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Query: UNIPROT:P06889 (Mol)
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Mucociliary clearance is a critical innate defense system responsible for clearing up invading pathogens including bacteria and virus. Although the right amount of mucus is good, excessive mucus causes airway obstruction and tends to precipitate disease symptoms. Rhinovirus (RV) is a common cold virus that causes asthma and chronic obstructive pulmonary disease exacerbation. Mucus overproduction has been linked to the pathogenesis of RV-induced diseases and disease exacerbations. However, the molecular mechanism is not clear. In this study, using one of the major airway mucin-MUC5AC as marker, we found that both major and minor groups of RV induced mucin production in primary human epithelial cells and cell line. RV1A (a minor group of RV) could induce mucous cell metaplasia in vivo. Viral replication was needed for RV-induced mucin expression, and this induction was also dependent on TLR3, suggesting the involvement of double-stranded (ds) RNA signaling. Indeed, dsRNA alone could also induce mucin expression. TLR3-mediated mucin induction was negatively regulated by MyD88, and only partially dependent on TRIF, which suggests a departure from well-documented TLR3 signaling paradigm that mediates inflammatory and other innate defense gene inductions. In addition, TLR3 signaling activated epidermal growth factor receptor (EGFR) through inductions of the expression of EGFR ligands (transforming growth factor-alpha and amphiregulin), which in turn activated EGFR-ERK signaling and mucin expression through an autocrine/paracrine loop. This novel coupling of antiviral defense machinery (i.e., TLR3) and major epithelial proliferation/repair pathway (i.e., EGFR) might play an important role in viral-induced airway remodeling and airway disease exacerbation.
Am J Respir Cell Mol Biol 2009 May
PMID:Rhinovirus-induced major airway mucin production involves a novel TLR3-EGFR-dependent pathway. 1897 2

Toll-like receptors (TLR) have been shown to be expressed on various types of cancers; however, their functional activity is not known. We examined TLR profiles of human melanoma cells and showed that TLR2, TLR3, and TLR4 were found to be highly expressed. By PCR array analysis, specific stimulation of TLR2, TLR3, and TLR4 on melanoma cells showed significant activation of the adaptor protein MyD88, as well as downstream signal transduction factors nuclear factor-kappaB and inflammatory response-related factors. Specific ligand activation of TLR2, TLR3, and TLR4 was shown to induce cell migration. Peripheral blood lymphocytes and melanoma purified RNA was shown to activate TLR3 on melanoma cells. These studies show expression and functional activity of specific TLRs on melanoma cells and as potential therapeutic targets to control tumor progression.
Mol Cancer Ther 2008 Nov
PMID:Activation of Toll-like receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors. 1900 46

Curcumin, an active ingredient of Curcumin longa mediates its anti-inflammatory effects through inhibition of NFkB. Several pathways including toll-like receptors (TLR) induce NFkB leading to inflammation. In this study, we investigated the effects of curcumin on the expression of TLR-4 and MyD88, the upstream signaling pathway in experimental colitis induced in the Sprague-Dawley male rats by intra-rectal administration of trinitrobenzenesulfonic acid (TNBS). The animals which received TNBS were divided into two groups: Group 1, received aqueous suspension of curcumin (100 mg/Kg body weight) 2 h prior to inducing colitis, and the treatment was repeated every day for 5 days, and Group 2 and non-colitis (Group 3) animals received phosphate buffered saline (PBS) in a similar fashion. Non-colitis animals (Group 4) received curcumin and served as controls. Animals were sacrificed on day 5 post-TNBS by cervical dislocation, colon was taken out, and cleaned with PBS. Levels of TLR-4, MyD88, and NFkB proteins were measured using ECL Western blot analysis, and TLR-4 mRNA by a competitive RT-PCR method. Colitis was confirmed histologically by measuring myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in the colonic tissues. TNBS-induced increase in the level of MPO activity and MDA concentrations was reversed by curcumin treatment, whereas the same dose of curcumin did not affect their levels in the non-colitis animals. Increases in the levels of TLR-4, MyD88, and NFkB proteins in inflamed tissue were also suppressed significantly by curcumin treatment. The level of TLR-4 mRNA remained unchanged in the colitis animals. These findings demonstrate that signaling pathway of curcumin-induced inhibition of inflammation involves TLR-4 and MyD88, and therefore may serve as an important therapeutic target in IBD.
Mol Cell Biochem 2009 Feb
PMID:Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. 1900 62

IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Although some of signaling events initiated by IL-4 in activated B cells have been characterized, the involvement of TLR/MyD88 and Btk pathway in IL-4-dependent mu to gamma1 CSR has not been thoroughly evaluated. In this study, we characterized receptors for 8-SGuo and differential roles of 8-SGuo and IL-4 in the induction and mu to gamma1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SGuo-induced AID expression and mu to gamma1 CSR was documented, as 8-SGuo did not act on CD38-stimulated splenic B cells from Tlr7(-/-) and Myd88(-/-) mice. CD38-activated B cells from Btk-deficient mice failed to respond to TLR7 ligands for the AID expression and CSR, indicating that Btk is also indispensable for the system. Stimulation of CD38-activated B cells with 8-SGuo induced significant AID expression and DNA double strand breaks, but IL-4 stimulation by itself did not trigger mu to gamma1 CSR. Intriguingly, the mu to gamma1 CSR in the B cells stimulated with CD38 and 8-SGuo totally depends on IL-4 stimulation. Similar results were obtained in the activated B cells through BCR and loxoribine, a well-known TLR7 ligand, in place of 8-SGuo. In vivo administration of TLR7 ligand and anti-CD38 antibody induced the generation of CD138(+) IgG1(+) cells. These results indicate that TLR7 is a receptor for 8-SGuo and plays an essential role in the AID and Blimp-1 expression; however it is not enough to complete mu to gamma1 CSR in CD38-activated B cells. IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR.
Mol Immunol 2009 Apr
PMID:Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production. 1915 56

Streptococcus gordonii, a potential mucosal vaccine delivery vector, is proficient at colonizing murine oral mucosa; however, it often fails to elicit significant antibody titers against its vaccine antigen payloads. The poor response may be due to an inability of S. gordonii to elicit cytokines needed to suppress mucosal tolerance; exogenously supplied cytokines, such as TNF, could overcome this effect. To test this, murine bone marrow-derived dendritic cells (BM-DCs) were stimulated with UV-killed S. gordonii PM14, that surface expresses a fragment of the immunodominant S1 subunit of pertussis toxin. Peptidoglycan (PGN), lipoteichoic acid (LTA), lipoprotein (LP), and DNA were also isolated from the bacteria, and used to stimulate BM-DCs. Stimulation with TNF, S. gordonii, PGN, LTA, or LP all resulted in increased surface expression of MHCII, CD80, and CD86, compared to unstimulated BM-DCs. Stimulation with S. gordonii elicited IL-6, IL-10, and IL-12p70 production from the BM-DCs, while stimulation with the bacterial components induced some or all of the three cytokines. When BM-DCs were simultaneously stimulated with S. gordonii and TNF, a marginal increase in surface marker upregulation was observed, and the two stimuli synergized to elicit substantially greater quantities of IL-6, IL-10, and IL-12p70. Synergy between TNF and the purified bacterial components was also observed. The effect of TNF was abolished when BM-DCs were obtained from mice deficient for either TNFR1 or TNFR2, and cytokine induction by S. gordonii was entirely dependent on functional MyD88. Synergistic IL-10 induction by S. gordonii and TNF was not observed in TLR-2(-/-) BM-DCs, and TNF was found to cause TLR-2 upregulation, providing at least a partial mechanism for the observed synergy. When S. gordonii and TNF were used to immunize mice, a more robust anti-S. gordonii IgG response was elicited as compared to immunization with S. gordonii alone. However, the addition of TNF did not result in stronger responses against the antigenic insert (S1 fragment) in immunized mice. These findings collectively demonstrate that TNF is able to prime BM-DCs to better respond to S. gordonii, through a mechanism at least partially involving TLR-2 upregulation.
Mol Immunol 2009 May
PMID:Synergistic BM-DC activation and immune induction by the oral vaccine vector Streptococcus gordonii and exogenous tumor necrosis factor. 1927 29

Both ubiquitination and phosphorylation are crucial mediators involved in controlling the functions of numerous proteins belonging to the Toll-like receptor (TLR) signaling pathways. Altering the aforementioned post-translational events can be detrimental to the host survival. Therefore, the importance of these modifications cannot be overestimated. This chapter describes techniques used to examine if a protein is ubiquitinated and/or phosphorylated. In addition, a method is provided to identify the modified amino acids. We have previously shown using these techniques that the protein MyD88 adapter-like (Mal) is phosphorylated and ubiquitinated following activation of the TLR2 and TLR4 signaling pathways. Both post-translational modifications are essential for the activation and degradation of Mal, and thus are crucial steps, in regulating these TLR signaling cascades and consequently the innate immune response.
Methods Mol Biol 2009
PMID:Analysis of ubiquitin degradation and phosphorylation of proteins. 1937 34

