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 effect of recombinant human interleukin 4 (IL-4) on the expression of antitumor activity of human alveolar macrophages (AM) obtained by bronchoalveolar lavage from healthy donors was examined. AM were incubated for 16 h in medium with various macrophage activators [lipopolysaccharide, des-methyl muramyldipeptide, Nocardia rubra cell wall skeleton, and heptanoyl-gamma-D-Glu-(L)-meso-alpha,epsilon-A2pm(L)-D-Al aOH] in the presence or absence of IL-4, and then their tumoricidal activity was assayed by measuring 125I-UdR release from human melanoma (A375) cells. The spontaneous tumoricidal activity of AM was slightly suppressed by IL-4 in 3 of 7 donors. Addition of IL-4 to cultures of AM with the activators resulted in dose-dependent suppression of AM-mediated cytotoxicity against A375 cells. IL-4 also inhibited AM-mediated cytotoxicity against A375-R cells, which are resistant to interleukin 1 (IL-1) and tumor necrosis factor alpha, HT-29 colon cancer cells, and KB cells. IL-4 inhibited the early induction phase of AM activation. Pretreatment of AM with IL-4 also suppressed their expression of antitumor activity in response to lipopolysaccharide. IL-4 inhibited the production of monokines (IL-1 and tumor necrosis factor alpha) by AM at the protein and mRNA levels. These findings suggest that IL-4 may be important in vivo in the down-regulation of antitumor expression of AM in the lung by inhibiting the production of monokines and other killing mechanisms.
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PMID:Down-regulation by interleukin 4 of activation of human alveolar macrophages to the tumoricidal state. 191 71

The precursor frequency for anti-DNA antibody-producing cells in the pre-immune B cell repertoire was investigated in young female BALB/c and NZW mice, and in young and aged female NZB x NZWF1 (B/WF1) mice. Spleen cells from these mice were diluted serially and stimulated polyclonally in vitro with lipopolysaccharide (LPS) and IL-4 to induce both IgM and IgG1 production. The results demonstrated that there existed virtually no difference in precursor frequency for IgM anti-DNA antibody-producing cells between normal and lupus mice, confirming previous observations made by other investigators. In contrast, the number of precursors for IgG1 anti-DNA antibody-producing cells was much higher in young and old B/WF1 mice than in normal mice. These results suggest that the high frequency of precursors for IgG1 anti-DNA antibody-producing cells in the pre-immune B cell repertoire of B/WF1 mice is a crucial factor for the pathogenesis of systemic lupus erythematosus.
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PMID:Qualitative difference of anti-DNA antibody-producing cell precursors in the pre-immune B cell repertoire between normal and lupus-prone mice. 191 23

Antigens and infectious agents that stimulate interferon alpha(IFN-alpha) production in mice induce antibody responses that are predominantly of the immunoglobulin (Ig)G2a isotype and contain little or no IgE. This suggested the possibility that IFN-alpha might have a role in directing Ig isotype selection. Consistent with this possibility, we have found that injection of mice with recombinant mouse IFN-alpha suppresses IgE secretion, enhances IgG2a secretion, and has no independent effect on IgG1 secretion in mice stimulated with a foreign anti-IgD antibody. Injection of mice with polyinosinic acid.polycytidylic acid (poly I.C), an inducer of macrophage IFN-alpha production, also suppresses the anti-IgD antibody-induced IgE response and stimulates the IgG2a response; these effects are blocked by a sheep antibody that neutralizes mouse IFN-alpha/beta. Both recombinant IFN-alpha and poly I.C have maximum IgE suppressive and IgG2a stimulatory effects when injected early in the anti-IgD antibody-induced immune response. Addition of IFN-alpha to mouse B cells cultured with lipopolysaccharide (LPS) + interleukin 4 (IL-4) suppresses both IgG1 and IgE production, but much less potently than IFN-gamma. IFN-alpha suppresses anti-IgD antibody-induced increases in the level of splenic IL-4 mRNA, but enhances the anti-IgD antibody-induced increase in the splenic level of IFN-gamma mRNA. These results are consistent with the effect of IFN-alpha on Ig isotype expression in mice, as IL-4 stimulates IgE and suppresses IgG2a secretion while IFN-gamma exerts opposite effects. These observations suggest that antigen presenting cells, by secreting IFN-alpha early in the course of an immune response, can influence the nature of that response both through direct effects on B cells and by influencing the differentiation of T cells.
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PMID:Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice. 194 Jul 96

