this innate immune receptor in BoDV1 immunity. In contrast, mice lacking piRNA-producing EBLNs were no more susceptible to BoDV1 infection than wild-type under the infection conditions used here. We thus expand the genetic evidence implicating specific conventional immune pathways in BoDV1 control and conclude that EBLN-derived piRNA-guided antiviral silencing, if it occurs, is relatively less impactful in intracerebral infection of neonates.

Animals↗
PubMed2005

Cyclosporine-induced renal injury induces toll-like receptor and maturation of dendritic cells.

BACKGROUND: The toll-like receptor (TLR) is stimulated by not only pathogen-associated molecular patterns but also endogenous TLR ligands provided by injured cells. The influence of cyclosporine A (CsA)-induced renal injury on TLR expression and subsequent signaling pathway was evaluated. METHODS: Induction of chronic CsA nephropathy was made by administering CsA (15 mg/kg/day) for 28 days in rats. The TLR2 and TLR4 mRNA and protein expression, TLR-signaling pathway (MYD88, NF-kappaB and AP-1), putative TLR ligand (heat shock protein 70 [HSP70]), and maturation of dendritic cells were evaluated in CsA-treated rat kidneys. RESULTS: Long-term CsA treatment upregulated TLR2 and TLR4 mRNA and protein expression on renal tubular cells, and these were accompanied by increased MYD88, NF-kappaB and AP-1 expression. Putative TLR ligand (HSP70) was also significantly increased in CsA-treated rat kidney compared with vehicle-treated rat kidney. CsA-treatment increased expression of TNF-alpha mRNA, the number of dendritic cells, and expression of MHC class II antigen. Double-labeling of markers of dendritic cells and MHC class II antigen revealed that matured dendritic cells increased in CsA-treated rat kidney. CONCLUSIONS: CsA-induced renal injury stimulates components of innate immunity, and this finding suggests close association between CsA-induced renal injury and activation of innate immunity.

Animals↗
PubMed2003

A dominant role of Toll-like receptor 4 in the signaling of apoptosis in bacteria-faced macrophages.

Conserved bacterial components potently activate host immune cells through transmembrane Toll-like receptors (TLRs), which trigger a protective immune response but also may signal apoptosis. In this study, we investigated the roles of TLR2 and TLR4 as inducers of apoptosis in Yersinia enterocolitica-infected macrophages. Yersiniae suppress activation of the antiapoptotic NF-kappaB signaling pathway in host cells by inhibiting inhibitory kappaB kinase-beta. This leads to macrophage apoptosis under infection conditions. Experiments with mouse macrophages deficient for TLR2, TLR4, or both receptors showed that, although yersiniae could activate signaling through both TLR2 and TLR4, loss of TLR4 solely diminished Yersinia-induced apoptosis. This suggests implication of TLR4, but not of TLR2, as a proapoptotic signal transducer in Yersinia-conferred cell death. In the same manner, agonist-specific activation of TLR4 efficiently mediated macrophage apoptosis in the presence of the proteasome inhibitor MG-132, an effect that was less pronounced for activation through TLR2. Furthermore, the extended stimulation of overexpressed TLR4 elicited cellular death in epithelial cells. A dominant-negative mutant of Fas-associated death domain protein could suppress TLR4-mediated cell death, which indicates that TLR4 may signal apoptosis through a Fas-associated death domain protein-dependent pathway. Together, these data show that TLR4 could act as a potent inducer of apoptosis in macrophages that encounter a bacterial pathogen.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation?

BACKGROUND: Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors. METHODS: Human peripheral blood monocytes were treated with LPS, TNFalpha, and IL-1beta in the presence or absence of 25mM alcohol for 1 hr. NF-kappaB activation was determined by electrophoretic mobility shift assays using nuclear extracts. Inhibitory kappaB(alpha) (IkappaB(alpha)) was estimated by Western blotting in cytoplasmic extracts. Chinese hamster ovary cells expressing human CD14 were treated with LPS in the presence or absence of alcohol to study NF-kappaB and IkappaB(alpha) regulation. RESULTS: Our results indicate that acute alcohol inhibits IL-1beta- and TNFalpha-induced NF-kappaB activation. We further show in CD14/toll-like receptor 4-expressing Chinese hamster ovary cells the specificity of alcohol-mediated inhibition of NF-kappaB via the toll-like receptor 4/CD14 receptors. Inhibition of NF-kappaB by acute alcohol was concomitant with decreased levels of the IkappaB(alpha) molecule in the cytoplasm of LPS, IL-1, and TNFalpha-activated monocytes. CONCLUSIONS: These data suggest a unique, IkappaB(alpha)-independent pathway for the inhibition of NF-kappaB activation by acute alcohol in monocytes. Universal inhibition of NF-kappaB by acute alcohol via these various receptor systems suggests a target for the effects of alcohol in the NF-kappaB activation cascade that is downstream from IkappaB(alpha) degradation. Further, these results demonstrate that acute alcohol is a potent inhibitor of NF-kappaB activation by mediators of early (LPS) or late (IL-1, TNF(alpha)) stages of inflammation in monocytes.

