Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary surfactant protein (SP)-A, an innate immune molecule, modifies lipopolysaccharide (LPS)-induced cell responses. Because SP-A avidly binds to the deep rough (Re) mutant of LPS, we first investigated the functional consequences of this interaction and found that preincubation of Re-LPS with SP-A significantly and in a dose-dependent manner decreased the sensitivity of rat alveolar macrophages and human mononuclear cells to Re-LPS-induced activation at limited amounts of LPS-binding protein (LBP). At high LBP concentrations, the SP-A-mediated cellular inhibition of Re-LPS-induced activation was abrogated. Because LBP-catalyzed binding of LPS to CD14 is essential for low-dose LPS-induced signaling, we then hypothesized that SP-A inhibits Re-LPS-induced immune cell activation via inhibiting the binding of Re-LPS to LBP. Binding competition experiments employing a surface plasmon resonance technique showed that Re-LPS preincubated with SP-A bound to LBP to a significantly lesser extent than Re-LPS alone. For enhanced cellular association of [(3)H]LPS/SP-A complexes to occur, the expression of membrane-bound CD14 by human embryonic kidney cells 293 was not essential. Therefore, the ability of SP-A to inhibit immune cell activation by Re-LPS may be due to its ability to block the binding of Re-LPS to LBP and prevent the initiation of the LBP/CD14 pathway for inflammatory reactions in the lung.
Am J Respir Cell Mol Biol 2002 Sep
PMID:Surfactant protein a inhibits lipopolysaccharide-induced immune cell activation by preventing the interaction of lipopolysaccharide with lipopolysaccharide-binding protein. 1220 98

The expression of CD14, a monocyte receptor for the bacterial lipopolysaccharide (LPS), is upregulated during monocytic cell differentiation. Although a Sp1 site at -110bp of the CD14 promoter was shown to be critical for activation of the promoter during the differentiation, how the Sp1 site is regulated has not been well understood. We have recently reported that expression of MEF2D protein increases during the differentiation of HL60 promyeloid cells to monocyte and that the upregulation of the protein is required for CD14 expression during the differentiation [Mol. Immunol. 36 (1999) 1209]. However, there is no obvious MEF2 binding site in the critical region of the CD14 promoter. In this study, which aimed to determine the regulatory role of MEF2D in monocytic cell differentiation, MEF2D was found to form a complex with Sp1 in U937 promyeloid cells. Transient transfection experiments showed that co-expression of MEF2D and Sp1 synergistically activated the CD14 promoter. The results support a model in which increased MEF2D protein during monocytic cell differentiation activates the CD14 promoter through interaction with Sp1.
Mol Immunol 2002 Sep
PMID:Synergistic interaction of MEF2D and Sp1 in activation of the CD14 promoter. 1221 24

Renal proximal tubular epithelial cells (PTEC) are target for LPS during sepsis and renal infections. In the present study, we evaluated whether stimulation of human PTEC by LPS is modulated through the soluble or the membrane form of the LPS receptor CD14. We found that PTEC lacked expression of the membrane form of CD14 and did not release soluble CD14 (sCD14). sCD14 was detected in the urine of normal subjects and it was increased in patients with renal sepsis or with proteinuria. In the presence of sCD14 and LPS binding protein (LBP), PTEC were 10 to 100-fold more sensitive to LPS activation, resulting in cytokine production (IL-6, IL-8 and TNF-alpha) and NO release. We found that sCD14 purified from urine was biologically active on PTEC. Moreover, the presence of sCD14 and LBP was required for cytotoxicity induced by low concentrations of LPS (1-10 ng/ml) in PTEC. Cell death showed the characteristics of both necrosis and apoptosis, as demonstrated by LDH release and by TUNEL and acridine orange staining and caspase-3 activation. Whereas the LPS alone was sufficient to induce necrosis, sCD14 and LBP were required for apoptosis. Our results suggest that sCD14 excreted in urine may participate with endotoxin in the activation and injury of renal proximal tubules. In particular, sCD14 may contribute to the tubulo-interstitial injury in clinical settings characterised by proteinuria and enhanced susceptibility to infections such as in diabetes.
Int J Mol Med 2002 Oct
PMID:Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. 1223 91

