Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor kappaB activation. These data suggest the existence of the TLR4-RP105 signaling module in the LPS-induced B cell activation.
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PMID:The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. 1088 May 23

The Toll family of receptors has been implicated in innate recognition and subsequent activation of defense programs against pathogens such as bacteria and fungi. TLR4, for example, signals the presence of lipopolysaccharide (LPS), a membrane constituent of Gram-negative bacteria. LPS signaling via TLR4 is greatly enhanced by a molecule referred to as MD-2, which is associated with the extracellular domain of TLR4. The TLR4/MD-2 complex, therefore, recognizes LPS. RP105, another member of the Toll family, has a striking similarity to TLR4 in that it is associated with an MD-2-like molecule MD-1. B-cells lacking RP105 are severely impaired in LPS-induced proliferation and antibody production. Studies employing transfectants showed that RP105/MD-1, like MD-2, enhances the LPS signaling via TLR4. RP105/MD-1 thus constitutes an LPS-signaling complex on B-cells. These results suggest that a variety of cell surface molecules regulate LPS recognition/signaling by TLR4.
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PMID:Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. 1152 Oct 60

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system and can be generated in vitro from bone-marrow cells. In this study, we systematically investigated by DNA array analysis the expression profiles of 514 immunologically relevant genes in two populations of mouse bone marrow-derived DC, immature (DC(IMAT)), and lipopolysaccharide (LPS)-stimulated mature (DC(MAT)) DCs. Our data showed that DC(IMAT) expressed transcripts for 69 (13.42% of the 514) of these genes and that, upon maturation, 32 (6.23%) of these were up-regulated and 40 (7.78%) down-regulated. Maturation-dependent up-regulation, defined by a differential expression (DE) ratio of >2, was observed among five cytokine (Flt-3L, TNF-alpha, IL-1alpha and -1beta, and IL-6), three chemokine (RANTES, MIP-2 and GROa) and three other (iNOS, MMP-13, and STRAP) genes. Reciprocally, maturation-dependent down-regulation occurred with one cytokine (IGF-1), two chemokine receptor (CCR2 and CCR5), and three other (RP105, Ax1, and UCP2) genes. Lower level, but nevertheless significantly enhanced expression of the chemokine receptor CCR7 and of NF-kappaB was also observed upon DC maturation. This DC maturation profile confirms previous findings from other lab, but it also substantially broadens our view of these cells by documenting expression changes among genes (e.g., IGF-1, MMP-13, STRAP) not reported previously in these cells.
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PMID:Analysis of the gene expression profiles of immature versus mature bone marrow-derived dendritic cells using DNA arrays. 1177 34

RP105 is a B-cell surface molecule that has been recently assigned as CD180. RP105 ligation with an antibody induces B-cell activation in humans and mice, leading to proliferation and up-regulation of a costimulatory molecule, B7.2/CD86. RP105 is associated with an extracellular molecule, MD-1. RP105/MD-1 has structural similarity to Toll-like receptor 4 (TLR4)/MD-2. TLR4 signals a membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS). MD-2 is indispensable for TLR4-dependent LPS responses because cells expressing TLR4/MD-2, but not TLR4 alone, respond to LPS. RP105 also has a role in LPS responses because B cells lacking RP105 show hyporesponsiveness to LPS. Little is known, however, regarding whether MD-1 is important for RP105-dependent LPS responses, as MD-2 is for TLR4. To address the issue, we developed mice lacking MD-1 and generated monoclonal antibodies (mAbs) to the protein. MD-1-null mice showed impairment in LPS-induced B-cell proliferation, antibody production, and B7.2/CD86 up-regulation. These phenotypes are similar to those of RP105-null mice. The similarity was attributed to the absence of cell surface RP105 on MD-1-null B cells. MD-1 is indispensable for cell surface expression of RP105. A role for MD-1 in LPS responses was further studied with anti-mouse MD-1 mAbs. In contrast to highly mitogenic anti-RP105 mAbs, the mAbs to MD-1 were not mitogenic but antagonistic on LPS-induced B-cell proliferation and on B7.2 up-regulation. Collectively, MD-1 is important for RP105 with respect to B-cell surface expression and LPS recognition and signaling.
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PMID:Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide. 1186 Dec 86

