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)

Interleukin (IL)-10 is known to be an autoregulatory factor of functions of monocyte macrophages. The purpose of this study was to determine whether IL-10 production by alveolar macrophages (AMs) is altered in patients with lung cancer. AMs were obtained by bronchoalveolar lavage from 25 patients with lung cancer and 14 control patients. The production of IL-10 by AMs was quantitated by enzyme immunoassay with or without stimulation with lipopolysaccharide (LPS). No significant difference in spontaneous and LPS-stimulated IL-10 production by AMs was observed between lung cancer patients and control patients (mean +/- SEM; 288.0 +/- 56.7 vs. 249.6 +/- 58.4 pg ml-1). IL-10 production of LPS-stimulated AMs was not impaired even in lung cancer patients with systemic metastasis. IL-4 failed to suppress LPS-induced production of IL-10 by AMs both in control patients and in lung cancer patients. In eight patients with lung cancer, IL-10 production by AMs was estimated before and after systemic chemotherapy and IL-10 production by LPS-stimulated AMs tended to increase after systemic chemotherapy from 152.3 +/- 51.9 to 278.0 +/- 112.8 pg ml-1. As IL-10 is a potent inhibitor of tumour angiogenesis, an important process of tumour progression, these results suggest that, even in advanced cancer patients, macrophages can produce potent angiogenesis inhibitor and systemic chemotherapy may augment this inhibitory activity in the lung.
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PMID:Production of interleukin-10 by alveolar macrophages from lung cancer patients. 1054 82

The purpose of the study was to assess the relation between the levels of endotoxins circulating in airways of patients with lung cancer and the ability of bronchoalveolar lavage (BAL) leukocytes for ex vivo release of nitric oxide (NO) and interleukin 6 (IL-6) and for in vitro lipopolysaccharide (LPS)-induced production of the mediators. Leukocytes isolated from the BAL of 11 patients and from 5 healthy individuals were cultured in the absence or presence of LPS(E. coli). The levels of endotoxins in the BAL fluids (BALF) and the amounts of NO released ex vivo from unstimulated cells from the patients were highly (p = 0.0025) elevated in comparison with those from healthy individuals. The release of NO was significantly correlated (R(S) = 0.638, p = 0.047) with the levels of endotoxins in BALF. In contrast, production of IL-6 remained very low and a negative correlation (R(S) = -0.623, p = 0.0542) was observed between the amounts of NO and IL-6. It was also found that, in response to LPS, bronchoalveolar leukocytes from patients with lung cancer express a reduced capacity for in vitro production of NO and IL-6. Our data suggest that, in patients with lung cancer, the activation of BAL cells by endotoxins circulating in the airways may contribute, at least in part, to overproduction of spontaneous NO and, subsequently, the NO may reduce IL-6 production. Moreover, the exposure in vivo of the BAL cells to LPS renders them unable to respond to the second signals.
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PMID:The contribution of endotoxins present in the respiratory tract to overproduction of nitric oxide associated with impaired interleukin 6 release in bronchoalveolar leukocytes from lung cancer patients. 1080 53

Previously we have established a clonal squamous cell carcinoma cell line OKa-C-1 derived from lung cancer of a patient with marked leukocytosis and hypercalcemia. OKa-C-1 cells simultaneously produce granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP) at the single cell level and cause paraneoplastic syndromes in nude mice bearing the tumor. It is known that the production of G-CSF and PTHrP is individually regulated by inflammatory cytokines in various malignant cells. To investigate the common factors in the regulation of G-CSF and PTHrP production in OKa-C-1 cells, we examined the effects of some inflammatory agents [lipopolysaccharide (LPS), phorbol-12-myristate-13-acetate (PMA), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) beta and IL-6] on G-CSF and PTHrP production, by means of enzyme-linked immunosorbent assay (ELISA), immunoradiometric assay (IRMA) and quantitative reverse transcription-polymerase chain reaction (RT-PCR). TNF-alpha or IL-1beta induced both G-CSF and PTHrP production in the conditioned medium. TNF-alpha synergized with IL-1beta to significantly increase G-CSF production. In addition, TNF-alpha and IL-1beta strongly induced G-CSF mRNA with peaks at 2 and 6 h respectively. Although PTHrP production was also strongly induced by TNF-a PTHrP mRNA expression was more strongly induced by PMA than by TNF-alpha. Thus, TNF-alpha and IL-1beta could be common factors that individually and synergistically regulate G-CSF and PTHrP production in OKa-C-1 cells. Moreover, G-CSF and PTHrP production could be not only transcriptionally, but also posttranscriptionally regulated by other factors.
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PMID:Regulation of granulocyte colony-stimulating factor and parathyroid hormone-related protein production in lung carcinoma cell line OKa-C-1. 1101 Nov 19