Animals↗
PubMed2006

Heat shock proteins as vaccine adjuvants in infections and cancer.

In addition to maintaining cell homeostasis under physiological and stress conditions, some heat shock proteins (HSPs) are potent inducers of immunity and have been harnessed as vaccine adjuvants targeted to cancers and infections. HSPs are a group of ubiquitous intracellular molecules that function as molecular chaperones in numerous processes, such as protein folding and transport, and are induced under stress conditions, such as fever and radiation. Certain HSPs are potent inducers of innate and antigen-specific immunity. They activate dendritic cells partly through toll-like receptors, activate natural killer cells, increase presentation of antigens to effector cells and augment T-cell and humoral immune responses against their associated antigens. Their roles in priming multiple host defense pathways are being exploited in vaccine development for cancer and infectious diseases.

Adjuvants, Immunologic↗
PubMed2000

Structure and function of Toll-like receptor proteins.

Beginning in 1997 with the identification of the first human homologue of the Drosophila protein Toll, a family of related molecules have been identified in both humans and other mammals. These Toll-like receptor (TLR) proteins appear to represent a conserved family of innate immune recognition receptors. TLR proteins share extended homology with receptors for the cytokines interleukin 1 (IL-1) and interleukin 18 (IL-18). These receptors are coupled to a signaling pathway that is conserved in mammals, insects, and plants, resulting in cellular activation, thereby stimulating innate immune defenses. A variety of bacterial and fungal products have been identified that serve as TLR ligands, and more recent studies have identified the first endogenous protein ligands for TLR proteins. While TLR signaling is likely to be a key feature of innate immune responses, these proteins may also regulate homeostasis via interaction with endogenous protein ligands.

Amino Acid Sequence↗
PubMed2003

Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling.

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA-induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell-independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.

Animals↗
PubMed2007

The negative regulatory roles of suppressor of cytokine signaling proteins in myeloid signaling pathways.

PURPOSE OF REVIEW: Suppressor of cytokine signaling proteins are key regulators of the response of myeloid cells to cytokines and other extracellular stimuli. This review explores recent developments that have shed light on how two of the best-characterized suppressor of cytokine signaling proteins, SOCS1 and SOCS3, attenuate myeloid signaling pathways that lead to inflammation, hematological malignancy, and related disorders. RECENT FINDINGS: In addition to its 'classic' role as an inhibitor of IFNgamma signaling, a number of new regulatory roles in IFNalpha and toll-like receptor signaling have been defined for SOCS1, and substantial progress has been made in identifying the factors that give rise to lethal inflammation in Socs1 neonatal mice. The aberrant transcriptional regulation of suppressor of cytokine signaling genes in myeloid leukemia and related proliferative disorders has also been further defined. Finally, positive signs have emerged in mice that exogenous delivery of SOCS3 may be of therapeutic value. SUMMARY: Suppressor of cytokine signaling proteins have pivotal roles in attenuating cytokine and toll-like receptor signaling in myeloid cells. Understanding how defective suppressor of cytokine signaling activity contributes to inflammatory and malignant disease promises to create significant new therapeutic opportunities.

Animals↗
PubMed2006

Innate immune recognition of, and regulation by, DNA.

DNA in microbes or host cells is normally sequestered from the immune system, and therefore inert, but becomes an active immunostimulatory molecule during infection or tissue damage. Recent evidence suggests that Toll-like receptor (TLR)9, currently the only known immune sensor for DNA, recognizes more diverse elements in its ligand than initially thought, and must cooperate with additional host factors to provoke an optimal innate immune response in the physiological environment. Moreover, the innate immune system possesses a TLR9-independent, as-yet-undefined intracellular recognition machinery of double-stranded DNA that induces type I interferons through distinct signaling pathways. TLR9-dependent and TLR9-independent immune recognition of DNA might play crucial roles in DNA-associated protective immunity and in pathological autoimmunity.

Animals↗
PubMed2005

Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.

Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKalpha, IKKbeta and IKKvarepsilon kinases by means of its C-terminal region, leading to the activation of NF-kappaB and IRF3. Overexpression of Cardif results in interferon-beta and NF-kappaB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.

Adaptor Proteins, Signal Transducing↗
PubMed2007

Prevention, control, and elimination of neglected diseases in the Americas: pathways to integrated, inter-programmatic, inter-sectoral action for health and development.

