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)

It has been demonstrated that alveolar macrophages (AM) are permissive for human immunodeficiency virus (HIV-1) after in vitro infection. However, data concerning in vivo infection of AM by HIV-1 still conflict. Therefore, we investigated AM collected by bronchoalveolar lavage from 15 HIV-1-infected patients. HIV-1 p24 and Gp120 antigens and viral RNA were not detected by immunocytochemistry and in situ hybridization, respectively, using 35S-labeled 3 kb Pol-Env, 0.350 kb Gag, and 0.150 kb U5 LTR cRNA probes. In contrast, when using polymerase chain reaction on DNA extracted from purified AM, HIV-1 DNA was detected in the seven patients tested. After short-term culture of alveolar cells from three HIV-1-infected patients and in vitro stimulation with granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha), HIV-1 replication was observed in most of the AM. These results demonstrate that AM are latently infected by HIV-1 in vivo but are not a site for viral replication. In contrast, HIV-1 replication occurs when AM are withdrawn from their local environment, enhanced by GM-CSF and TNF-alpha stimulation. This suggests either a negative control or an inadequate stimulation of HIV-1 replication in the alveolar environment.
Am J Respir Cell Mol Biol 1994 Jan
PMID:HIV-1 in human alveolar macrophages from infected patients is latent in vivo but replicates after in vitro stimulation. 829 83

Granulocyte macrophage colony-stimulating factor (GM-CSF) binds to the high-affinity GM-CSF receptor (GMR) consisting of alpha and beta subunits and induces rapid tyrosine phosphorylation, activation of early response genes, and proliferation of hematopoietic cells. The alpha subunit is the primary cytokine binding component and the beta subunit is required for high-affinity binding as well as for signal transduction. Using tyrosine kinase inhibitors and cytoplasmic deletion mutants of the beta subunit, we obtained evidence that there are at least two distinct pathways downstream of the GMR in BA/F3 cell, one which is essential for proliferation, leads to the c-myc gene activation, and is sensitive to herbimycin and genistein. Activation of this pathway depends on the cytoplasmic region between amino acid positions 455 and 517 of the beta subunit. The second pathway, which leads to activation of c-fos and c-jun genes, is only partially sensitive to herbimycin, is resistant to genistein and depends on the region between amino acid positions 626 and 763 of the beta subunit. Unexpectedly, the c-fos mRNA induction was augmented by genistein. The enhanced expression of c-fos mRNA by genistein also occurred with stimulation with cAMP, PMA, or EGF in NIH3T3 cells. It thus seems likely that genistein affects a common pathway downstream of these signals.
Mol Biol Cell 1993 Oct
PMID:Differential regulation of early response genes and cell proliferation through the human granulocyte macrophage colony-stimulating factor receptor: selective activation of the c-fos promoter by genistein. 829 95

The c-fms gene encodes the receptor for the macrophage colony-stimulating factor (M-CSF), and its extracellular domain consists of five immunoglobulin-like subdomains. To identify which of the five immunoglobulin-like regions are involved in ligand binding, we polymerase chain reaction-cloned five segments of the extracellular domain of the murine c-fms gene, each starting with the normal initiation codon and containing successive additions of the immunoglobulin-like subdomains. These protein segments are designated A, B, C, D, and E and contain, from the N-terminal end, either one, two, three, four, or all five immunoglobulin-like subdomains, respectively. Each segment was expressed as a secreted soluble protein from a baculovirus expression vector in Sf9 insect cells. In addition, segments A, B, C, and E were produced as soluble alkaline phosphatase fusion proteins, as was a segment containing only the fourth and fifth immunoglobulin domains. These segments of the Fms extracellular domain were used to assess M-CSF binding by competition radioimmunoassays, plate binding immunoassays, and immunoprecipitation analyses. The results indicated that the first two N-terminal immunoglobulin-like domains did not interact with M-CSF but, in combination with the third immunoglobulin-like domain, provided high-affinity M-CSF binding. The fourth and fifth immunoglobulin-like domains near the cell membrane did not exhibit M-CSF binding and may inhibit interaction of M-CSF with the first three immunoglobulin domains. These results suggest that the three N-terminal immunoglobulin-like domains constitute the high-affinity M-CSF binding region and that the fourth and fifth immunoglobulin-like domains may perform functions other than ligand binding.
Mol Cell Biol 1993 Sep
PMID:Identification of the ligand-binding regions in the macrophage colony-stimulating factor receptor extracellular domain. 835 86

