Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TOLL pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,657 records · Page 92Linked to original sources
PubMed2006

Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts.

Rheumatoid arthritis (RA) is characterized by infiltrations of inflammatory cells accompanied by neovascularization in the joint. We hypothesized that cell activation via the toll-like receptor (TLR) may be involved in the induction of angiogenic molecules, which are relevant to the pathogenesis of RA. RA fibroblast like synoviocytes (FLS) were stimulated with TLR-2 ligand bacterial peptidoglycan (PGN), TLR-4 ligand lipopolysaccharide (LPS) and various cytokines. Vascular endothelial growth factor (VEGF) and IL-8 were measured by ELISA in culture supernatants; mRNA levels were assessed by RT-PCR and real time PCR. The levels of TLR-2, VEGF and IL-8 were analyzed by dual immunohistochemistry in RA synovium and compared with osteoarthritis (OA). Regulation of MyD88, IRAK4, IRAK1, IRAK-M and TRAF-6 mRNA expression levels by PGN were analyzed by RT-PCR. Phosphorylation of I kappa B alpha was evaluated by western blotting. Levels of VEGF and IL-8 were upregulated in culture supernatants of RA FLS stimulated with PGN, similar to the levels of IL-1beta and IL-17 stimulation. Neutralization of TLR-2 with a blocking monoclonal antibody significantly reduced both VEGF and IL-8 levels (P<0.05), which reflected the functional relevance of TLR-2 activation to the induction of VEGF and IL-8 production. Downstream intracellular signaling following TLR-2 stimulation involved MyD88-IRAK-4-TRAF-6 pathways, resulting in NF-kappaB activation. Thus, TLR-2 activation in RA FLS by microbial constituents could be involved in the induction of VEGF and IL-8 and thereby promote inflammation either directly or via angiogenesis. This possibly contributes to the perpetuation of synovitis in patients with RA.

Angiogenesis Inducing Agents↗
PubMed2005

Enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids.

Teichoic acids (TAs), and especially lipoteichoic acids (LTAs), are one of the main immunostimulatory components of pathogenic Gram-positive bacteria. Their contribution to the immunomodulatory properties of commensal bacteria and especially of lactic acid bacteria has not yet been investigated in detail. To evaluate the role of TAs in the interaction between lactic acid bacteria and the immune system, we analyzed the antiinflammatory properties of a mutant of Lactobacillus plantarum NCIMB8826 affected in the TA biosynthesis pathway both in vitro (mononuclear cells stimulation) and in vivo (murine model of colitis). This Dlt- mutant was found to incorporate much less D-Ala in its TAs than the WT strain. This defect significantly impacted the immunomodulation reactions induced by the bacterium, as shown by a dramatically reduced secretion of proinflammatory cytokines by peripheral blood mononuclear cells and monocytes stimulated by the Dlt- mutant as compared with the parental strain. Concomitantly, a significant increase in IL-10 production was stimulated by the Dlt- mutant in comparison with the WT strain. Moreover, the proinflammatory capacity of L. plantarum-purified LTA was found to be Toll-like receptor 2-dependent. Consistent with the in vitro results, the Dlt- mutant was significantly more protective in a murine colitis model than its WT counterpart. The results indicated that composition of LTA within the whole-cell context of L. plantarum can modulate proinflammatory or antiinflammatory immune responses.

Analysis of Variance↗
PubMed2000

The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense.

The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor NF-kappaB and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (termed IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and the Toll-like receptors TLR-2 and TLR-4, which bind molecules from Gram-positive and Gram-negative bacteria, respectively. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by IL-18R and TLR-4. The receptor superfamily is evolutionarily conserved; members occur in plants and insects and also function in host defense. The signaling proteins activated are also conserved across species. This receptor superfamily therefore represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.

Animals↗
PubMed2002

Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity.

The astounding adjuvanticity and Th1-polarizing immunobiology of bacterial CpG-DNA and mimicking CpG-oligonucleotides continue to mirror promising therapeutic potential. The past year has witnessed some particularly impressive progress in knowledge of its molecular mode of action. Accordingly, CpG-DNA acts as a "pathogen-associated" molecular pattern that is recognized by TLR9 expressed, in particular, by dendritic cells. Interactions between CpG-DNA and TLR9 rapidly activate antigen-presenting dendritic cells through the ancient Toll/IL-1-receptor signaling pathway to upregulate co-stimulatory molecules and to produce Th1-polarizing cytokines, such as interleukin-12 and interleukin-18. Thus, interactions between CpG-DNA and TLR9 effectively bridge innate and acquired immunity.

