Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cells have been implicated in autoimmune renal injury. To examine the role of T-cells in lupus nephritis we propagated T-cell clones from the cortical interstitium of MRL/lpr mice. All isolated kidney-infiltrating (KI) T-cell clones [6] express surface markers identical to the T-cells regulated by the lpr gene (Thy 1.2+, TCR alpha/beta +, Lyt-2-, L3T4-, B220+). Although KI T-cell clones have the same surface markers as lymph node-infiltrating (LNI) T-cells, they differ functionally. KI T-cells, but not LNI T-cells, are autoreactive and kidney-specific, exclusively proliferating to renal tubular epithelial (TEC) and mesangial cells. In addition, unlike LNI T-cell supernatants (SN), KI T-cell clones SN induce class II and ICAM-1 on cultured TEC. When KI T-cell clones are injected under the renal capsule, class II is increased on TEC. All clones transcribe mRNA for cytokines capable of inducing class II and ICAM-1 (IL-4, TNF-alpha, IFN-gamma). Anti-IFN-gamma mAb prevents the induction of class II and ICAM-1 on cultured TEC. Since class II and ICAM-1 expression on TEC precedes renal injury, the ability to propagate autoreactive, kidney-specific T-cell clones that induce these molecules provides evidence for their role in initiating renal injury in MRL/lpr mice.
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PMID:Autoreactive kidney-infiltrating T-cell clones in murine lupus nephritis. 136 May 51

Treatment of EMT 6 mammary adenocarcinoma cells with Interferon-gamma (IFN-gamma, 10 U.ml-1) plus endotoxin lipopolysaccharide (LPS, 100 ng.ml-1) induces concomitantly a growth arrest and production of citrulline and nitrite from L-arginine. A similar L-arginine-dependent metabolism is responsible for the vascular smooth muscle relaxing effect of stimulated endothelial cells. We therefore investigated the ability of EMT 6 cells to induce the relaxation of endothelium-denuded rat aortic rings precontracted with noradrenaline (1 microM). Pretreatment of EMT 6 cells with IFN-gamma + LPS increased their relaxing potency by 5-10 times. The relaxin effects of control and treated EMT 6 cells were entirely counteracted by NG-monomethyl-L-arginine (300 microM), a specific inhibitor of nitrite and citrulline production from L-arginine, and by methylene blue (10 microM) and LY 83583 (10 microM), two inhibitors of NOo-induced activation of guanylate cyclase. The effect of NG-monomethyl-L-arginine was reversed by L- but not D-arginine (1 mM). It is concluded that IFN-gamma + LPS increase the production of a relaxing factor in EMT 6 cells through the L-arginine-NOo-synthase pathway.
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PMID:Production of an arginine-derived relaxing factor induced by IFN-gamma plus endotoxin in murine adenocarcinoma EMT 6 cells. 212 6

Antiviral and cell-differentiating (CD) activities of immune interferon (IFN-gamma) preparation were investigated. Male STD-ddY mice were sensitized with BCG. Three weeks later, they were challenged with BCG or purified protein derivative (PPD), and exsanguinated at intervals. The sera were assayed for antiviral and CD activities. The CD activity appeared and reached the maximum earlier than the antiviral activity. The CD activity was thermostable, whereas the antiviral activity was thermolabile. By dialysis at pH 2 for 24 h, the CD activity was reduced to 15%, while the antiviral titer was completely lost. Lipopolysaccharide (LPS) given 24 h before the challenge has markedly suppressed the appearance of antiviral activity following the challenge, but did not so much affect the CD activity. The challenge with PPD stimulated greater antiviral activity and poorer CD activity than the challenge with BCG did. These findings suggest that IFN-gamma preparations contain a CD factor(s) besides IFN.
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PMID:Differentiation in mouse leukemia cells mediated by an immune interferon preparation. 643 99