Inhalation of particulate matter (PM) may result in exacerbation of inflammatory airways disease, including asthma. Results from this laboratory have shown that the coarse inhalable particle fraction (PM(2.5-10)) is responsible for most of the PM effects on human airway macrophages (AM), including induction of cytokine production. Endotoxins associated with these particles account for a large part of their potency, as activity of PM can be inhibited by polymixin B and an activating moiety bound by lipopolysaccharide (LPS)-binding protein (LBP). The hypothesis behind the present study was that not only particle-bound LPS, but also Gram-negative (Gram-) and Gram-positive (Gram+) bacteria are responsible for PM-induced stimulation of AM, and therefore that PM are likely to activate receptors involved in recognition of microbes. Low level contamination of model pollution particles with environmental Staphyloccocus, Streptococcus, and Pseudomonas species was found to confer cytokine-inducing activity on inactive particles. Only one Gram- bacterium was sufficient for significant stimulatation of 100 AM, whereas at least three times more Gram+ bacteria were required for a similar level of response. Cytokine responses induced by PM as well as Gram+ and Gram- bacteria were inhibited by anti-CD14 antibody and required the presence of LBP-containing serum. The involvement of Toll-like receptor (TLR) 2 and 4 in recognition of PM(2.5-10) was investigated in transfected Chinese hamster ovary cells expressing CD14 and TLR2 or TLR4. TLR4 was found to be involved in PM(2.5-10) and Pseudomonas-induced activation, whereas TLR2 activation was induced by both Gram+ and Gram- bacteria and by PM. The synthetic lipid A analog E5531 fully inhibited the response to purified LPS and partially inhibited the response to PM and Pseudomonas. In contrast, E5531 had no effect on the response to Staphylococcus. Taken together, these results implicate microbial components as important players in AM-dependent inflammatory responses to PM.
Am J Respir Cell Mol Biol 2002 Nov
PMID:Involvement of microbial components and toll-like receptors 2 and 4 in cytokine responses to air pollution particles. 1239 21

Dendritic cells (DCs) in the rheumatoid arthritis (RA) joint mediate the immunopathological process and act as a potent antigen presenting cell. We compared the expression of co-stimulatory and adhesion molecules on DCs in RA patients versus controls with traumatic joint lesions and evaluated the correlation between the immunophenotypical presentation of DCs and the clinical status of the disease. Samples of peripheral venous blood, synovial fluid (SF) and synovial tissue (ST) were obtained from 10 patients with RA at the time of hip or knee replacement and from 9 control patients with knee arthroscopy for traumatic lesions. Clinical status was appreciated using the DAS28 score. Blood, SF and dissociated ST cell populations were separated by centrifugation and analyzed by flow cytometry. Cells phenotypes were identified using three-color flow cytometry analysis for the following receptors HLA-DR, CD80, CD83, CD86, CD11c, CD18, CD54, CD58, CD3, CD4, CD8, CD19, CD20, CD14, CD16, CD56. HLA-DR molecules, co-stimulatory receptors CD80, CD86, CD83 and adhesion molecules CD18, CD11c, CD54, CD58, were analyzed by two-color immunofluorescence microscopy on ST serial sections. In patients with active RA (DAS28>5.1) we found a highly differentiated subpopulation of DCs in the ST and SF that expressed an activated phenotype (HLA-DR, CD86+, CD80+, CD83+, CD11c+, CD54+, CD58+). No differences were found between circulating DCs from RA patients and control patients. Our data suggest an interrelationship between clinical outcome and the immunophenotypical presentation of DCs. Clinical active RA (DAS28>5.1) is associated with high incidence of activated DCs population in the ST and SF as demonstrated by expression of adhesion and co-stimulatory molecules.
J Cell Mol Med
PMID:Co-stimulatory and adhesion molecules of dendritic cells in rheumatoid arthritis. 1241 58