Toll-like receptors (TLRs) serve as recognition and signaling elements for bacterial substances. To examine the role of TLRs in endothelial cells of larger vessels in lipopolysaccharide (LPS)-induced signaling, the expression and function of TLRs in human umbilical vein endothelial cells (HUVEC) were analyzed. A high level of TLR4 mRNA expression was found in HUVEC, human peripheral blood mononuclear cells (PBMC) and human monocyte cell line THP-1 cells. Little or no TLR2 mRNA expression was observed in HUVEC. In contrast, strong TLR2 mRNA expression was observed in PBMC and THP-1 cells. Moderate and high levels of TLR1 mRNA expression were found in HUVEC, PBMC and THP-1 cells, respectively. TLR3 mRNA expression was moderate in PBMC but weak in HUVEC and THP-1 cells. Little or no TLR5 and RP105 mRNA expression was observed in HUVEC, whereas a moderate level was detected in PBMC and THP-1 cells. The LPS-induced E-selectin expression in HUVEC was significantly inhibited by pretreatment with an anti-TLR4 mAb. Preincubation of HUVEC with an anti- TLR4 mAb significantly reduced the LPS-induced IL-6 production. LPS induced E-selectin and IL-6 production by HUVEC only in the presence of human serum, suggesting the involvement of soluble CD14. Anti-CD14 mAb strongly inhibited the LPS-induced E-selectin and IL-6 production by HUVEC. The inhibition with the concomitant treatment with anti-TLR4 and anti-CD14 mAbs was stronger than that with anti-CD14 mAb only, although it was slight. These results show that TLR4 in the presence of soluble CD14 plays a major role in the signaling of LPS in endothelial cells of larger vessels.
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PMID:Possible involvement of toll-like receptor 4 in endothelial cell activation of larger vessels in response to lipopolysaccharide. 1241 88

TLR4 and RP105 are unique members of the Toll-like receptor (TLR) family molecules. They are associated with small molecules called MD-2 and MD-1, respectively, to form heterodimers (TLR4/MD-2 and RP105/MD-1) and function as recognition/signaling molecules of lipopolysaccharide (LPS), a membrane component of Gram-negative bacteria. Analysis of transfectant cell lines and gene-targeted mice revealed that both MD-2 and MD-1 are involved in the recognition of LPS as well as in the regulation of intracellular distribution and the surface expression of TLR4 and RP105, respectively. Since RP105 or MD-1-deficient mice show a reduced but not complete lack of LPS responsiveness, there may be functional associations between TLR4/MD-2 and RP105/MD-1. In addition, there was an increased frequency of RP105-negative B-lymphocytes in the peripheral blood in several rheumatic diseases, such as systemic lupus erythematosus, suggesting the involvement of RP105 in the pathophysiology of autoimmunity. Further analysis of the structure and function of TLR4/MD-2 and RP105/MD-1 will provide a better understanding of the pathophysiology, and a chance to develop evidence-based treatments for septic shock syndrome and autoimmunity.
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PMID:Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide. 1462 Jan 36

PI3K (phosphoinositide 3-kinase) I(A) family members contain a regulatory subunit and a catalytic subunit. The p110delta catalytic subunit is expressed predominantly in haematopoietic cells. There, among other functions, it regulates antigen receptor-mediated responses. Using mice deficient in the p110delta subunit of PI3K, we investigated the role of this subunit in LPS (lipopolysaccharide)-induced B cell responses, which are mediated by Toll-like receptor 4 and RP105. After injection of DNP-LPS (where DNP stands for 2,4-dinitrophenol), p110delta(-/-) mice produced reduced levels of DNP-specific IgM and IgG when compared with wild-type mice. In vitro, the proliferation and up-regulation of surface activation markers such as CD86 and CD25 induced by LPS and an antibody against RP105 were decreased. We analysed the activation state of key components of the LPS pathway in B cells to determine whether there was a defect in signalling in p110delta(-/-) B cells. They showed normal extracellular-signal-regulated kinase phosphorylation, but anti-RP105-induced protein kinase B, IkappaB (inhibitor of nuclear factor kappaB) and c-Jun N-terminal kinase activation was severely reduced. This demonstrates that the p110delta subunit of PI3K is involved in the LPS response in B cells and may represent a link between the innate and the adaptive immune system.
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PMID:The p110delta subunit of phosphoinositide 3-kinase is required for the lipopolysaccharide response of mouse B cells. 1549 16