The tyrosine kinase JAK2 is an integral part of the signal transduction pathways of a number of cytokines and growth factors, including IFN-gamma. Previously, we identified a species-nonspecific binding site for the C terminus of IFN-gamma, encompassed by IFN-gamma peptide IFN-gamma(95-133), on the membrane proximal region of the cytoplasmic domain of the IFN-gamma R alpha-chain. Using both a radioligand binding assay and coimmunoprecipitation with antireceptor antiserum, we were able to demonstrate specific interaction of JAK2 with the murine IFN-gamma R(MIR) alpha-chain. Furthermore, this interaction is increased by the addition of murine IFN-gamma or its C-terminal peptide, muIFN-gamma(95-133). We also identified two regions of the cytoplasmic domain of the receptor that interact with JAK2 using synthetic peptides of the MIR alpha-chain in receptor competition studies. These regions are encompassed by receptor peptide MIR(283-309), which is adjacent to the membrane proximal region at which the C terminus of IFN-gamma binds, and receptor peptide MIR(404-432), which lies near the C terminus of the receptor, encompassing a potentially important phosphorylation site. These data show site-specific interaction between JAK2 and IFN-gamma with the IFN-gamma R and have broader implications for the role of the IFN-gamma ligand in the IFN-gamma signal transduction pathway. Furthermore, the data support previous studies that demonstrated that intracellular IFN-gamma plays a role in cell activation.
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PMID:Identification of IFN-gamma receptor binding sites for JAK2 and enhancement of binding by IFN-gamma and its C-terminal peptide IFN-gamma(95-133). 749 45

The thymic stromal network is complex and heterogeneous, containing thymic epithelial cells which are thought to play an important role during T-cell development and thymic fibroblasts which role is less defined. We herein present a phenotypic and functional comparison between defined thymic stromal cell populations. We transfected SV40 ori- into fetal and postnatal thymic stromal cell cultures and obtained SV40-immortalized clones of epithelial and fibroblastic nature as demonstrated by expression of intracellular keratin. These various clones were characterized in detail and compared to their untransfected bulk culture counterparts for phenotype, cytokine gene expression and cytokine production. All the different thymic stromal cells examined, constitutively expressed ICAM-1, LFA-3, MHC class I antigens, CD44, and the genes coding for IL-7, SCF and TGF-beta, but not TNF-alpha. After IL-1 stimulation, epithelial cells seemed to produce more GM-CSF than fibroblasts, and that trend was also seen for IL-6 secretion. SV40 cells were also regulated by IFN-gamma which induced MHC class II antigens and inhibited the IL-1 induced GM-CSF production. SV40 cells differed from their untransfected counterparts by an atypical expression of CD40 and lacked constitutive IL-1 alpha gene expression. We isolated clones with distinct properties, 24SV48, a highly proliferative CD34 positive TEC secreting low levels of GM-CSF and lacking constitutive IL-1 alpha and beta gene expression, and CT1SV93, an epithelial clone of postnatal origin with a high IL-1-induced cytokine production. In spite of differences with untransfected bulk cultures, the various SV40 immortalized clones may represent useful tools to further study the human thymic stroma.
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PMID:Untransfected and SV40-transfected fetal and postnatal human thymic stromal cells. Analysis of phenotype, cytokine gene expression and cytokine production. 750 57

We have isolated U6A, a mutant cell line which lacks the STAT2 subunit of the transcription factor interferon (IFN)-stimulated gene factor 3 (ISGF3). The response of U6A cells to IFN-alpha is almost completely defective, but the response to IFN-gamma is normal. Complementation of U6A cells with a cDNA encoding STAT2 restores the IFN-alpha response, proving that STAT2 is required in this pathway. Binding of IFNs to their receptors triggers tyrosine phosphorylation and activation of the receptors, JAK family kinases, STAT1, and STAT2. In IFN-alpha-treated U6A cells, phosphorylation of the essential tyrosine kinases TYK2 and JAK1 is normal, but the phosphorylation of STAT1 is weak. A mutant STAT2 protein in which the phosphorylated tyrosine at position 690 is changed to phenylalanine does not restore normal phosphorylation of STAT1 in response to IFN-alpha. The dependence of STAT1 phosphorylation on the presence of STAT2 but not vice versa (T. Improta, C. Schindler, C. M. Horvath, I. M. Kerr, G. R. Stark, and J. E. Darnell, Jr., Proc. Natl. Acad. Sci. USA 91:4776-4780, 1994) indicates that in the formation of ISGF3, these two proteins may be phosphorylated sequentially in response to IFN-alpha and that phosphorylated STAT2 may be required to allow unphosphorylated STAT1 to bind to the activated IFN-alpha receptor.
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PMID:Role of STAT2 in the alpha interferon signaling pathway. 753 78

