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

The Oct-2 gene appears to encode a developmental regulator of immunoglobulin gene transcription. We demonstrate that the Oct-2 gene is expressed at low levels in a variety of transformed pre-B-cell lines and is induced specifically in these cells by lipopolysaccharide signalling. This work extends an earlier observation in the pre-B-cell line 70Z/3 and therefore suggests that the inducible expression of the Oct-2 gene, like that of the kappa gene, is a characteristic feature of the pre-B stage of B-cell development. In 70Z/3 cells, the lymphokine interleukin-1 also induces the expression of the Oct-2 and kappa loci. Interestingly, expression of the Oct-2 gene is rapidly induced at the transcriptional level and may not require de novo protein synthesis. Since the changes in the activity of the Oct-2 locus completely correlate with the changes of the activity of the kappa locus, the two genes may be transcriptionally regulated by a common trans-acting factor. In 70Z/3 cells, transforming growth factor beta, an inhibitor of kappa-gene induction, blocks the upregulation of Oct-2 but not the activation of NF-kappa B. These results suggest that the combinatorial action of increased levels of Oct-2 and activated NF-kappa B may be necessary for the proper stage-specific expression of the kappa locus.
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PMID:Regulation and a possible stage-specific function of Oct-2 during pre-B-cell differentiation. 192 24

Treatment of splenic B lymphocytes and certain B-lineage cell lines with the mitogen lipopolysaccharide (LPS) and the lymphokine interleukin-4 (IL-4) induces expression of germ line immunoglobulin C epsilon transcripts and class switching to the C epsilon gene. We show that LPS-plus-IL-4 induction of germ line epsilon transcripts (termed I epsilon transcripts) occurs at the transcriptional level in an Abelson murine leukemia virus-transformed pre-B-cell line. A 1.1-kb region of DNA surrounding the I epsilon promoter endows inducible transcription to a heterologous reporter gene stably transfected into these cells; such inducible expression depends on combined treatment with LPS and IL-4. Analyses of constructs transiently introduced into a B-cell lymphoma line demonstrated that LPS-plus-IL-4-inducible expression can be conferred by a 179-bp segment of DNA spanning the I epsilon transcriptional initiation site. Mutational analyses demonstrated that this expression depended on DNA sequences within a conserved region directly upstream from the I epsilon transcriptional initiation region. One nuclear protein that is constitutively expressed in normal B cells binds to the downstream end of the conserved sequence; its binding specificity correlates with the functional effect of several mutations. Two additional proteins, which are induced by IL-4 treatment of splenic B cells, bind to the transcription initiation sites of I epsilon. These proteins are indistinguishable in binding assays from proteins previously shown to bind an enhancer region of the class II major histocompatibility complex gene A alpha.
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PMID:Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. 192 63

Anti-immunoglobulin (Ig)-activated B lymphoblasts, prepared by culturing high-density B cells with anti-Ig-Sepharose for 48 h, can be induced to secrete IgM and IgG1 by a mixture of T cell-derived lymphokines containing interleukin (IL) 4. In this study we have examined the conditions required for lymphokine-mediated induction of IgG1 secretion and membrane (m)IgG1 expression in B lymphoblasts. Resting B cells exposed to IL 4 (10-100 U/ml) during anti-Ig-mediated blast transformation did not secrete IgG1 upon subsequent culture with lipopolysaccharide (LPS) regardless of whether IL 4 was present or absent during the secondary culture. In contrast, B lymphoblasts previously exposed to IL 4 did secrete IgG1 in response to T cell-derived lymphokines [EL 4 supernatant depleted of IL 4; (D)EL 4 SN]. However, optimal IgG1 secretion was obtained when B lymphoblasts were simultaneously exposed to IL 4 and other lymphokines. Pre-exposure to (D)EL 4 SN, which contains IL 5 and IL 2, failed to prepare anti-Ig blasts to secrete IgG1 in response to LPS and IL 4. Inhibition of IL 5 and IL 2 activity in EL 4 SN suppressed IL 4-mediated IgG1 secretion. Together, these data indicate that B lymphoblasts require IL 5 and IL 2 in addition to IL 4 to secrete IgG1, and that the IL 4 signal(s) must precede or accompany those provided by the other lymphokines. As a measure of the fraction of cells capable of switching to IgG1, we assessed expression of mIgG1 on B lymphoblasts by fluorescence flow cytometry. B lymphoblasts cultured for 3 days with (D)EL 4 SN and IL 4 (10-100 U/ml) were 8% to 20% mIgG1+; in the absence of IL 4 blasts did not express detectable mIgG1. Although anti-Ig blasts treated with LPS and IL 4 did not secrete appreciable IgG1, a substantial fraction of B lymphoblasts (4% - 19%) cultured with LPS and IL 4, but not LPS alone, expressed mIgG1. These results suggest that LPS and IL 4 are sufficient to commit B lymphoblasts to mIgG1 expression, but that additional signals provided by T cell-derived lymphokines are required to elicit IgG1 secretion.
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PMID:Isotype switching in anti-immunoglobulin-activated B lymphoblasts: differential requirements for interleukin 4 and other lymphokines to elicit membrane vs. secreted IgG1. 200 12

