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PubMed2005

Microbial compounds induce the expression of pro-inflammatory cytokines, chemokines and human beta-defensin-2 in vaginal epithelial cells.

Vaginal epithelium has a powerful innate immune system that protects the female reproductive organs from bacterial and fungal infections. In the present study, we aimed to explore whether the Toll-like receptor (TLR) signaling pathway and the induction of pro-inflammatory cytokines and antimicrobial peptides could contribute to the protection against pathogenic microorganisms in vaginal epithelia, using an immortalized vaginal epithelial cell line PK E6/E7 as a model. We found that TLR2 and TLR4 receptors are expressed in vivo in the vaginal epithelia and in vitro in PK E6/E7 vaginal epithelial cell line. The Gram-negative cell wall compound lipopolysaccharide (LPS), the Gram-positive compound peptidoglycan (PGN), heat-killed Candida albicans and zymosan significantly (P<0.05) induced the expression of pro-inflammatory cytokines and chemokines such as TNF-alpha and IL-8/CXCL8 in vaginal epithelial cells. Furthermore, the expression and production of human beta-defensin-2 (hBD2), an antimicrobial peptide with chemotactic functions, was also up-regulated in PK E6/E7 cells after treatment with LPS, PGN or C. albicans. Treatment of vaginal epithelial cells with microbial compounds induced the activation and nuclear translocation of NF-kappaB transcription factor, a key element of innate and adaptive immune responses. In our work, we provide evidence that microbial compounds induce the production of pro-inflammatory cytokines, chemokines and antimicrobial peptides in vaginal epithelial cells. In vivo, vaginal epithelial cell-derived inflammatory mediators and antimicrobial peptides may play important roles in vaginal immune responses and in the elimination of pathogens from the female reproductive tract.

Candida albicans↗
PubMed2005

Chlamydophila pneumoniae induces expression of toll-like receptor 4 and release of TNF-alpha and MIP-2 via an NF-kappaB pathway in rat type II pneumocytes.

BACKGROUND: The role of alveolar type II cells in the regulation of innate and adaptive immunity is unclear. Toll-like receptors (TLRs) have been implicated in host defense. The purpose of the present study was to investigate whether Chlamydophila pneumoniae (I) alters the expression of TLR2 and/orTLR4 in type II cells in a (II) Rho-GTPase- and (III) NF-kappaB-dependent pathway, subsequently (IV) leading to the production of (IV) pro-inflammatory TNF-alpha and MIP-2. METHODS: Isolated rat type II pneumocytes were incubated with C. pneumoniae after pre-treatment with calcium chelator BAPTA-AM, inhibitors of NF-kappaB (parthenolide, SN50) or with a specific inhibitor of the Rho-GTPase (mevastatin). TLR2 and TLR4 mRNA expressions were analyzed by PCR. Activation of TLR4, Rac1, RhoA protein and NF-kappaB was determined by Western blotting and confocal laser scan microscopy (CLSM) and TNF-alpha and MIP-2 release by ELISA. RESULTS: Type II cells constitutively expressed TLR4 and TLR2 mRNA. A prominent induction of TLR4 but not TLR2 mRNA was detected after 2 hours of incubation with C. pneumoniae. The TLR4 protein expression reached a peak at 30 min, began to decrease within 1-2 hours and peaked again at 3 hours. Incubation of cells with heat-inactivated bacteria (56 degrees C for 30 min) significantly reduced the TLR4 expression. Treated bacteria with polymyxin B (2 mug/ml) did not alter TLR4 expression. C. pneumoniae-induced NF-kappaB activity was blocked by TLR4 blocking antibodies. TLR4 mRNA and protein expression were inhibited in the presence of BAPTA-AM, SN50 or parthenolide. TNF-alpha and MIP-2 release was increased in type II cells in response to C. pneumoniae, whereas BAPTA-AM, SN50 or parthenolide decreased the C. pneumoniae-induced TNF-alpha and MIP-2 release. Mevastatin inhibited C. pneumoniae-mediated Rac1, RhoA and TLR4 expression. CONCLUSION: The TLR4 protein expression in rat type II cells is likely to be mediated by a heat-sensitive C. pneumoniae protein that induces a fast Ca2+-mediated NF-kappaB activity, necessary for maintenance of TLR4 expression and TNF-alpha and MIP-2 release through possibly Rac and Rho protein-dependent mechanism. These results indicate that type II pneumocytes play an important role in the innate pulmonary immune system and in inflammatory response mechanism of the alveolus.