A major CSF-1 (Colony-Stimulating Factor 1) mRNA 4.0 kb long was expressed during the proliferation of the L6 alpha 1 rat myogenic cells and was down-regulated after their differentiation into myotubes. A complete cDNA encoding the rat CSF-1 gene (rmCSF-1) was isolated from a cDNA library of L6 alpha 1 myoblasts and sequenced. The overall deduced amino acid sequence was 100% and 68% identical to the mouse and human CSF-1, respectively. While the previously reported mechanisms about the regulation of CSF-1 expression in TPA-treated-monocytes (Horiguchi, J., Sariban, E. and Kufe, D. (1988) Mol. Cell. Biol. 8, 3951-3954) and in fibroblasts (Falkenburg, J.H.F., Harrington, M.A., De Paus, R.A., Walsh, M.K., Daub, R., Landegent, J.E. and Broxmeyer, H.E. (1991) Blood 78, 658-665) involved a control at the transcriptional level, in contrast, the CSF-1 mRNA (half-life approximately 3 h in L6 alpha 1 myoblasts) was post-transcriptionally down-regulated during myogenesis. Inhibition of protein synthesis with cycloheximide (CHX) increased differentially the half-life of CSF-1 mRNA in L6 alpha 1 myotubes compared to L6 alpha 1 myoblasts. Finally, L6 alpha 1 myoblasts were shown to synthesize a 140 kDa homodimeric form of CSF-1. Thus, these findings, together with other results, indicate that CSF-1 gene products may play a role in the normal and neoplastic proliferation of muscular cells.
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PMID:Isolation and characterization of a cDNA clone encoding for rat CSF-1 gene. Post-transcriptional repression occurs in myogenic differentiation. 835 31

Fibroblasts of the pulmonary interstitium are intimately involved in the response of the lung to inflammation as well as in repair of injured tissues. The response of fibroblasts within an inflammatory site appears to be directed, in part, by peptide mediators. Neutral endopeptidase (NEP), a metallopeptidase on the surface membrane of fibroblasts, can inactivate various vasoactive peptides, including kinins and tachykinins. Because lung fibroblasts both secrete cytokines and respond to mediators within the immediate environment, NEP might be regulated by locally generated cytokines. We found that several cytokines, including interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor, interleukin-6, and granulocyte macrophage colony-stimulating factor, enhanced activity of NEP on the surface of intact fibroblasts. In contrast, cultured pleural mesothelial cells had much lower levels of NEP than fibroblasts, and the enzyme was not enhanced by either IL-1 or TNF-alpha. Further studies with IL-1 showed that the effect required at least 6 h of exposure to the cytokine and depended upon final cytokine concentration. Combinations of IL-1 with other cytokines increased NEP activity beyond that in cells treated with individual cytokines, but combinations had less than additive effects. Selected pharmacologic agents indicated that the mechanism involves second messenger pathways. The cytokine effect on NEP was attenuated by indomethacin, an inhibitor of cyclooxygenase, by N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride, an inhibitor of protein kinase, and by adenosine 3',5' cyclic monophosphothionate, an analog of cyclic adenosine monophosphate (cAMP) that competitively inhibits the cAMP signal pathway. It was mimicked by dibutyryl cAMP and by forskolin, an activator of adenyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Jan
PMID:Cytokines increase neutral endopeptidase activity in lung fibroblasts. 838 Feb 49

Triakontatetraneuropeptide (TTN) is the major processing product of the endogenous anxiogenic peptide ligand of the benzodiazepine receptor, diazepam binding inhibitor. In the present study, we demonstrated by Northern blot analysis that the mRNA levels for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, granulocyte/macrophage colony-stimulating factor, IL-6, and IL-8 were significantly increased after 4 hr of incubation of human monocytes with lipopolysaccharide (LPS) and TTN (10(-11) M), compared with cells incubated with LPS alone. Exposure of monocytes for 20 hr to LPS and TTN (10(-11) M) also stimulated TNF-alpha, IL-1 beta and granulocyte/macrophage colony-stimulating factor release by 80%, 110%, and 98%, respectively, relative to the response elicited by LPS alone. Smaller stimulatory effects were observed using the prototypic pharmacological peripheral benzodiazepine Ro5-4864 (10(-11) M) (55%, 72%, and 62%, assessed by means of specific enzyme immunoassays). In contrast, TTN and Ro5-4864 did not modulate LPS-induced IL-6 and IL-8 production. Treatment with the cyclooxygenase inhibitor indomethacin increased IL-1 beta and TNF-alpha secretion but not that of IL-6 or IL-8. The observed stimulatory effects of TTN and indomethacin were not additive. Taken together, these findings suggest a common mechanism of action for TTN and indomethacin, involving PG formation. In this respect, TTN inhibited prostaglandin (PG) E2 production by 30%. The fact that the observed modulatory effects correlated with PG levels suggests the existence of a second-messenger pathway associated with the peripheral-type benzodiazepine receptor. These results indicate that human TTN differentially modulates the LPS-induced expression of proinflammatory cytokines, and they further support the concept that this endogenous psychoactive peptide could be involved in physiological control of the inflammatory response.
Mol Pharmacol 1993 Jan
PMID:Modulation of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-8, and granulocyte/macrophage colony-stimulating factor expression in human monocytes by an endogenous anxiogenic benzodiazepine ligand, triakontatetraneuropeptide: evidence for a role of prostaglandins. 838 Aug 85