B lymphocytes respond to bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) and CD180 (previously called RP105). We show here that the responses of B lymphocytes to LPS require the function of the Vav family of guanine nucleotide exchange factors. Vav1-mutant mice generate defective humoral immunoglobulin G (IgG) responses following administration of low doses of LPS but respond normally to higher doses, while mice lacking both Vav1 and Vav2 manifest defective responses even after a high dose of LPS. Vav1/2-mutant B cells fail to divide extensively in vitro in response to LPS or CD180, while deficiency of Vav1 alone impairs CD180-but not LPS-driven proliferation. Likewise, activation of Akt (a PI3K [phosphatidylinositol 3-kinase] target) and phosphorylation of IkappaBalpha in response to CD180 or LPS required Vav1 and Vav2, while Vav1 deficiency led to defective responses to CD180. In addition, activation of ERK (extracellular signal regulated kinase) required Vav1 and Vav2 in response to CD180 but was Vav1 and vav2 independent in response to LPS. Induction of CD86 and CD25 by anti-CD180 also required Vav function, as did the induction of the anti-apoptotic protein Bcl-xL (B-cell leukemia XL). These data provide evidence for the function for the Vav proteins in regulating the responses of B cells to LPS.
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PMID:Vav proteins are required for B-lymphocyte responses to LPS. 1581 61

In this study, we cloned the cDNAs encoding porcine RP105 (poRP105) and porcine MD-1 (poMD-1) from Peyer's patches of adult swine. The complete open reading frames of poRP105 and poMD-1 contain 1986 and 480bp and encode 661 and 159 amino acid residues, respectively. These two proteins were more similar to the human (77.6% and 76.5% amino acid identity) than the mouse counterparts (70.0% and 71.1% amino acid identity). The results of several experiments in cells cotransfected with poRP105 and poMD-1 indicated both lipopolysaccharide and extracellular phosphopolysaccharide from Lactococcus lactis subsp. cremoris (Lc.cremoris) strongly activate nuclear factor-kappaB and induce the expression of various cytokines via RP105. These effects were mediated by phosphatidylinositol 3-kinase and Bruton's tyrosine kinase. Thus, we identified extracellular polysaccharide from Lc.cremoris as an active substance that can induce immune activation via RP105 and MD-1.
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PMID:Molecular cloning of porcine RP105/MD-1 involved in recognition of extracellular phosphopolysaccharides from Lactococcus lactis ssp. cremoris. 1725 34

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that is markedly up-regulated in sensory neurons in vivo following peripheral inflammation and plays a key role in pain physiology. To identify substances that up-regulate N/OFQ expression in sensory neurons, we carried out an in vitro screen using purified adult mouse dorsal root ganglion (DRG) neurons and identified the potent proinflammatory agent bacterial lipopolysaccharide (LPS) as a very effective inducer of N/OFQ. The robust response of these neurons to LPS enabled us to identify the components of a putative neuronal LPS receptor complex. In contrast to the immune system, where the functional LPS receptor complex is composed of CD-14 together with either MD-2 and TLR4 on myeloid cells or the homologous receptors MD-1 and RP105 on mature B cells, DRG neurons express the unusual combination of CD-14, TLR4, and MD-1. Blocking antibodies against TLR4 and MD-1 prevented induction of N/OFQ by LPS, and, in immunoprecipitation experiments, MD-1 coprecipitated with TLR4. Our findings suggest that LPS regulates N/OFN expression in sensory neurons via a novel combination of LPS receptor components and demonstrate for the first time a direct action of a key initiator of innate immune responses on neurons.
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PMID:Bacterial lipopolysaccharide regulates nociceptin expression in sensory neurons. 1802 46


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