Animals↗
PubMed2006

Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta.

Vaccinia virus (VV) has been used extensively as a vaccine vehicle in the clinical application for infectious diseases and cancer. Previous studies have suggested that the unique potency of VV-based vaccine lies in its effective activation of the innate immune system. However, how VV activates innate immune pathways remains largely unknown. In this study, we showed that VV elicited innate immune response through both Toll-like receptor (TLR)-dependent and -independent pathways. The TLR pathway was mediated by TLR2 and MyD88, leading to the production of proinflammatory cytokines, whereas activation of the TLR-independent pathway resulted in the secretion of IFN-beta. More importantly, both TLR-dependent and -independent pathways were required for activating innate and adaptive immunity to VV in vivo. These findings represent the first evidence that innate immune recognition of VV is mediated by TLR2, demonstrate that one pathogen can target both TLR and non-TLR innate immune pathways to work together in achieving efficient activation of host defense, and suggest potential new strategies for the design of effective vaccines.

Animals↗
PubMed1994

Dorsal, a Drosophila Rel-like protein, is phosphorylated upon activation of the transmembrane protein Toll.

The nuclear import of dorsal, a Drosophila Rel homolog, is directed by a spatially restricted extracellular ligand in blastoderm embryos. We have demonstrated both that dorsal is an embryonic phosphoprotein and that its phosphorylation state is regulated by an intracellular signaling pathway initiated by the transmembrane receptor Toll. Immunoblot analysis of cytoplasm from precisely staged embryos revealed that the phosphorylation state of dorsal is altered during the time period that Toll is activated. Moreover, mutations that constitutively activate Toll stimulated dorsal phosphorylation, while mutations that block Toll activation reduced the level of dorsal phosphorylation. We further demonstrated that signal-dependent dorsal phosphorylation is modulated by three intracellular proteins, pelle, tube, and cactus. Using double-mutant embryos, we then explored the nature of the kinase activity responsible for dorsal phosphorylation. We found that free dorsal is a substrate for a signal-independent kinase activity. In addition, our results imply that dorsal is a substrate for a Toll-dependent kinase. These results are consistent with the hypothesis that phosphorylation of Rel-related proteins may be required for the proper nuclear localization and transcriptional activity of these proteins.

Animals↗
PubMed2004

Peptidoglycan recognition proteins (PGRPs).

Innate immune system recognizes microorganisms through a series of pattern recognition receptors that are highly conserved in evolution. Peptidoglycan recognition proteins (PGRPs) are pattern recognition molecules that are conserved from insects to mammals and recognize bacteria and their unique cell wall component, peptidoglycan (PGN). Drosophila, mosquito, and mammals have families of 13, 7, and 4 PGRP genes, respectively, and some of these genes are alternatively spliced. PGRPs are differentially expressed in various cells and tissues, their expression is often upregulated by bacteria, and they mediate host responses to bacterial infections. Insect PGRPs have four known effector functions that are unique for insects: activation of prophenoloxidase cascade, activation of Toll receptor, activation of Imd pathway, and induction of phagocytosis. One function, amidase activity, is shared by some insect and mammalian PGRPs, whereas antibacterial activity of some mammalian PGRPs is unique for mammals.

Animals↗
PubMed2006

Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice.