Animals↗
PubMed2002

Induction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression.

Tolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.

Bacterial Outer Membrane Proteins↗
PubMed2006

Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release.

BACKGROUND: Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity. OBJECTIVE: In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human T(H)2 cells was performed. METHODS: The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells. RESULTS: The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-alpha, and IL-6 by CD14(+) cells and IFN-alpha and CXCL10 by blood dendritic cell antigen (BDCA)-4(+) plasmacytoid dendritic cells. A nuclear factor kappaB-dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific T(H)2 cells toward the T(H)1/T(H)0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors. CONCLUSION: Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific T(H)2 cells to a T(H)1/T(H)0 phenotype. CLINICAL IMPLICATIONS: Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.

Adenine↗
PubMed2006

The ASK1-MAP kinase pathways in immune and stress responses.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase which plays pivotal roles in stress and immune responses. This review is focused on three major subjects on ASK1: the regulatory mechanisms of the kinase activity, the pathophysiological roles in stress response and innate immunity, and the evolutionary perspectives.

Animals↗
PubMed2001

Regulation of antibacterial and antifungal innate immunity in fruitflies and humans.

Insects have been very successful in adapting to their environment, and the ability of the insect immune system to detect and elicit the appropriate response against various invading pathogens has helped in this success. Unlike the vertebrate immune system, which consists of both innate and adaptive components, insect immunity probably consists entirely of an innate immune response, as no evidence of an adaptive response has been found. The innate immune response is described as either a reaction against "lack of self," or the interaction between host germline-encoded receptors and molecules unique to a particular class of invading organisms. Once the invading organism is recognized, the host immune response can be activated via signaling pathways that lead to the appropriate reaction. This review endeavors to put forth how through genetic, molecular, and biochemical studies of the fruit fly Drosophila melanogaster, as well as other insects, it is now understood that aspects of the insect and vertebrate innate immune system are very similar.

Animals↗
PubMed2005

Dendritic cells and NK cells stimulate bystander T cell activation in response to TLR agonists through secretion of IFN-alpha beta and IFN-gamma.

Recognition of conserved features of infectious agents by innate pathogen receptors plays an important role in initiating the adaptive immune response. We have investigated early changes occurring among T cells after injection of TLR agonists into mice. Widespread, transient phenotypic activation of both naive and memory T cells was observed rapidly after injection of molecules acting through TLR3, -4, -7, and -9, but not TLR2. T cell activation was shown to be mediated by a combination of IFN-alphabeta, secreted by dendritic cells (DCs), and IFN-gamma, secreted by NK cells; notably, IFN-gamma-secreting NK cells expressed CD11c and copurified with DCs. Production of IFN-gamma by NK cells could be stimulated by DCs from TLR agonist-injected mice, and although soluble factors secreted by LPS-stimulated DCs were sufficient to induce IFN-gamma, maximal IFN-gamma production required both direct contact of NK cells with DCs and DC-secreted cytokines. In vitro, IFN-alphabeta, IL-18, and IL-12 all contributed to DC stimulation of NK cell IFN-gamma, whereas IFN-alphabeta was shown to be important for induction of T cell bystander activation and NK cell IFN-gamma production in vivo. The results delineate a pathway involving innate immune mediators through which TLR agonists trigger bystander activation of T cells.

Animals↗
PubMed2005

Priming effect of lipopolysaccharide on acetyl-coenzyme A:lyso-platelet-activating factor acetyltransferase is MyD88 and TRIF independent.

LPS has a priming effect on various stimuli. For instance, LPS priming enhances the production of platelet-activating factor (PAF), a proinflammatory lipid mediator that is induced by PAF itself. Among various enzymes responsible for PAF biosynthesis, acetyl-coenzyme A:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase is one of the enzymes activated by PAF receptor stimulation. In this study we investigated the priming effect of LPS on the acetyltransferase activation by PAF in TLR4-knockout (KO) mice, MyD88-KO mice, and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF)-KO mice. This enzyme was biphasically activated by LPS. Although the first peak occurred within 30 min in wild-type (WT), but not TLR4-KO or MyD88-KO, macrophages, the second phase reached a maximum within hours in WT, MyD88-KO, and TRIF-KO, but not in TLR4-KO, macrophages. Only in the second phase was the increase in acetyltransferase activity upon PAF receptor activation remarkably enhanced in WT, MyD88-KO, and TRIF-KO cells, but not in TLR4-KO cells. These data demonstrated that LPS exerted a priming effect on PAF receptor-mediated acetyltransferase activation through the TLR4-dependent, but MyD88- and TRIF-independent, pathway.

