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)

Interleukin (IL)-10 was initially recognized on the basis of its capacity to inhibit production of interferon (IFN)-gamma by T helper (Th)1 lymphocytes; we examined whether this cytokine can bias the primary antibody (Ab) response to the hapten penicillin. We previously reported that BALB/c and SJL mice develop different responses to benzylpenicillin coupled to tetanus toxoid (BPO-TT). The response of SJL mice was characterized as Th2 on the basis of early and high IL-4 mRNA expression and production of BPO-specific Ab of the IgG1 isotype. In contrast, the response of BALB/c mice was characterized as Th1 on the basis of delayed and weaker IL-4 mRNA expression associated with high anti-BPO IgG2a production (Kerdine, S. et al., Mol. Immunol. 1996. 33: 71). In this report, we demonstrate that in naive animals, the level of expression of IL-10 mRNA in LN cells was high in SJL and barely detectable in BALB/c. In addition, injection of BPO-TT resulted in rapid and large increase of IL-10 mRNA expression in SJL. Neutralization of IL-10 in vivo promoted the production of BPO-specific IgG2a in SJL, and injection of IL-10-CHO cells inhibited BPO-specific IgG2a production in BALB/c. Neutralization on administration of IL-10 had effects very similar to neutralization or administration of IL-4. However, co-neutralization of IL-10 and IL-4 in SJL did not evidence additive or synergistic effects of the two cytokines. Administration of IL-10 or IL-4 in BALB/c inhibited BPO-TT-induced expression of IL-12 p40 mRNA without modulating IFN-gamma mRNA. Together, these data demonstrate that endogenous production of IL-10 regulates the production of IgG2a Ab in response to BPO-TT and that IL-10, like IL-4, is critical for controlling primary responses to antibiotics which behave as haptenic compounds.
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PMID:Interleukin-10 and interleukin-4 have similar effects on hapten-specific primary antibody responses to penicillin in vivo. 897 82

Late allergic airway responses can be transferred by CD4+ T cells in the rat. To investigate the role of T-cell cytokines in these responses, we examined the expression of mRNA for Th2 (interleukin [IL]-4 and IL-5) and Th1 (IL-2 and interferon gamma [INF-gamma])-type cytokines in Brown Norway rats that were administered either antigen-primed W3/25(CD4)+ or OX8(CD8)+ T cells. Donors were actively sensitized by subcutaneous injection of ovalbumin (OVA) in the neck and T cells were obtained from the cervical lymph nodes by immunomagnetic cell sorting for administration to unsensitized rats. Control rats received bovine serum albumin (BSA)-primed CD4+ and CD8+ T cells. Two days later, recipient rats were challenged with aerosolized OVA, and bronchoalveolar lavage (BAL) was performed 8 h after challenge. BAL cells expressing mRNA for IL-2, IL-4, IL-5, and INF-gamma were analyzed using the technique of in situ hybridization. Recipients of OVA-primed CD4+ T cells had an increase in the fraction of BAL cells expressing mRNA for IL-4 and IL-5 compared with BSA-primed CD4+ or OVA-primed CD8+ cells (P < 0.001). Recipients of CD8+ T cells had an increase in INF-gamma mRNA expression after OVA challenge compared with recipients of BSA-primed-CD8+ or OVA-primed CD4+ T cells (P < 0.001). In conclusion, T-cell-dependent allergen-induced late responses are associated with the expression of mRNA for IL-4 and IL-5, indicating Th2 cell activation. Furthermore, the increased expression of INF-gamma in allergen challenge recipients of antigen-primed CD8+ T cells suggests that CD8+ T cells may be important in modulating allergic responses.
Am J Respir Cell Mol Biol 1997 Jan
PMID:Adoptively transferred late allergic airway responses are associated with Th2-type cytokines in the rat. 899 81