BACKGROUND: In the Latin America and Caribbean region over 210 million people live below the poverty line. These impoverished and marginalized populations are heavily burdened with neglected communicable diseases. These diseases continue to enact a toll, not only on families and communities, but on the economically constrained countries themselves. DISCUSSION: As national public health priorities, neglected communicable diseases typically maintain a low profile and are often left out when public health agendas are formulated. While many of the neglected diseases do not directly cause high rates of mortality, they contribute to an enormous rate of morbidity and a drastic reduction in income for the most poverty-stricken families and communities. The persistence of this "vicious cycle" between poverty and poor health demonstrates the importance of linking the activities of the health sector with those of other sectors such as education, housing, water and sanitation, labor, public works, transportation, agriculture, industry, and economic development. SUMMARY: The purpose of this paper is three fold. First, it focuses on a need for integrated "pro-poor" approaches and policies to be developed in order to more adequately address the multi-faceted nature of neglected diseases. This represents a move away from traditional disease-centered approaches to a holistic approach that looks at the overarching causes and mechanisms that influence the health and well being of communities. The second objective of the paper outlines the need for a specific strategy for addressing these diseases and offers several programmatic entry points in the context of broad public health measures involving multiple sectors. Finally, the paper presents several current Pan American Health Organization and other institutional initiatives that already document the importance of integrated, inter-programmatic, and inter-sectoral approaches. They provide the framework for a renewed effort toward the efficient use of resources and the development of a comprehensive integrated solution to neglected communicable diseases found in the context of poverty, and tailored to the needs of local communities.

Caribbean Region↗
PubMed2003

Activation of signaling pathways by putative scavenger receptor class A (SR-A) ligands requires CD14 but not SR-A.

Macrophage scavenger class A type I and type II receptors (SR-A) are trimeric, integral membrane glycoproteins that bind an unusually broad array of macromolecular ligands. These ligands include modified proteins and lipoproteins, nucleic acids, and a variety of plant and microbial cell wall constituents, such as fucoidan and lipoteichoic acid. Early studies of SR-A functions indicated that the receptors bound, internalized, and degraded their ligands without provoking any macrophage activating signaling events. More recent studies have provided evidence that several SR-A ligands can activate macrophage gene expression via utilization of a receptor-linked, PI3-kinase pathway. To investigate the role of SR-A in engaging signal transduction events, we employed macrophages taken from mice lacking these receptors. Using either fucoidan or lipoteichoic acid, we confirm that both ligands stimulate tyrosine phosphorylation of PI3-kinase and production of modest levels of the cytokine, TNFalpha. However, macrophages taken from SR-A null mice did not differ from wild type macrophages in these responses, indicating that these signaling events arise independently of SR-A activity. Employing mice lacking CD14, a GPI anchored receptor that binds bacterial lipopolysaccharide and signals via activation of Toll-like receptors, we show that the fucoidan and lipoteichoic acid responses are largely abrogated when CD14 is absent. These data do not provide support for direct SR-A involvement in signal transduction events and suggest that the early characterization of these receptors as initiators of a non-phlogistic, pathogen clearance pathway was correct.

Animals↗
PubMed2004

Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice.

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostanoid biosynthesis, plays a key role in gastrointestinal carcinogenesis. Among various prostanoids, prostaglandin E2 (PGE2) appears to be most responsible for cancer development. To investigate the role of PGE2 in gastric tumorigenesis, we constructed transgenic mice simultaneously expressing COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the gastric epithelial cells. The transgenic mice developed metaplasia, hyperplasia and tumorous growths in the glandular stomach with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics treatment did not affect the macrophage accumulation. Notably, treatment of the transgenic mice with lipopolysaccharides induced proinflammatory cytokines through Toll-like receptor 4 in the gastric epithelial cells. These results indicate that an increased level of PGE2 enhances macrophage infiltration, and that they are activated through epithelial cells by the gastric flora, resulting in gastric metaplasia and tumorous growth. Furthermore, Helicobacter infection upregulated epithelial PGE2 production, suggesting that the COX-2/mPGES-1 pathway contributes to the Helicobacter-associated gastric tumorigenesis.

Animals↗
PubMed2005

Transcriptional signaling by double-stranded RNA: role of TLR3.

Mammalian Toll-like receptors recognize components of invading microbes and trigger the first line of innate immune response that is mediated by transcriptional induction of a large number of cellular genes. Toll-like receptor 3 (TLR3) is thought to be a major mediator of cellular response to viral infection, because it responds to double-stranded (ds) RNA, a common by-product of viral replication. This article is focused on the nature of the signaling pathways activated by TLR3 and dsRNA. The genes induced by TLR3 activation include those that encode secreted antiviral cytokines, such as interferon (IFN), and those that encode intracellular viral stress-inducible proteins. Recent studies have revealed several unique features of TLR3 signaling that are highlighted here. Specifically, we discuss the roles of receptor tyrosine phosphorylation, PI3 kinase and two-step activation of the transcription factors, IRF-3 and NF-kappaB, in mediating TLR3-signaling.

Animals↗