Effective suppression of HIV-1 replication requires inhibition of critical viral target molecules. Tat and Rev are indispensable regulatory factors for HIV-1 replication, whereas Env mediates virus entry by direct interaction with surface receptor CD4 and coreceptor CCR5 or CXCR4. Anti-HIV-1 tat-rev and env ribozymes and Rev aptamers were previously demonstrated to provide relatively long-term protection against HIV-1 infection in vitro. However, further improvements in these constructs for clinical application in a stem-cell-based gene therapy setting requires in vivo characterization. Toward this end, we introduced these constructs into CD34(+) hematopoietic progenitor cells by retrovirus-mediated gene transduction. Ribozyme- and aptamer-transduced CD34(+) cells differentiated normally into multiple lineages of erythroid and myeloid progenies in a colony-forming unit assay. Macrophages that differentiated from the transduced CD34(+) cells expressed anti-tat-rev and -env ribozymes and Rev aptamers and displayed their normal characteristic surface markers CD14, CD4, and CCR5. Using the SCID-hu mouse in vivo human thymopoiesis model, we demonstrated that ribozyme- and aptamer-transduced CD34(+) cells retained their normal capacity to reconstitute human fetal thymus and liver tissue (thy/liv) grafts. Reconstitution by ribozyme- and aptamer-transduced CD34(+) cells reached levels of up to 87% based on HLA surface marker staining. Differentiated thymocytes derived from reconstituted grafts expressed anti-tat-rev and -env ribozymes and Rev aptamers and showed significant resistance to HIV-1 infection upon challenge. Analysis of reconstituted thymocytes by hybridization revealed an average of 0.4 to 2 copies of vector sequences per cell. Southern analysis of proviral integration junctions in progeny thymocytes demonstrated that the human thy/liv grafts were reconstituted by a few primitive hematopoietic stem cells. These results highlight the utility of RNA-based anti-HIV-1 gene therapeutic approaches and their preclinical testing in a surrogate animal model harboring human tissue.
Mol Ther 2002 Dec
PMID:RNA-based anti-HIV-1 gene therapeutic constructs in SCID-hu mouse model. 1249 73

Geldanamycin (GA) is an antibiotic produced by Actinomyces, which specifically inhibits the function of the heat shock protein 90 family. Treatment of a murine macrophage cell line (J774) with GA resulted in a reduced response to Escherichia coli lipopolysaccharide (LPS) as visualized by a decrease of NF-kappaB translocation into the nucleus and secretion of tumor necrosis factor alpha (TNF-alpha). To elucidate the mechanism of this effect, the expression of CD14, the formal LPS receptor, was analyzed. Cells treated with GA showed a reduced level of surface CD14 detected by immunostaining, whereas the expression of other surface receptors, such as FC-gamma receptor and tumor necrosis factor receptors (TNF-R1 and TNF-R2), was unaffected. The reduced surface level of CD14 was not due to a reduction in its expression because CD14 steady state mRNA levels or the total cellular pool of CD14 was not altered by GA treatment. Surface CD14 was more rapidly internalized after GA treatment (2-3 h) than after incubation with cycloheximide. Immunostaining of permeabilized cells after GA treatment revealed a higher intracellular content of CD14 colocalizing with calnexin, an endoplasmic reticulum (ER) protein. These results suggest that the decrease in CD14 surface expression after GA treatment is due to rapid internalization without new replacement. These effects may be due to the inhibition of Hsp90 and Grp94 by GA in macrophages.
Mol Biol Cell 2003 Feb
PMID:Geldanamycin treatment ameliorates the response to LPS in murine macrophages by decreasing CD14 surface expression. 1258 68

CD14 functions as a cell surface receptor for endotoxin (lipopolysaccharide [LPS]) and is thought to have an essential role in innate immune responses to infection. Previous studies have revealed attenuation of the systemic response after sepsis by blocking CD14. In this study, we tested the hypothesis that CD14 blockade protects against inflammatory responses associated with LPS pneumonia. We examined the effect of an anti-murine CD14 monoclonal antibody (4C1) on the development of acute lung injury induced by intratracheal LPS in mice. We also measured the production of cytokines (tumor necrosis factor-alpha, interleukin-6, and macrophage inflammatory protein-2) and nitric oxide by murine peritoneal macrophages exposed to LPS in vitro. Nuclear factor (NF)-kappa B translocation was evaluated in nuclear extracts from lung homogenates. 4C1 significantly attenuated pulmonary edema and neutrophil emigration after LPS administration. The production of cytokines and nitric oxide by LPS-stimulated macrophages was significantly decreased by 4C1 treatment. NF-kappa B translocation induced by LPS instillation was also suppressed by 4C1. These results suggest that blockade of CD14 might attenuate acute lung injury after intratracheal instillation of LPS through the suppression of NF-kappa B translocation. The inhibitory effect of CD14 blockade on cytokine production and nitric oxide release of macrophages might contribute to the attenuation of lung injury.
Am J Respir Cell Mol Biol 2003 Aug
PMID:Effect of CD14 blockade on endotoxin-induced acute lung injury in mice. 1263 39