Acetyl Coenzyme A↗
PubMed2007

TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat.

Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in diabetes, we used a model of viral induction of autoimmune diabetes in genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop diabetes in viral-Ab-free environments, but approximately 25% of animals infected with the parvovirus Kilham rat virus (KRV) develop autoimmune diabetes via a mechanism that does not involve beta cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-alpha. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-kappaB. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and autoimmune diabetes in the BBDR rat.

Animals↗
PubMed2026

Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation.

Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 ("Pam2ODN") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.

Animals↗
PubMed2004

Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family.

TIR8, also known as single Ig IL-1-related receptor, is a member of the IL-1 receptor/Toll-like receptor (TLR) superfamily, which acts as an intracellular decoy for components of the signaling pathway. Here we report that Tir8 has a unique pattern of expression, which includes mucosal tissues and dendritic cells (DC). Tir8-deficient DC showed increased cytokine production in response to TLR agonists (lipopolysaccharide, CpG oligodeoxynucleotides). Tir8-deficient mice had normal susceptibility to systemic lipopolysaccharide toxicity and to i.p. or s.c. inflammation. However, Tir8-deficient mice were more susceptible to intestinal inflammation. Thus, TIR8 represents a negative pathway of regulation of the IL-1 receptor/TLR system, expressed in epithelial cells and DC, crucial for tuning inflammation in the gastrointestinal tract.

Animals↗
PubMed2000

Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes.

MD-2 is associated with TLR4 on the cell surface and enables TLR4 to respond to LPS. TLR2 without MD-2 does not respond to pure protein-free endotoxic LPS, ReLPS, and lipid A. MD-2 enables TLR2 to respond to non-activating LPS, ReLPS, and lipid A, and enhances TLR2-mediated responses to Gram-negative and Gram-positive bacteria, protein-containing LPS, peptidoglycan, and lipoteichoic acid. MD-2 enables TLR4 to respond to a wide variety of endotoxic LPS partial structures, Gram-negative bacteria, and Gram-positive lipoteichoic acid, but not to Gram-positive bacteria, peptidoglycan, and lipopeptide. MD-2 physically associates with both TLR4 and TLR2, but the association with TLR2 is weaker than with TLR4. Also, MD-2 and TLR2 and TLR4 enhance each other's expression. The highest induced genes in human monocytes stimulated with Gram-positive and Gram-negative bacterial cell wall components are chemokine genes, and IL-8 is the highest induced chemokine. Both Gram-positive and Gram-negative bacteria activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-->kappaB signal transduction pathway that induces transcription of the IL-8 gene. Therefore, TLR2 is a functional receptor for both Gram-positive and Gram-negative bacteria and it induces activation of IL-8.

Animals↗
PubMed2004

Chlamydia pneumoniae stimulates IFN-gamma synthesis through MyD88-dependent, TLR2- and TLR4-independent induction of IL-18 release.

Recent studies suggest that inflammation plays a central role in the pathogenesis of atherosclerosis, and IFN-gamma is a prominent proinflammatory mediator in this context. However, it is unclear what stimuli are responsible for initial stimulation of IFN-gamma synthesis in the vessel wall. In the present study, we demonstrate that Chlamydia pneumoniae is an important stimulus for IFN-gamma synthesis, and this production depends on release of endogenous IL-18, IL-12, and IL-1, but not of TNF. The production of the proinflammatory cytokines TNF and IL-1beta from PBMC by sonicated C. pneumoniae was mediated through TLR2-dependent pathways. In contrast, C. pneumoniae stimulated the production of IL-18 through MyD88-dependent, TLR2-, TLR4-, and CD14-independent pathways, mediated by posttranscriptional mechanisms not involving de novo protein synthesis. In conclusion, C. pneumoniae is a potent stimulus of IFN-gamma production, in addition to the proinflammatory cytokines TNF and IL-1beta, which may contribute to its proatherogenic effects. Most interestingly, C. pneumoniae is also a potent inducer of IL-18 production through pathways independent of TLR2 and TLR4.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The MyD88-dependent, but not the MyD88-independent, pathway of TLR4 signaling is important in clearing nontypeable haemophilus influenzae from the mouse lung.