Signal transduction by insulin and IGF-1, several interleukins (IL-2, IL-4, IL-9, IL-13), interferons, GH, and other cytokines involves IRS proteins, which link the receptors for these factors to signaling molecules with Src homology-2 domains (SH2-proteins). We recently reported the amino acid sequence of murine IRS-2; in order to examine a potential genetic role for this molecule in disease, we isolated the murine IRS-2 gene and compared the expression pattern of IRS-2 against IRS-1. Like IRS-1, IRS-2 is encoded by a single exon. Whereas IRS-1 is located on murine chromosome 1, IRS-2 is located on murine chromosome 8 near the insulin receptor. IRS-2 is expressed together with IRS-1 in many cells and tissues; however, IRS-2 predominates in murine hematopoietic cells where it may be essential for cytokine signaling; IRS-1 predominates in adipocytes and differentiated 3T3-L1 cells where it contributes to the normal insulin response. In 32D cells, IRS-1 and IRS-2 undergo differential tyrosine phosphorylation during insulin or IL-4 stimulation, as assessed indirectly by interaction with various recombinant SH2 domains. Thus, signaling specificity through the IRS proteins may be accomplished by specific expression patterns and distinct phosphorylation patterns during interaction with various activated receptors.
Mol Endocrinol 1997 Feb
PMID:The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. 901 72

Members of the nuclear factor of activated T cells (NFAT) are involved in the induction of a number of cytokine genes. We report here cDNA cloning and chromosomal localization of a murine homologue of human NFATx, designated as mNFATx1, and its splicing variants mNFATx2 and m delta NFATx. Northern blot analysis showed mNFATx1 to be predominantly expressed in the thymus. mNFATx1, but not m delta NFATx, produced in COS-7 cells, bound to all NFAT-binding sites of the interleukin (IL)-2 and IL-4 promoters tested. Immunofluorescence assay showed that both mNFATx1 and m delta NFATx introduced into COS-7 cells localized predominantly to the cytoplasm, but did translocate to the nucleus, either by cotransfection with an active form of calcineurin or wild-type calcineurin followed by stimulation with calcium ionophore. Translocation of mNFATx1 correlated well with activation of the murine IL-2 promoter; mNFATx1 translocated under conditions described above, in combination with phorbol 12-myristate 13-acetate, activated the transiently transfected murine IL-2 promoter. Thus, nuclear-translocated mNFATx1 is involved in activation of the IL-2 promoter. These results provide the first evidence for the requirement of calcineurin in the control of mNFATx imported from the cytoplasm to the nucleus and implies that mNFATx may possibly be a substrate of calcineurin in vivo.
Mol Biol Cell 1997 Jan
PMID:Calcineurin-dependent nuclear translocation of a murine transcription factor NFATx: molecular cloning and functional characterization. 901 3

The lung is richly supplied with peptidergic nerves that store and secrete substance P (SP), vasoactive intestinal peptide (VIP), and other neuropeptides known to potently modulate leukocyte function in vitro and airway inflammation in vivo. To investigate and characterize neuromodulation of immune responses compartmentalized in lung parenchyma, neuropeptide release and expression of neuropeptide receptors were studied in lungs of antigen-primed C57BL/6 mice after intratracheal challenge with sheep erythrocytes. The concentrations of cytokines in bronchoalveolar lavage (BAL) fluid rose early and peaked on day 1 for interleukin (IL)-2, interferon gamma, and IL-10; days 1 to 2 for IL-6; and day 3 for IL-4, whereas the total number and different types of leukocytes in BAL fluid peaked subsequently on days 4 to 6 after i.t. antigen challenge. Immunoreactive SP and VIP in BAL fluid increased maximally to nanomolar concentrations on days 1 to 3 and 2 to 7, respectively in lungs undergoing immune responses. The high-affinity SP receptor (NK-1 R), and VIP types I (VIPR1) and II (VIPR2) receptors were localized by immunohistochemistry to surface membranes of mononuclear leukocytes and granulocytes in perivascular, peribronchiolar, and alveolar inflammatory infiltrates during immune responses. As quantified by reverse transcription-polymerase chain reaction, significant increases were observed in levels of BAL lymphocyte mRNA encoding NK-1 R (days 2 to 4), VIPR1 (days 2 to 4), and VIPR2 (days 4 to 6), and in alveolar macrophage mRNA encoding NK-1 R (days 2 to 6) and VIPR1 (days 2 to 4), but not VIPR2. Systemic treatment of mice with a selective, nonpeptide NK-1 R antagonist reduced significantly the total numbers of leukocytes, lymphocytes, and granulocytes retrieved by BAL on day 5 of the pulmonary immune response. The results indicate that SP and VIP are secreted locally during pulmonary immune responses, and are recognized by leukocytes infiltrating lung tissue, and thus their interaction may regulate the recruitment and functions of immune cells in lung parenchyma.
Am J Respir Cell Mol Biol 1997 Feb
PMID:Upregulation of neuropeptides and neuropeptide receptors in a murine model of immune inflammation in lung parenchyma. 903 20

Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two populations of effector cells (eTh1 and eTh2), each one expressing a specific pattern of cytokines that distinguishes them from their precursors. eTh2 cells are the major source of IL-4, while gamma interferon is produced by eTh1 cells. Here we have used reporter transgenic mice to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways. However, although NFAT DNA binding is similarly induced in both eTh1 and eTh2 cells upon antigen stimulation, only the NFAT complexes present in eTh2 cells are able to mediate high-level transcription, and relatively little NFAT transcriptional activity was induced in eTh1 cells. In contrast to activated pTh cells, neither eTh1 nor eTh2 cells produced significant IL-2 upon stimulation, but the high levels of NFAT transcriptional activities directly correlate with the IL-4 production induced in response to antigen stimulation in eTh2 cells. These data suggest that activated NFAT is involved in the effector function of eTh2 cells and that the failure of eTh1 cells to produce IL-4 in response to an antigen is due, at least partially, to a failure to induce high-level transcription of the IL-4 gene by NFAT. Regulation of NFAT could be therefore a critical element in the polarization to eTh1 or eTh2.
Mol Cell Biol 1997 Mar
PMID:Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells. 903 80

Bone marrow stromal cells play a critical role in the proliferation and differentiation of hematopoietic stem and progenitor cells by secreting numerous hematopoietic growth factors and colony-stimulating factors (CSFs). We have previously reported that monocyte chemotactic protein-1 (MCP-1 or MCP-1/JE) and interferon-inducible protein 10 KD (IP-10) are both induced in murine bone marrow stromal cell line +/(+)-1.LDA11 upon stimulation with various inflammatory agents, including IL-1 alpha, IFN-gamma, TNF-alpha, or LPS. In addition, the expression of MCP-1/JE and IP-10 mRNA by these inducers is potentiated by IL-4 and TGF-beta 1. In the present study we have investigated the mechanism of IL-4-mediated upregulation of MCP-1/JE gene expression. Our results of nuclear run-on experiments show that IL-4 enhances the IL-1-induced transcription of MCP-1/JE gene. Because the transcription of genes is regulated by DNA binding nuclear factors and binding sites for transcription factors AP-1 and SP-1, and NF-kB in the enhancer region of MCP-1/JE have been demonstrated, we examined the effect of IL-4 on the levels of these factors in stromal cells stimulated with IL-1. Whereas AP-1 and SP-1 are constitutively expressed in stromal cells, NF-kB is detected only after stimulation with IL-1. Furthermore, while unable to induce the activation of NF-kB alone, IL-4 enhanced the activation of NF-kB by IL-1. Taken together, these data suggest that upregulation of NF-kB may be the mechanism by which IL-4 increases the transcription of MCP-1/JE gene resulting in overabundance of the chemokine mRNA.
Hematopathol Mol Hematol 1996
PMID:IL-4 upregulates IL-1-induced chemokine gene expression in bone marrow stromal cells by enhancing NF-kB activation. 904 60