Dendritic cells (DCs) consist of a heterogeneous population of hematopoietic cells characterized by their unique dendritic morphology, their efficient antigen-presenting capability to activate naive CD4(+) and CD8(+) T cells, and their lack of lineage specific markers. Functional properties comparing umbilical cord blood monocyte-derived and umbilical cord blood stem cell-derived DCs have not yet been investigated. CD14(+) monocytes and CD34(+) stem cells were isolated from human umbilical cord blood and were induced to differentiate into dendritic cells using 100 ng/mL granulocyte-macrophage colony stimulating factor (GM-CSF), 25 ng/mL IL-4, 2.5 ng/mL tumor necrosis factor-alpha (TNF-alpha), 100 ng/mL GM-CSF, 25 ng/mL stem cell factor, and 2.5 ng/mL TNF-alpha, respectively. Flow cytometric analysis revealed that the 14-day-old dendritic cells were CD80(+), CD86(+), CD83(+), CD54(+), CD1a(+), CD11b(+), CD11c(+), HLA-DR(+), CD34(-), CD3(-), CD19(-), CD14(-), and CD16(-). Reverse transcription polymerase chain reaction was employed to detect expression of mRNA for CD80 and CD86. Differentiating monocytes initially expressed CD86 while CD80 appeared on day 2. Differentiating stem cells expressed CD80 and CD86 on day 2 of culture. The surface expression of CD80 and CD86 was studied over the course of differentiation. Mixed lymphocyte reaction was employed to evaluate the two types of lineage-derived DCs. Prior to the functional assay, CD14(+) and CD34(+) derived DCs were stimulated for 18 h with 0.1 mg/mL and 1.0 mg/mL E. coli lipopolyssacharide, respectively. Monoclonal antibodies (mabs) to CD80 and CD86 were employed to assess their costimulatory roles. A decrease of stimulation as depicted by decreased T cell activation was significant with mabs to both CD80 and CD86 on monocyte-derived DCs while only mabs to CD86 induced decreased T cell activation by stem cell-derived DCs. The varied functional role of CD80 and CD86 costimulatory molecules is associated with DC differentiation from distinct cord blood isolated hematopoietic lineages. These studies demonstrate that DC association with distinct hematopoietic lineages is of relevance in transplantation and vaccine therapies.
Exp Mol Pathol 2003 Aug
PMID:Costimulatory function of umbilical cord blood CD14+ and CD34+ derived dendritic cells. 1283 22

The lung collectin surfactant protein A (SP-A) has both anti-inflammatory and prophagocytic activities. We and others previously showed that SP-A inhibits the macrophage production of tumor necrosis factor (TNF)-alpha stimulated by the gram-negative bacterial component LPS. We propose that SP-A decreases the production of proinflammatory cytokines by alveolar macrophages via a CD14-independent mechanism. SP-A inhibited LPS-simulated TNF-alpha production in rat and mouse macrophages in the presence and absence of serum (72% and 42% inhibition, respectively). In addition, SP-A inhibited LPS-induced mRNA levels for TNF-alpha, IL-1 alpha, and IL-1 beta as well as NF-kappa B DNA binding activity. SP-A also diminished ultrapure LPS-stimulated TNF-alpha produced by wild-type and CD14-null mouse alveolar macrophages by 58% and 88%, respectively. Additionally, SP-A inhibited TNF-alpha stimulated by PMA in both wild-type and TLR4-mutant macrophages. These data suggest that SP-A inhibits inflammatory cytokine production in a CD14-independent manner and also by mechanisms independent of the LPS signaling pathway.
Am J Physiol Lung Cell Mol Physiol 2004 Jan
PMID:Surfactant protein A inhibits alveolar macrophage cytokine production by CD14-independent pathway. 1295 32


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