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis. Here we describe a novel role for a caspase in dampening responses to bacterial infection. We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock. The resulting survival advantage was conferred by the ability of the caspase-12-deficient mice to clear bacterial infection more efficiently than wild-type littermates. Caspase-12 dampened the production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-18 (interferon (IFN)-gamma inducing factor) and IFN-gamma, but not tumour-necrosis factor-alpha and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma receptors ablated the survival advantage that otherwise occurred in these animals. Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity. Notably, the protease function of caspase-12 was not necessary for this effect, as the catalytically inactive caspase-12 mutant Cys299Ala also inhibited caspase-1 and IL-1beta production to the same extent as wild-type caspase-12. In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade. In mice, caspase-12 deficiency confers resistance to sepsis and its presence exerts a dominant-negative suppressive effect on caspase-1, resulting in enhanced vulnerability to bacterial infection and septic mortality.

Animals↗
PubMed2006

Targeting signal transduction as a strategy to treat inflammatory diseases.

Inflammatory diseases are a major burden on humanity, despite recent successes with biopharmaceuticals. Lack of responsiveness and resistance to these drugs, delivery problems and cost of manufacture of biopharmaceuticals mean that the search for new anti-inflammatory agents continues. Progress in our understanding of inflammatory signalling pathways has identified new targets, notably in pathways involving NF-kappaB, p38 MAP kinase, T lymphocyte activation and JAK/STAT. Other targets such as transcription factor complexes and components of pathways activated by TNF, Toll-like receptors and Nod-like receptors also present possibilities, and might show efficacy without being limited by effects on host defence. The challenge is to place a value on one target relative to another, and to devise strategies to modulate them.

Animals↗
PubMed2002

Constitutive expression of a single antimicrobial peptide can restore wild-type resistance to infection in immunodeficient Drosophila mutants.

One of the characteristics of the host defense of insects is the rapid synthesis of a variety of potent antibacterial and antifungal peptides. To date, seven types of inducible antimicrobial peptides (AMPs) have been characterized in Drosophila. The importance of these peptides in host defense is supported by the observation that flies deficient for the Toll or Immune deficiency (Imd) pathway, which affects AMP gene expression, are extremely susceptible to microbial infection. Here we have developed a genetic approach to address the functional relevance of a defined antifungal or antibacterial peptide in the host defense of Drosophila adults. We have expressed AMP genes via the control of the UAS/GAL4 system in imd; spätzle double mutants that do not express any known endogenous AMP gene. Our results clearly show that constitutive expression of a single peptide in some cases is sufficient to rescue imd; spätzle susceptibility to microbial infection, highlighting the important role of AMPs in Drosophila adult host defense.

Animals↗
PubMed2006

Key inflammatory signaling pathways are regulated by the proteasome.

Lipopolysaccharide (LPS) is a major structural component of all Gram-negative organisms and has been implicated in Gram-negative sepsis and septic shock. In the present study, Affymetrix microarray analysis of RNA derived from murine macrophages treated with LPS in the absence or presence of the proteasome inhibitor lactacystin revealed that the vast majority of genes regulated by LPS is under control of the proteasome. Analysis of the data has revealed that the products of these genes participate in 14 distinct signaling pathways. This represents a novel approach to the identification of signaling pathways that are both toll-like receptor 4- and proteasome-dependent and may lead to the development of new drug targets in Gram-negative sepsis and septic shock.

Acetylcysteine↗
PubMed2006

Mammalian PGRPs: novel antibacterial proteins.