The in vitro polyclonal stimulation of B cells through their surface immunoglobulin (Ig) induces substantial increases in CD44 protein levels within 24 hours, whereas other stimuli (e.g., lipopolysaccharide, phorbol 12,13 dibutyrate, and interleukin 4) fail to significantly upregulate CD44. The marked increase in CD44 protein expression on anti-Ig-treated B lymphocytes correlates with an increase in CD44-specific mRNA. Cell sorting experiments with B cells isolated from trinitrophenyl-keyhole limpet hemocyanin-immunized mice demonstrate that both short-term antigen-specific, IgG-secreting cells and long-term antigen-primed B cells are exclusively CD44high. We speculate that the rapid and sustained increase in CD44 expression mediated by surface Ig stimulation may alter the homing properties of antigen-primed B cells.
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PMID:High levels of CD44 expression distinguish virgin from antigen-primed B cells. 199 54

Peripheral blood monocytes can be induced by stimuli such as bacterial lipopolysaccharide (LPS) to secrete an array of cytokines. We have studied the effects of interleukin 7 (IL-7) on human peripheral blood mononuclear cells (PBMC) and found that IL-7 is a relatively potent inducer of IL-6 secretion IL-6 protein levels were determined either by the B9 hybridoma growth factor assay or by enzyme-linked immunosorbent assay, and mRNA for IL-6 was analyzed by Northern hybridization. Detailed examination revealed that, among PBMC, monocytes, rather than lymphocytes, were secreting IL-6 in response to IL-7. In contrast to the low concentrations of IL-7 required to stimulate T cell growth and differentiation (as low as 0.1 ng/ml), relatively high concentrations of IL-7 were necessary to induce IL-6 secretion by monocytes (at least 10 ng/ml). An optimal concentration of IL-7 (100 ng/ml) induced monocytes to secrete 10-fold more IL-6 than an optimal concentration of IL-1 beta (10 ng/ml), and almost as much as LPS. However, significantly more IL-7 than IL-1 beta was required to induce detectable levels of IL-6. The kinetics of IL-6 secretion by monocytes were identical in response to IL-7, IL-1 beta, or LPS, with IL-6 protein detectable in culture supernatants as early as 2 h after the initiation of culture. IL-4 was found to markedly inhibit the ability of IL-7 or LPS to induce IL-6 mRNA and IL-6 secretion. In addition to promoting IL-6 production, IL-7 induced the secretion of immunoreactive IL-1 alpha, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) by monocytes. IL-7 also induced monocyte/macrophage tumoricidal activity against a human melanoma cell target, an activity that may be related to the secretion of IL-1 alpha, IL-1 beta, and TNF-alpha. Finally, we used a whole blood culture system as a bridge to in vivo analysis to demonstrate that IL-7 induces cytokine secretion in the absence of culture medium, fetal calf serum, and adherence to plastic. Our data suggest that IL-7, in addition to regulating lymphocyte growth and differentiation, has potent effects on cells of the monocytic lineage. Thus, IL-7 may be an important mediator in inflammation and in the macrophage immune response to tumors.
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PMID:Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes. 200 58

Initiation of the immunoglobulin heavy chain switch DNA rearrangement event is thought to involve conversion of the target switch region DNA to an accessible state. Accessibility is likely to be mediated by the binding of regulatory proteins to sequences in or near switch regions. A DNase hypersensitivity assay was used to recognize possible regions of protein binding in the gamma 1 switch region of the B cell hybridoma 470.25. A strong DNase hypersensitive site was identified 5' of the tandemly repeated S gamma 1 sequences. Data from other laboratories suggest that this hypersensitive site is associated with switch recombination to gamma 1. However, the 470.25 cell does hypersensitive sites within the repetitive portion of the gamma 1 switch region was also identified. A gel retardation assay for protein--DNA interaction revealed a sequence present in several copies in the gamma 1 switch region that specifically binds nuclear proteins. This binding sequence, SG1BS, contains the octanucleotide sequence ATGCAAAA, a 7/8 match to the transcriptional enhancer octamer motif found in immunoglobulin promoters and the heavy chain enhancer. Binding competition studies of SG1BS demonstrate that both the octamer and flanking sequences are critical for binding. By size- and tissue-distribution, the factors that bind SG1BS are not distinguishable from the previously identified octamer-binding factors OTF-1 and OTF-2. The ability of proteins to bind the S gamma 1 octamer motif is increased 2.3-fold upon IL-4 induction of lipopolysaccharide-stimulated B cells.
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PMID:Nuclear protein binding to octamer motifs in the immunoglobulin gamma 1 switch region. 202 12