Mucus hypersecretion and plugging of lower respiratory tract airways contributes to the morbidity and mortality associated with asthma. Interleukin (IL)-4 plays a putative role in some forms of asthma. Thus, transgenic mice that overexpress murine IL-4 selectively within the lung were used to study the effect of IL-4 on mucus glycoprotein gene expression and mucin release. Histologic examination of lung sections from IL-4 mice revealed that nonciliated epithelial cells from conducting airways were hypertrophic, due at least in part to the accumulation of mucus glycoprotein. The cytoplasm of these cells stained positively for glycoproteins using mucicarmine, alcian blue (AB), and periodic acid-Schiff (PAS). Ciliated cells were also enlarged but did not show any mucin-specific staining. Inclusion granules typically found in nonciliated (Clara) cells of control mice were absent in the IL-4 transgenic mice. Northern blot analysis of total RNA from lung tissue revealed that the expression of the MUC5AC, but not MUC2, mucin gene was distinctly upgraded in IL-4 transgenic mice compared to transgene-negative controls. In addition, a 5- to 10-fold increase in AB- and PAS-positive material was found in lavage fluid from IL-4 overexpressing mice compared to transgene-negative controls. Thus, the overexpression of IL-4 locally within the lung enhances mucus glycoprotein synthesis by altering gene expression, results in the accumulation of mucus glycoprotein in nonciliated epithelial cells, and induces the release of mucus into the airway lumen. We therefore hypothesize that the overproduction of mucus seen in some patients with asthma may be a direct result of the action of IL-4 within the inflamed lung.
Am J Respir Cell Mol Biol 1997 Apr
PMID:A novel role for murine IL-4 in vivo: induction of MUC5AC gene expression and mucin hypersecretion. 911 59

CD40 is one of the key molecules involved in the survival, growth and differentiation of B lymphocytes. In contrast, Fas (Apo-1, CD95) mediates apoptosis of a variety of cell types, including lymphocytes. Recent studies have found that Fas expression on mouse B cells could be strongly induced by CD40 ligation, a helper T cell-derived signal. Here, evidence is provided that CD40 ligation induced two distinct signals: one leading to the upregulation of Fas and the other leading to the enhanced Fas susceptibility. B lymphoma cell lines, CH31 and WEHI279, expressed Fas on cell surfaces, but were resistant to anti-Fas antibody (Ab) induced apoptosis. Treatment with CD40 ligand (CD40L), however, greatly enhanced Fas susceptibility of these cells. Similarly, normal splenic B cells became highly susceptible to Fas-mediated apoptosis following prolonged signaling through CD40. While CD40 ligation enhanced Fas-mediated apoptosis, stimulation with anti-IgM and IL-4 partially protected CD40L-activated B cells from Fas-mediated apoptosis. It was found that bcl-xL gene expression in normal splenic B cells was induced drastically by treatment with anti-IgM and IL-4, but not CD40L. By contrast, the expression of bcl-2 or bax was not significantly affected by these treatments. Moreover, in three of the four B lymphoma cell lines tested, Fas susceptibility correlated with the status of bcl-xL expression. The data suggest that an increase in bcl-xL expression may protect B cells from Fas-mediated apoptosis.
Mol Immunol 1996 Nov
PMID:Regulation of bcl-xL expression and Fas susceptibility in mouse B cells by CD40 ligation, surface IgM crosslinking and IL-4. 912 61

We analyzed the effect of rapamycin on autocrine mast cell tumor lines with abnormally stable interleukin-3 (IL-3) transcripts due to a defect in mRNA degradation. Rapamycin inhibited IL-3 mRNA expression specifically, while transcripts of IL-4 and IL-6 were not affected. As indicated by the use of the transcriptional inhibitor actinomycin D or by reporter constructs, inhibition was posttranscriptional and resulted from destabilization of the mRNA. Transcripts from transgenes lacking the AU-rich 3' untranslated region were refractory to drug-induced degradation, suggesting that these 3' sequences contain the target of the rapamycin effect. Rapamycin did not promote IL-3 mRNA degradation in cells of a tumor variant lacking expression of FKBP12, the binding protein of rapamycin. Experiments with wortmannin indicated that rapamycin does not act via p70S6 kinase. FK-506, another ligand of FKBP12 affecting the phosphatase calcineurin, did not antagonize but shared the effect of rapamycin. Our data fit a model whereby both FKBP12 and calcineurin target an unknown regulator of IL-3 mRNA turnover.
Mol Cell Biol 1997 Jun
PMID:Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region. 915 24


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