Peptidoglycan recognition proteins (PGRPs) are innate immunity molecules conserved from insects to mammals. Insects have up to 19 PGRPs, which activate Toll or Imd signal transduction pathways or induce proteolytic cascades that generate antimicrobial products, induce phagocytosis, hydrolyse peptidoglycan, and protect insects against infections. Mammals have four PGRPs, which were hypothesized to function as signal-transducing pattern recognition receptors. However, all mammalian PGRPs are secreted, usually as disulphide-linked homo- and heterodimers. One mammalian PGRP, PGLYRP-2, is an N-acetylmuramoyl-L-alanine amidase that hydrolyses bacterial peptidoglycan and reduces its proinflammatory activity. PGLYRP-2 is secreted from liver into blood, and is also induced by bacteria in epithelial cells. The three remaining mammalian PGRPs are bactericidal or bacteriostatic proteins. PGLYRP-1 is expressed primarily in the granules of polymorphonuclear leucocytes (PMNs) , and PGLYRP-3 and PGLYRP-4 are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach and intestine, and protect the host against infections. They kill bacteria by interacting with their cell wall peptidoglycan, rather than permeabilizing their membranes. These PGRPs therefore are a new class of bactericidal and bacteriostatic proteins that have different structure, mechanism of action, and expression pattern from currently known vertebrate antimicrobial peptides. Direct bactericidal activity of these PGRPs either evolved in vertebrates or mammals, or it is yet to be discovered in insects.

Animals↗
PubMed2006

Innate immune defense through RNA interference.

RNA interference (RNAi, also known as RNA silencing) has recently emerged as a fundamental and widespread regulator of gene expression. New developments in this field implicate RNAi in the innate immune response to infection in plants and animals. Evidence from plants, tissue culture cells, and Caenorhabditis elegans-based systems previously suggested that RNAi plays a role in the defense against viral infection, but definitive evidence using viruses and whole animals has been lacking. Two recent reports now show that both Drosophila embryos and adult flies mount a substantial innate immune response to insect viruses that requires the RNAi machinery. This innate response is distinct from known bacterial and fungal defense systems provided by the Toll and immune deficiency (Imd) pathways, thus defining a previously unrecognized strategy to fight viral infection. Whether RNAi, aside from its function in counteracting viruses, is also used to fight bacterial infection remained enigmatic. New evidence, however, now shows that in Arabidopsis, the bacterial component, flagellin, induces the expression of a specific microRNA, which in turn leads to the down-regulation of the signaling pathways that are implicated in disease susceptibility. This down-regulation then increases the plant's resistance to infection. Whether RNAi mechanisms also exist for combating bacterial diseases in animals remains an intriguing question for future studies.

Animals↗
PubMed2006

Induction of in vivo antipolysaccharide immunoglobulin responses to intact Streptococcus pneumoniae is more heavily dependent on Btk-mediated B-cell receptor signaling than antiprotein responses.

The relative role of Btk-dependent B-cell receptor (BCR) signaling in the induction of antipolysaccharide (anti-PS) and antiprotein immunoglobulin (Ig) responses to an intact extracellular bacterium in vivo is unknown. Btklow mice exhibit reduced BCR signaling but largely restore B-cell development. Btklow mice immunized with intact Streptococcus pneumoniae elicit reduced anti-PS but normal antiprotein Ig responses. Immunization of Btklow mice with PS-protein conjugate in saline results in an even more profound defect in the anti-PS but not antiprotein response, which is largely restored by use of a CpG-containing oligodeoxynucleotide as an adjuvant. These data demonstrate a greater dependence on Btk-mediated BCR signaling for physiologic anti-PS relative to antiprotein responses, as well as the existence of a compensatory Toll-like-receptor-mediated signaling pathway naturally triggered in response to intact bacterial pathogens.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Illuminating the role of type I IFNs in colitis.

Recently, type I interferons IFN-alpha and IFN-beta (IFN-alpha/beta) have been evaluated in pilot clinical trials for the treatment of active ulcerative colitis. However, the underlying mechanisms that may contribute to a potential therapeutic effect are incompletely understood. A new study in this issue demonstrates a protective role for IFN-alpha/beta, induced by activation of a Toll-like receptor 9-dependent pathway, in a rodent model of experimental colitis.

Animals↗
PubMed2005

Airway epithelial cell tolerance to Pseudomonas aeruginosa.