TLRs are important for the recognition of conserved motifs expressed by invading bacteria. TLR4 is the signaling receptor for LPS, the major proinflammatory component of the Gram-negative cell wall, whereas CD14 serves as the ligand-binding part of the LPS receptor complex. Triggering of TLR4 results in the activation of two distinct intracellular pathways, one that relies on the common TLR adaptor MyD88 and one that is mediated by Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF). Nontypeable Haemophilus influenzae (NTHi) is a common Gram-negative respiratory pathogen that expresses both TLR4 (LPS and lipooligosaccharide) and TLR2 (lipoproteins) ligands. To determine the roles of CD14, TLR4, and TLR2 during NTHi pneumonia, the following studies were performed: 1) Alveolar macrophages from CD14 and TLR4 knockout (KO) mice were virtually unresponsive to NTHi in vitro, whereas TLR2 KO macrophages displayed a reduced NTHi responsiveness. 2) After intranasal infection with NTHi, CD14 and TLR4 KO mice showed an attenuated early inflammatory response in their lungs, which was associated with a strongly reduced clearance of NTHi from the respiratory tract; in contrast, in TLR2 KO mice, lung inflammation was unchanged, and the number of NTHi CFU was only modestly increased at the end of the 10-day observation period. 3) MyD88 KO, but not TRIF mutant mice showed an increased bacterial load in their lungs upon infection with NTHi. These data suggest that the MyD88-dependent pathway of TLR4 is important for an effective innate immune response to respiratory tract infection caused by NTHi.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation.

Reactivation of latent human cytomegalovirus (HCMV) following allogeneic transplantation is a major cause of morbidity and mortality and predisposes to severe complications, including superinfection by Aspergillus species (spp). Antimicrobial polypeptides, including defensins and mannan-binding lectin, are known to block viral fusion by cross-linking sugars on cell surface. Pentraxin 3 (PTX3), a member of the long pentraxin family, successfully restored antifungal immunity in experimental hematopoietic transplantation. We assessed here whether PTX3 binds HCMV and murine virus (MCMV) and the impact on viral infectivity and superinfection in vivo. We found that PTX3 bound both viruses, reduced viral entry and infectivity in vitro, and protected from MCMV primary infection and reactivation as well as Aspergillus superinfection. This occurred through the activation of interferon (IFN) regulatory factor 3 (IRF3) in dendritic cells via the TLR9/MyD88-independent viral recognition sensing and the promotion of the interleukin-12 (IL-12)/IFN-gamma-dependent effector pathway.

Animals↗
PubMed2006

TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae.

We present evidence for a novel TLR2 function in transmodulating the adhesive activities of human monocytes in response to the fimbriae of Porphyromonas gingivalis, a pathogen implicated in chronic periodontitis and atherosclerosis. Monocyte recruitment into the subendothelium is a crucial step in atherosclerosis, and we investigated the role of P. gingivalis fimbriae in stimulating monocyte adhesion to endothelial cells and transendothelial migration. Fimbriae induced CD11b/CD18-dependent adhesion of human monocytes or mouse macrophages to endothelial receptor ICAM-1; these activities were inhibited by TLR2 blockade or deficiency or by pharmacological inhibitors of PI3K. Moreover, this inducible adhesive activity was sensitive to the action of Clostridium difficile toxin B, but was not affected by Clostridium botulinum C3 exoenzyme, pertussis toxin, or cholera toxin. Accordingly, we subsequently showed through the use of dominant negative signaling mutants of small GTPases, that Rac1 mediates the ability of fimbria-stimulated monocytes to bind ICAM-1. A dominant negative mutant of Rac1 also inhibited the lipid kinase activity of PI3K suggesting that Rac1 acts upstream of PI3K in this proadhesive pathway. Furthermore, fimbriae stimulated monocyte adhesion to HUVEC and transmigration across HUVEC monolayers; both activities required TLR2 and Rac1 signaling and were dependent upon ICAM-1 and the high-affinity state of CD11b/CD18. P. gingivalis-stimulated monocytes displayed enhanced transendothelial migration compared with monocytes stimulated with nonfimbriated isogenic mutants. Thus, P. gingivalis fimbriae activate a novel proadhesive pathway in human monocytes, involving TLR2, Rac1, PI3K, and CD11b/CD18, which may constitute a mechanistic basis linking P. gingivalis to inflammatory atherosclerotic processes.

Animals↗