Monocytes (MO) from cancer patients present functional abnormalities, such as an altered secretion of soluble factors. In the present study, our aim was to evaluate the levels of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and prostaglandin-E2 (PGE2) secreted in vitro by MO from lung cancer patients (LCP), spontaneously or after stimulation with lipopolysaccharide (LPS). Results showed that cytokine secretion was higher for MO from LCP than for MO from healthy controls, while in the 25% of the patients analysed, an absence of response to LPS treatment was found.
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PMID:In vitro secretion of cytokines and prostaglandin-E2 by monocytes from lung cancer patients. 1131 4

Lung cancer is strongly associated with cigarette smoking. More than 20 lung carcinogens have been identified in cigarette smoke and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We hypothesized that NNK modulates alveolar macrophage (AM) mediator production, thus contributing to carcinogenesis. An AM cell line, NR8383, was treated with [3H]NNK and lipopolysaccharide (LPS), and NNK metabolites released in supernatants were analysed by high-performance liquid chromatography (HPLC). NNK was metabolized by carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol (NNAL) or activated by alpha-carbon hydroxylation. AMs were also treated with NNK (100-1000 micro M), with and without LPS, for different periods of time (6-72 h), and mediators released in supernatants were quantified by enzyme-linked immunosorbent assay (ELISA) or the Griess reaction. NNK inhibited (in a concentration-dependent manner) AM production of tumour necrosis factor (TNF), macrophage inflammatory protein-1alpha (MIP-1alpha), interleukin (IL)-12 and nitric oxide (NO), whereas IL-10 production was increased. Cyclooxygenase inhibitors - NS-398 and indomethacin - and anti-prostaglandin E2 (anti-PGE2) antibody abrogated the NNK-inhibitory effect on MIP-1alpha production by AM. NNK stimulated the release of PGE2, and exogenous PGE2 inhibited AM MIP-1alpha production, suggesting that the NNK immunomodulatory effect may be mediated by PGE2 production. Thus, in addition to its carcinogenic effects, NNK may contribute to the lung immunosuppression observed in tobacco smokers.
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PMID:Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages. 1269 10

Data from both rodent models and humans suggest that intact neuronal melanocortin signaling is essential to prevent obesity, as mutations that decrease the melanocortin signal within the brain induce hyperphagia and excess body fat accumulation. Melanocortins are also involved in the pathogenesis of disorders at the opposite end of the spectrum of energy homeostasis, the anorexia and weight loss associated with inflammatory and neoplastic disease processes. Studies using melanocortin antagonists (SHU9119 or agouti-related peptide) or genetic approaches (melanocortin-4 receptor null mice) suggest that intact melanocortin tone is required for anorexia and weight loss induced by injected lipopolysaccharide (an inflammatory gram-negative bacterial cell wall product) or by implantation of prostate or lung cancer cells. Although the precise mechanism whereby peripheral inflammatory/neoplastic factors activate the melanocortin system remains unknown, the proinflammatory cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) that are produced in the hypothalamus of rodents during both inflammatory and neoplastic disease processes likely play a role. The data presented in this paper summarize findings that implicate neuronal melanocortin signaling in inflammatory anorexia.
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PMID:Melanocortin signaling and anorexia in chronic disease states. 1285 26

CD44 is a cell surface receptor for osteopontin (OPN) and hyaluronate. Transformation of normal tissue to a variety of cancers has been demonstrated to be associated with alterations of CD44 isoform expression. However, few reports have paid attention on differences in CD44S expression between non-small cell lung cancer (NSCLC) and adjacent normal lung tissue. In this study, we demonstrate that CD44S expression is down-regulated in NSCLC tissue when compared with paired normal lung tissue. To investigate the role of CD44S down-regulation in NSCLC cells, we reintroduced the CD44S back into the NSCLC cell line, H322 cells, which originally lack CD44S expression. The cytotoxicity by activated macrophage (RAW264.7 cells stimulated with lipopolysaccharide and interferon-gamma) against the H322 cells transfected with the CD44S gene (H322DeltaS) is more prominent than that against the H322 control transfectants (H322Deltaneo). The enhanced susceptibility of H322DeltaS cells to the activated macrophage cytotoxicity appears to be mediated by the interaction between CD44S expression on H322DeltaS cells and OPN produced by activated macrophages since it is completely blocked by either anti-OPN or anti-CD44 antibody. Moreover, H322DeltaS cells are attracted toward OPN produced by activated RAW264.7 cells to a much greater extent than H322Deltaneo cells. These findings suggest that CD44S down-regulation in NSCLC cells may confer a protective advantage of allowing escape from tumoricidal effector cells including activated macrophages of the host.
Lung Cancer 2003 Aug
PMID:Restoration of CD44S in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity. 1287 77

Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Their binding to specific cell membrane receptors allows for noninvasive assessment of regional receptor proteomics in vivo. Information thus obtained can be used for diagnostic purposes and for predicting and monitoring response to treatment. This paradigm also applies to pulmonary diseases. In this review, available radiopharmaceuticals of great potential or already in clinical use for imaging of lung cancer, lung inflammation and infection and pulmonary embolism are discussed. In lung cancer, somatostatin receptor imaging by means of technetium-99m (99mTc)-octreotide scintigraphy has proven useful for characterizing malignancy in solitary pulmonary nodules. Additionally, several radiopharmaceuticals targeting tyrosine-kinase, e.g. 99mTc labeled epidermal growth factor and indium-111 (111In)-diethylene triamine penta-acetic acid-trastuzumab, or G-protein coupled receptors, e.g. 99mTc-bombesin, iodine-123-vasoactive intestinal peptide and 111In-tetraazacyclododecane tetra-acetic acid (DOTA)-cholecystokinine-B, are being explored for their diagnostic as well as treatment monitoring potential. With the purpose of better evaluating the source of pulmonary embolism, as well as to differentiate acute from chronic deep venous thrombosis, several radiolabeled peptides targeting the glycoprotein IIb/IIIa fibrinogen receptor found on activated platelets have been developed. Out of these, 99mTc-P280 is now approved by the US Food and Drug Administration for scintigraphic imaging of suspected acute venous thrombosis in the lower extremities of patients. In the field of lung inflammation and infection, non-specific 111In and 99mTc-human polyclonal immunoglobulins have been successfully used to identify the presence and extent of Pneumocystis carinii, cytomegalovirus, Mycobaterium avium and fungal infections in patients with HIV infection. The clinical role of other radiopharmaceuticals such as 99mTc-J001X, a nonpyrogenic acylated polygalactoside isolated from Klebsiella pneumoniae and binding with high affinity to CD11b and CD14 lipopolysaccharide receptors expressed on monocytes/macrophages, and 111In-octreotide, binding to up-regulated somatostatin receptors on activated lymphocytes needs to be further defined.
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PMID:Peptide receptor imaging: advances in the diagnosis of pulmonary diseases. 1472 55

Iron-regulatory protein 2 (IRP2), a posttranscriptional regulator of iron metabolism, undergoes proteasomal degradation in iron-replete cells, while it is stabilized in iron deficiency or hypoxia. IRP2 also responds to nitric oxide (NO), as shown in various cell types exposed to pharmacological NO donors and in gamma interferon/lipopolysaccharide-stimulated macrophages. However, the diverse experimental systems have yielded conflicting results on whether NO activates or inhibits IRP2. We show here that a treatment of mouse B6 fibroblasts or human H1299 lung cancer cells with the NO-releasing drug S-nitroso-N-acetyl-penicillamine (SNAP) activates IRP2 expression. Moreover, the exposure of H1299 cells to SNAP leads to stabilization of hemagglutinin (HA)-tagged IRP2, with kinetics analogous to those elicited by the iron chelator desferrioxamine. Similar results were obtained with IRP2(Delta)(73), a mutant lacking a conserved, IRP2-specific proline- and cysteine-rich domain. Importantly, SNAP fails to stabilize HA-tagged p53, suggesting that under the above experimental conditions, NO does not impair the capacity of the proteasome for protein degradation. Finally, by employing a coculture system of B6 and H1299 cells expressing NO synthase II or IRP2-HA cDNAs, respectively, we demonstrate that NO generated in B6 cells stabilizes IRP2-HA in target H1299 cells by passive diffusion. Thus, biologically synthesized NO promotes IRP2 stabilization without compromising the overall proteasomal activity. These results are consistent with the idea that NO may negatively affect the labile iron pool and thereby trigger responses to iron deficiency.
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PMID:Nitric oxide inhibits the degradation of IRP2. 1568 86

CHOP is a C/EBP family transcription factor involved in endoplasmic reticulum (ER) stress-mediated apoptosis. To determine if the ER stress pathway is involved in the pathogenesis of LPS-treated mouse lung injury, mice were given lipopolysaccharide (LPS) intraperitoneally. The mRNAs for activating transcription factor (ATF) 4 and X-box binding protein (XBP) 1, transcriptional activators of the CHOP gene, and that for CHOP were induced by or after the LPS treatment. Apoptosis induced by LPS treatment was suppressed in the lungs of Chop-knockout mice. Overexpression of CHOP induced apoptosis in a lung cancer-derived cell line. These results suggest that the ER stress pathway, involving CHOP, is activated and plays a role in the pathogenesis of septic shock lung.
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PMID:The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. 2221 Sep 5


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