BACKGROUND: The respiratory tract epithelium is a critical environmental interface that regulates inflammation. In chronic infectious airway diseases, pathogens may permanently colonize normally sterile luminal environments. Host-pathogen interactions determine the intensity of inflammation and thus, rates of tissue injury. Although many cells become refractory to stimulation by pathogen products, it is unknown whether the airway epithelium becomes either tolerant or hypersensitive in the setting of chronic infection. Our goals were to characterize the response of well-differentiated primary human tracheobronchial epithelial cells to Pseudomonas aeruginosa, to understand whether repeated exposure induced tolerance and, if so, to explore the mechanism(s). METHODS: The apical surface of well-differentiated primary human tracheobronchial epithelial cell cultures was repetitively challenged with Pseudomonas aeruginosa culture filtrates or the bacterial media control. Toxicity, cytokine production, signal transduction events and specific effects of dominant negative forms of signaling molecules were examined. Additional experiments included using IL-1beta and TNFalpha as challenge agents, and performing comparative studies with a novel airway epithelial cell line. RESULTS: An initial challenge of the apical surface of polarized human airway epithelial cells with Pseudomonas aeruginosa culture filtrates induced phosphorylation of IRAK1, JNK, p38, and ERK, caused degradation of IkappaBalpha, generation of NF-kappaB and AP-1 transcription factor activity, and resulted in IL-8 secretion, consistent with activation of the Toll-like receptor signal transduction pathway. These responses were strongly attenuated following a second Pseudomonas aeruginosa, or IL-1beta, but not TNFalpha, challenge. Tolerance was associated with decreased IRAK1 protein content and kinase activity and dominant negative IRAK1 inhibited Pseudomonas aeruginosa--stimulated NF-kappaB transcriptional activity. CONCLUSION: The airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1.

Cell Line↗
PubMed2006

Suppressor of cytokine signaling 1 inhibition strategy to enhance anti-HIV vaccination.

Extensive efforts aimed at stimulating immune responses by modifying HIV antigens and using various delivery systems and adjuvants have so far failed to generate promising HIV vaccines, highlighting the urgent need to explore alternative immunization approaches. Antigen-presenting cells, such as dendritic cells, play a critical role in the initiation and maintenance of immune responses against HIV infection and dendritic cells are regulated by stimulatory, as well as inhibitory signaling. Recent studies demonstrate that the suppressor of cytokine signaling 1 (SOCS1) functions as an antigen-presentation attenuator by restricting the Janus-activated kinase-signal transducers and activators of transcription and Toll-like receptor-signaling pathways. SOCS1-silenced dendritic cells produce higher levels of both T-helper 1- and 2-polarizing cytokines, broadly enhance memory HIV-specific B-cell and T-cell responses and activate natural killer cells owing to unbridled cytokine feedback signaling loops. Therefore, the inhibition of antigen-presentation attenuators represents a generally applicable and alternative strategy for enhancing the potency of various forms of prophylactic and therapeutic HIV vaccines.

AIDS Vaccines↗
PubMed2006

Targeting the inflammatory response in healing myocardial infarcts.

Healing of myocardial infarcts depends on an inflammatory cascade that ultimately results in clearance of dead cells and matrix debris and formation of a scar. Myocardial necrosis activates complement, Nuclear Factor (NF)-kappaB and Toll-like Receptor (TLR)-dependent pathways, and generates free radicals, triggering an inflammatory response. Chemokines and cytokines are markedly induced in the infarct and mediate recruitment and activation of neutrophils and mononuclear cells. Extravasation of platelets and plasma proteins, such as fibrinogen and fibronectin, results in formation of a clot, consisting of platelets embedded in a mesh of crosslinked fibrin. This provisional matrix provides a scaffold for migration of cells into the infarct. Monocytes differentiate into macrophages and secrete fibrogenic and angiogenic growth factors inducing formation of granulation tissue, containing myofibroblasts and neovessels. Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition. Infarct myofibroblasts deposit extracellular matrix proteins and a collagen-based scar is formed. As the wound matures, fibroblasts undergo apoptosis and neovessels regress, resulting in formation of a scar with a low cellular content containing dense, cross-linked collagen. The pathologic and structural changes associated with infarct healing directly influence ventricular remodeling and affect prognosis in patients with myocardial infarction. Understanding the mechanisms involved in the regulation of the post-infarction inflammatory response, and the spatial and temporal parameters of wound healing is necessary in order to identify specific molecular targets for therapeutic intervention.