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BL/6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-alpha (TNF-alpha) which is known to be a potent macrophage (M phi) stimulator in other parasitic diseases. In the present study we investigated whether TNF-alpha activates M phi for killing of L. major parasites. In the absence of interferon-gamma (IFN-gamma) or lipopolysaccharide, TNF-alpha (0.025-25,000 U/ml) failed to activate peritoneal exudate M phi from BALB/c mice for killing of L. major amastigotes. In the presence of suboptimal doses of IFN-gamma (5 or 10 U/ml), however, TNF-alpha mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-gamma alone. The combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conclude that the presence of IFN-gamma is crucial for TNF-alpha-mediated killing of L. major parasites by M phi. Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-gamma and a predominance of interleukin 4 rather than the result of an excess amount of TNF-alpha.
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PMID:Tumor necrosis factor-alpha in combination with interferon-gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes. 211 75

We have characterized circular DNA in mouse splenocytes treated with the mitogen lipopolysaccharide (LPS) and various cytokines, including transforming growth factor beta (TGF-beta) and interleukin 4 (IL-4). Using probes of immunoglobulin heavy chain constant genes (CH), excision products of class switch recombination were identified. The majority of the clones contained the 3' portion of the switch mu (S mu) region and the 5' portion of other switch regions. Some clones contained 3'-S gamma sequences instead of 3'-S mu. This indicates that isotype switching may occur not only from C mu, but also from one of the C gamma genes to other CH genes further down-stream. In the presence of LPS, the cytokine TGF-beta enhanced the detection of 5'-S alpha-positive clones, while the lymphokine IL-4 enhanced 5'-S gamma 1 positives. The data support the notion that TGF-beta and IL-4 can direct isotype-specific class switching.
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PMID:Switch circular DNA formed in cytokine-treated mouse splenocytes: evidence for intramolecular DNA deletion in immunoglobulin class switching. 211 19

Urokinase-type plasminogen activator (u-PA), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) activities were measured for highly purified human monocytes cultured for 18 hr with recombinant human interleukin-3 (IL-3). IL-3 alone stimulated monocyte u-PA activity, but not TNF-alpha or IL-1 activity. However, IL-3, together with interferon-gamma (IFN-gamma), stimulated the TNF-alpha, but not IL-1, activities of monocytes from several donors. In parallel cultures, granulocyte-macrophage colony-stimulating factor (GM-CSF) behaved similarly. IL-3, like GM-CSF, synergized weakly and sometimes irregularly with lipopolysaccharide (LPS) for increased TNF-alpha and IL-1 activities. Thus, IL-3 can selectively stimulate monocyte mediator production depending on the costimulus present; however, the stimulatory properties of IL-3 vary from those of IFN-gamma and IL-4. The similarities in activity between IL-3 and GM-CSF may be explained by a common or associated IL-3/GM-CSF receptor(s), as suggested by biochemical studies.
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PMID:Regulation by interleukin-3 of human monocyte pro-inflammatory mediators. Similarities with granulocyte-macrophage colony-stimulating factor. 212 Jan 30

The effect of interleukin 4 (IL-4) on expression of antitumor activity of blood monocytes purified by counter-flow centrifugal elutriation from healthy donors was examined. The blood monocytes were incubated for 24 h in medium with lipopolysaccharide, interferon gamma (IFN-gamma) or desmethyl muramyl dipeptide (norMDP) or with IFN-gamma and norMDP in the presence of IL-4, and then their tumoricidal activity was assayed by measuring 125IUdR release from human melanoma (A375) cells. Irrespective of activation stimulus, addition of IL-4 to cultures of monocytes and activators resulted in dose-dependent suppression of the tumoricidal activity of monocytes against parent A375 melanoma cells and the variant cells, A375-R resistant to IL-1 and tumor necrosis factor alpha. IL-4 suppressed the early induction phase of monocyte activation. Rabbit anti-IL-4 antisera completely blocked the IL-4-mediated suppression of monocyte activation to the tumoricidal state. These findings suggest that IL-4 is important in vivo in down-regulation of anti-tumor expression of monocytes.
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PMID:Suppression by interleukin 4 of activation of human blood monocytes to the tumoricidal state. 212 95


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