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.
Am J Respir Cell Mol Biol 1993 Sep
PMID:Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract. 839 62

Although studies of nitrogen dioxide (NO2) inhalation, in both animals and humans, have demonstrated that this agent can cause epithelial cell damage and inflammation of the airway epithelium, the mechanisms underlying these effects are not well understood. We have cultured human bronchial epithelial cells, as explant cultures from surgical tissue, and studied these firstly from their ability to constitutively synthesize specific proinflammatory cytokines and then investigated the effect of exposure to NO2 on the generation of these cytokines. Constitutive synthesis of cytokines was evaluated by analysis of both the expression of the mRNA for interleukin (IL)-1 beta, IL-4, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), by the polymerase chain reaction (PCR), and by immunocytochemical staining for the presence of cell-associated IL-1 beta, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, using specific monoclonal and polyclonal antibodies directed towards these cytokines. Release of IL-4, IL-8, GM-CSF, TNF-alpha, and IFN-gamma following exposure to 5% CO2 in air or 400 ppb and 800 ppb NO2 for 6 h was investigated by enzyme-linked immunosorbent assay. PCR demonstrated that the human bronchial epithelial cells expressed the mRNA for IL-1 beta, IL-8, GM-CSF, and TNF-alpha but not for IL-4 and IFN-gamma. Immunocytochemical staining confirmed the presence of endogenous IL-1 beta, IL-8, GM-CSF, and TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Sep
PMID:Effect of nitrogen dioxide on synthesis of inflammatory cytokines expressed by human bronchial epithelial cells in vitro. 839 64

A panel of steady-state cytokine mRNAs was analyzed in the bronchoalveolar lavage (BAL) cells from asthmatic subjects or patients challenged with ragweed allergen. This was achieved by combining both qualitative and quantitative assays using the reverse transcription-polymerase chain reaction (RT-PCR). Analysis of BAL cells from six mild allergic asthmatic and five nonasthmatic, nonallergic subjects showed no qualitative differences in the profile of cytokine mRNAs (including interleukin [IL]-1 beta, IL-2, IL-5, IL-6, IL-8, and granulocyte/macrophage colony-stimulating factor), except for tumor necrosis factor-alpha, which was detected in three out of six asthmatic BAL samples but in none of the controls. A key cytokine, IL-5, has been implicated in the pathogenesis of allergic inflammation through the recruitment of eosinophils. We found a significant enhancement of steady-state IL-5 transcripts in the BAL cells from allergen-challenged as compared with the saline-challenged control sites of four asthmatic patients; furthermore, the cellular source for IL-5 mRNA was identified in the mononuclear cell fraction, but not in the purified eosinophils, of the allergen-challenged BALs. These results suggest that the significant increase of IL-5 transcripts is primarily from the infiltrating mononuclear cells. Our study also demonstrates the power of qualitative and quantitative PCR analysis in determining the molecular basis of allergic inflammatory diseases.
Am J Respir Cell Mol Biol 1993 Sep
PMID:Analysis of cytokine transcripts in the bronchoalveolar lavage cells of patients with asthma. 839 65

We investigated the effects of Dermatophagoides farinae (Df) and interleukin (IL)-2 on the release of eosinophil colony-stimulating factor (Eo-CSF) activity from mononuclear cells (MNC) and lymphocytes of patients with bronchial asthma (BA) who were sensitive to Df to clarify its relationship with IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF). MNC and T cells of patients cultured with IL-2 and Df released Eo-CSF activity. These Eo-CSF activities were partially inhibited by anti-IL-5 and anti-GM-CSF antibodies. In 11 of 15 cases studied, MNC from patients produced GM-CSF in response to IL-2. In four of 15 cases studied, MNC from patients produced GM-CSF in response to Df. On culture with IL-2 or Df, the releases of IL-5 into the medium by MNC from individual patients varied. The results indicate that in BA responsiveness of lymphocytes to Df is increased, and suggest that IL-5 and GM-CSF produced by T cells play a role in the induction of eosinophilia and the pathogenesis of BA.
Am J Respir Cell Mol Biol 1993 Oct
PMID:Production of interleukin-5 and granulocyte/macrophage colony-stimulating factor by T cells of patients with bronchial asthma in response to Dermatophagoides farinae and its relation to eosinophil colony-stimulating factor. 839 76


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