Chemokines↗
PubMed2001

Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction.

Gram-negative sepsis is mediated by the actions of proinflammatory genes induced in response to microbes and their products. We report that flagellin, the monomeric subunit of flagella, is a potent proinflammatory species released by Salmonella. Flagellin (1 microgram/ml) induces IkappaBalpha degradation, NF-kappaB nuclear translocation, and inducible NO synthase expression in cultured intestinal epithelial cells (IEC). Aflagellic Salmonella mutants do not induce NF-kappaB activation or NO production by cultured IEC. Antiserum to flagellin blocks NO production in IEC induced by medium conditioned by a variety of motile Gram-negative enteric pathogens (Escherichia coli, Salmonella muenchen, Serratia marcescens, Proteus mirabilis, and Proteus vulgaris). Flagellin, when injected systemically (approximately 10 microgram/mouse), induces systemic inflammation characterized by the systemic expression of a range of proinflammatory cytokines and chemokines and of inducible NO synthase. At higher doses (approximately 300 microgram/mouse), flagellin induces shock, characterized by hypotension, reduced vascular contractility in mice, and death. The effects of flagellin do not diminish in C3H/HeJ LPS-resistant mice, indicating that the Toll-like receptor-4 receptor is not involved in flagellin's actions. In LPS-resistant mice, i.p. injection of S. dublin flagellin or medium conditioned by wild-type S. dublin induces serum IFN-gamma and TNF-alpha, whereas medium conditioned by aflagellic mutants has no effect. Flagellin can be detected in the blood of rats with septic shock induced by live bacteria at approximately 1 microg/ml. We propose that flagellin released by Gram-negative pathogens may contribute to the inflammatory response by an LPS- and Toll-like receptor-4-independent pathway.

Amino Acid Sequence↗
PubMed2004

Autoreactive T cells persist in rats protected against experimental autoimmune encephalomyelitis and can be activated through stimulation of innate immunity.

Lewis rats can be rendered unresponsive to experimental autoimmune encephalomyelitis by immunization with myelin basic protein (MBP), or MBP68-86, the dominant encephalitogenic MBP epitope for this strain, administered in IFA. However, protected rats harbor potentially encephalitogenic T cells, which are maintained in an inactive state. We investigated whether these quiescent effector cells could be activated in vitro. Although these T cells respond poorly to MBP68-86, they proliferate vigorously whether cocultured with MBP68-86 and either IL-2 or IL-12, suggesting that the T cells are in a state of anergy. Moreover, we could activate these anergic T cells with peptide and cytosine-guanine dinucleotide (CpG) oligonucleotide, but not control oligonucleotide, suggesting that products of the innate immune response are capable of activating anergic autoreactive T cells. The activated T cells produced the proinflammatory cytokine, IFN-gamma in response to IL-12, and IL-6 was secreted in response to CpG oligonucleotide. IL-6 has been reported to play a role in T cell activation by blocking T regulatory/suppressor (Treg) cell-mediated suppression through a Toll-like receptor-dependent pathway. However, anti-IL-6 mAb did not block CpG activation of the anergized cells. In contrast, anti-TGF-beta(1) Ab released the unresponsive T cells from the anergic state in the presence of MBP68-86, whereas TGF-beta(1) inhibited proliferation of MBP68-86- plus CpG-activated T cells. Because TGF-beta(1) has previously been implicated in Treg activity, this finding is consistent with a role for Treg cells in maintaining autoreactive T cells in the anergic state.

Amino Acid Sequence↗