A big bang expansion of the Vertebrate-type (V-type) TLRs was reported in amphioxus. To shed lights on its implications, a unique TLR which is reversely inserted into an intron of amphioxus PSMB7-10 by retrotransposition in the highly polymorphic proto-MHC region was cloned from Chinese amphioxus (Branchiostoma belcheri tsingtauense) and named as bbtTLR1. In situ assays showed that bbtTLR1 was predominantly expressed in pharynx and gut from larva to adult stages, which are considered as the first frontlines of amphioxus defense system. Acute immune challenges revealed that the expression of bbtTLR1 was stimulated by bacteria and their cell wall components, while suppressed by Glucan and Poly I:C in the digestive system. Amphioxus also had dozens of TIR adaptors from which we cloned bbtMyD88. BbtMyD88 expressed in 293T cells led to the activation of NF-kappaB pathway through its DEATH and middle domains. Moreover, this activation could be enhanced by bbtTLR1 through the direct association with bbtMyD88. In summary, this study provides evidence for the immune-relation of amphioxus V-type TLRs, and suggests that amphioxus TLR1 and MyD88 represent a basic evolutionary pathway.
Mol Immunol 2009 Jul
PMID:An amphioxus TLR with dynamic embryonic expression pattern responses to pathogens and activates NF-kappaB pathway via MyD88. 1939 98

The innate immune system is triggered when pathogen-associated molecular patterns (PAMPs) expressed by infectious microorganisms interact with toll-like receptors (TLR) present on immune cells. Individual TLRs signal through distinct molecular pathways. For example, TLR9 interacts with unmethylated CpG motifs expressed by bacterial DNA and triggers via a MyD88 dependent pathway whereas TLR3 recognizes viral RNA through a MyD88-independent pathway. Bioinformatic analysis of microarray data was used to identify the regulatory patterns underlying changes in gene expression induced when RAW 264.7 macrophages were stimulated via TLR9 by CpG oligonucleotides (ODN) and/or via TLR3 by poly (I:C). While the genes activated by each ligand mediated similar functions, poly (I:C) elicited a larger and more diverse change in gene expression. Co-stimulation with both ligands accelerated gene expression and synergistically activated genes primarily associated with immune function. This is the first work to compare global changes in gene regulation triggered by distinct TLR pathways and clarify their impact on gene expression.
Mol Immunol 2009 Aug
PMID:Global changes in gene expression and synergistic interactions induced by TLR9 and TLR3. 1953 42

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that is one of the causative agents of chronic adult periodontal disease. Among the potential virulence factors of P. gingivalis are the hemagglutinins. Recombinant Hemagglutinin B (rHagB) from P. gingivalis has been shown to activate the immune system by inducing specific antibodies that protect against experimental periodontal bone loss following P. gingivalis infection. Since different microbial products can stimulate dendritic cells (DC) through Toll-like receptors (TLRs), subsequently leading to T cell activation and antibody production, we wanted to investigate the immunostimulatory effect of rHagB on DC and the role of TLR signaling in this process. Using an endotoxin free rHagB preparation, our results show that stimulation of murine bone marrow-derived DC with rHagB leads to upregulation of the costimulatory molecules CD86 and CD40, activation of p38 and ERK MAP kinases, transcription factors NF-kappaB, CREB and IRF-3 and the production of IL-6, TNF-alpha, IL-12p40 and to a lesser extent IL-10 and IFN-beta. This activation process was absolutely dependent on TLR4 and CD14. While upregulation of CD86 was independent of the adaptor molecule MyD88, CD40 upregulation and optimal cytokine (IL-6, TNF-alpha, IL-12p40, IL-10 and IFN-beta) production required both MyD88 and TRIF molecules. These results are of importance since they are the first to provide insights into the interaction of rHagB with DC and TLRs. The information from this study will aid in the design of effective vaccines strategies against chronic adult periodontal disease.
Mol Immunol 2009 Aug
PMID:Requirement of TLR4 and CD14 in dendritic cell activation by Hemagglutinin B from Porphyromonas gingivalis. 1954 May 94

Initiation of proinflammatory host immunity in response to infection represents as a key event in effective control and containment of the pathogen at the site of infection as well as in elicitation of robust immune memory responses. In the current investigation, we demonstrate that an integral cell wall antigen of the mycobacterial envelope, Phosphatidyl-myo-inositol dimannosides (PIM2) triggers Suppressor of cytokine signaling (SOCS) 3 expression in macrophages in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Data derived from signaling perturbations suggest the involvement of phosphoinositide-3 kinase (PI3K) and protein kinase C (PKC) signaling pathways during PIM2 induced SOCS3 expression. Further, pharmacological inhibition of ERK1/2, but not of p38 MAP kinase or JNK abrogated the induced expression of SOCS3. The PIM2 induced activation of ERK1/2 was dependent on the activation of PI3K or PKC signaling which in turn regulated p65 nuclear factor -kappaB (NF-kappaB) nuclear translocation. Overall, current study delineates the role for PI3K-PKC axis and ERK1/2 signaling as key signaling events during PIM2 induced SOCS3 expression in macrophages.
Mol Immunol 2009 Sep
PMID:SOCS3 expression induced by PIM2 requires PKC and PI3K signaling. 1960 79


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