We have examined the effects of interleukin 2 (IL-2) treatment either alone or in combination with interferon (IFN) gamma or beta on the expression of several activation associated genes (e.g. tumor necrosis factor alpha (TNF alpha), IFN-inducible 10-kDa protein (IP-10] in murine peritoneal macrophages. IL-2 alone did not induce the expression of either gene while IFN gamma or IFN beta had a modest inductive effect on IP-10 but no effect on TNF alpha expression. When either form of IFN was used in combination with IL-2 there was a marked synergistic induction of both mRNAs. IFN gamma and IL-2 were maximally effective when both agents were added simultaneously, and induced mRNA expression declined over a 24-h period in cells pretreated with IFN gamma prior to addition of IL-2. Expression of both genes following combination lymphokine treatment was mediated by increased transcriptional activity. The responses to all three lymphokines were dose dependent; the concentration requirement for IL-2 indicated interaction with an intermediate or low affinity receptor. The expression of both monokine genes was transient and was comparable although not identical to that seen in cells stimulated with lipopolysaccharide. IFN gamma and IL-2 could synergize to stimulate the expression of either TNF alpha or IP-10 mRNA using sequential non-overlapping treatment periods regardless of the order in which the two stimuli were applied to the cells. The effect of either agent alone induced a transient (1-5 h) responsive state with respect to subsequent stimulation with the second agent. Expression of both monokine genes in response to IFN gamma/IL-2 treatment was independent of protein synthesis as cycloheximide did not inhibit the accumulation of specific mRNA. Interestingly, the combination of IL-2 and cycloheximide was as effective as IFN gamma and IL-2 together. In concert, these results indicate that both IFN and IL-2 generate independent intracellular signals which alone are incapable of inductive effect but which are potent activators of inflammatory gene expression when coincidentally expressed.
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PMID:Interferon gamma and interleukin 2 synergize to induce selective monokine expression in murine peritoneal macrophages. 210 65

Cytokines produced by mononuclear cells are important regulatory and effector molecules and evidence has been presented to support a role at least for tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in host defense against Leishmania. In the present study, we examined the production of TNF-alpha and interleukin 1 (IL-1) by resting and IFN-gamma-primed peripheral blood monocytes infected in vitro with Leishmania donovani. Monocytes produced neither IL-1 nor TNF-alpha during challenge with Leishmania. Cells preinfected with Leishmania synthesized normal amounts of TNF-alpha, but had diminished production of IL-1 in response to stimulation with either S. aureus or lipopolysaccharide (LPS). The induction by S. aureus or LPS of IL-1 beta mRNA accumulation in infected cells was normal despite diminished intracellular or supernatant IL-1 protein and bioactivity. Thus, inhibition of IL-1 production by Leishmania most probably reflected diminished translation of IL-1 beta mRNA. Pretreatment of cells with IFN-gamma abrogated infection-induced inhibition of IL-1 production and primed cells for the production of both IL-1 and TNF-alpha upon subsequent exposure to Leishmania. These results indicate that L. donovani has evolved the capacity to infect mononuclear phagocytes, without stimulating the production of two potentially host-protective monokines. The ability of IFN-gamma to prime monocytes to produce TNF-alpha and IL-1 in response to infection with Leishmania and to prevent inhibition of IL-1 production may have implications for immunotherapy with this lymphokine.
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PMID:Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1. 211 57

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

In order to identify novel mediators synthesized in activated macrophages, a cDNA library was prepared from cultures of the mouse macrophage cell line RAW 264.7 that had been treated with lymphokine-rich conditioned medium from mitogen-stimulated mouse spleen cells. Differential plaque hybridization identified a cDNA, designated m119, that detected a 1.6-kilobase mRNA that accumulated in response to gamma-interferon (IFN-gamma) but not in response to other macrophage activators, including IFN-alpha, IFN-beta, and lipopolysaccharide. The mRNA encoded a predicted protein of Mr 14,461 containing a 21-amino acid signal peptide. The primary structure of the predicted protein indicated that it is a member of a recently described family of cytokines related to platelet factor 4, including Gro/melanoma growth stimulatory activity and neutrophil-activating peptide/interleukin 8. The selective induction of the m119 mRNA by IFN-gamma that the predicted m119 protein mediates a macrophage activity regulated by IFN-gamma. The m119 protein may be a cytokine that affects the growth, movement, or activation state of cells that participate in immune and inflammatory responses. It is proposed that the gene encoding this protein be called mig, for monokine induced by gamma interferon.
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PMID:A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines. 211 67

Alterations of immune activity are often accompanied by reproductive disorders. Because interleukins mediate the host's response to immune activation, we first examined the effect of the central injection of several lymphokines on LH secretion by gonadectomized rats. We then studied the ability of the most potent lymphokine in this system, interleukin-1 beta (Il-1 beta), to interfere with the proestrous LH surge and ovulation in the intact female rat as well as the dependence of this effect on the activation of opiate receptors. Finally, we investigated the possibility that increased brain levels of Ils, as induced by the central administration of a bacterial endotoxin, might also alter the normal ovulatory process. After intracerebroventricular (icv) injection, Il-1 beta, Il-6, and tumor necrosis factor all lowered plasma LH levels in castrated rats. On a molar basis, Il-1 beta was the most potent inhibitor of LH secretion. In gonadectomized animals, 2.5 and 10 ng Il-1 beta administered icv significantly (P less than or equal to 0.01) decreased plasma LH levels for 6 h, while the effect of 40 ng lasted up to 12 h. By contrast, FSH secretion was only measurably altered by 40 ng Il-1 beta 8 and 12 h posttreatment. In intact cycling female rats, icv injection of 40 ng Il-1 beta or 400 ng Il-1 alpha at 0830 h on the morning of proestrus significantly (P less than 0.01 and P less than 0.05, respectively) interfered with the proestrous surge of LH. In contrast, the peripheral administration of either lymphokine was without measurable effect. Centrally injected Il-1 beta (40 ng at 0830 h on proestrus) also blocked ovulation in most animals, while a dose of 25 ng injected iv was ineffective. Finally, we observed that the icv injection of endotoxin (a lipopolysaccharide), also interfered with ovulation. The possible involvement of opiate-dependent pathways in mediating the inhibitory action of Il-1 beta on reproductive processes was tested by implanting naloxone pellets 16-24 h before lymphokine treatment. The pellets, which released 200, 400, or 800 micrograms naloxone/h (corresponding to approximately 0.6, 1.32, or 2.64 mg/kg BW.h), had no effect on ovulation by themselves. When given before icv Il-1 beta, all naloxone regimens countered the effect of the cytokine, with the 800-micrograms/h dose restoring ovulation in eight of nine rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. 211 35

The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.
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PMID:Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS. 211 42

Stimulated human monocytes/macrophages are a source of interleukin-6 (IL-6), which is a likely mediator involved in immune and inflammatory reactions. The means to control production of IL-6 by these cells could therefore have therapeutic applications. We report here, for lipopolysaccharide (LPS)-stimulated human monocytes in vitro, that the lymphokine, interferon-gamma (IFN-gamma) (100 U/ml), enhanced the level of IL-6 activity, whereas another lymphokine, interleukin-4 (IL-4) (greater than or equal to 0.1 U/ml; greater than or equal to 1.2 x 10(-11) M), suppressed it. The effects of the two lymphokines were manifested at the level of mRNA. The action of the IL-4 was similar to that of the glucocorticoid, dexamethasone, but observed at a lower molar concentration. Such regulation of monocyte IL-6 activity is similar to that found previously for interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) synthesis.
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PMID:Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human monocytes. 212 Jan 29


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