Germ line C transcripts can be induced by IL-4 in the human B cell line, BL-2. Utilizing a IFN-gamma activation site-like DNA sequence element located upstream of the I epsilon exon, we demonstrated by gel mobility shift assays that IL-4 induced a binding activity in the cytosol and nucleus of BL-2 cells. This factor was designated IL-4 NAF (IL-4-induced nuclear-activating factors) and was identified as a tyrosine phosphoprotein, which translocates from the cytosol to the nucleus upon IL-4 treatment. Because these are the characteristics of a signal transducer and activator of transcription (Stat) protein, we determined whether antibodies to Stat proteins will interfere with gel mobility shift and found that antibodies to IL-4 Stat, also known as Stat6, but not antibodies to other Stat proteins, interfere with the formation of the IL-4 NAF complex. Congruous with the involvement of a Stat protein, IL-4 induced robust Janus kinase 3 (JAK3) activity in BL-2 cells. Cotransfection of JAK3 with IL-4 Stat into COS-7 cells produced an intracellular activity which bound the same IFN-gamma activation site-like sequence and comigrated with IL-4 NAF in electrophoretic mobility shift assay. These results show that IL-4 NAF is IL-4 Stat, which is activated by JAK3 in response to IL-4 receptor engagement.
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PMID:Interleukin 4 activates a signal transducer and activator of transcription (Stat) protein which interacts with an interferon-gamma activation site-like sequence upstream of the I epsilon exon in a human B cell line. Evidence for the involvement of Janus kinase 3 and interleukin-4 Stat. 763 85

To investigate the role of B cells in the development of experimental Staphylococcus aureus-induced arthritis, we used X-linked immunodeficiency (xid) mice that carry a Bruton's tyrosine kinase mutation affecting the function of B cells. NFR/N.xid and congenic NFR/N mice were inoculated i.v. with a toxic syndrome toxin-1 producing S. aureus LS-1 strain. B cell-deficient NFR/N.xid mice developed less frequent (p < 0.01) and less severe (p < 0.01) arthritis than NFR/N mice did. These clinical findings were corroborated by histopathologic evaluation, indicating that NFR/N.xid mice had significantly lower (p < 0.01) erosivity of the disease. Interestingly, infected NFR/N.xid mice showed decreased bacterial burden in blood, joints, and other organs compared with the control mice. Serologic studies displayed poor B cell responses to staphylococcal cell walls, toxic shock syndrome toxin-1, and ssDNA, accompanied by a low level of Igs in infected NFR/N.xid mice. More importantly, xid defect affected cytokine profile. The in vitro experiments showed that the lymphocytes from NFR/N.xid mice had low IL-6, but high IFN-gamma production upon stimulation with staphylococcal cell walls compared with NFR/N mice. Furthermore, the in situ hybridization technique revealed the relative increase of IFN-gamma, but marked decrease of IL-1 beta mRNA expression in spleens of infected NFR/N.xid mice. No significant difference in IL-4, IL-10, and TNF-alpha mRNA expression was found between both strains. Our findings demonstrate that B cells may, directly or indirectly, contribute to the pathogenesis of septic arthritis. The results indicate that increased IFN-gamma production along with low IL-6 and IL-1 beta synthesis found in xid mice may provide a more favorable outcome of S. aureus arthritis.
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PMID:Mice with the xid B cell defect are less susceptible to developing Staphylococcus aureus-induced arthritis. 763 57

Thrombopoietin (TPO) is a newly cloned cytokine which is the major regulator of circulating platelet levels, acting on both proliferation and differentiation of megakaryocytes. We have investigated the ability of TPO to activate the JAK/STAT pathway in megakaryocytic cell lines. We used either the granulocyte-macrophage colony-stimulating factor (GM-CSF)- and/or erythropoietin (EPO)-dependent UT7 cell line in which the murine TPO receptor (mumpl) had been transfected (mumpl-UT7 transfectants) or the MO7E and DAMI cells which express endogenous human TPO receptors. We demonstrated that TPO activates the kinase JAK2 and a STAT5-like transcriptional factor but not STAT1, STAT2, STAT3 or STAT4, in a very rapid and transient manner. In order to better ascertain the specificity of the activation of STAT5-related factor by TPO, we investigated the effect of other cytokines/growth factors. Both GM-CSF and EPO activated the STAT5-like factor. In contrast, neither interferon (IFN)-gamma nor the mitogenic stem cell factor (SCF) activated STAT5, although IFN-gamma did activate STAT1 in those cells. The hematopoietic DNA binding activity related to STAT5 was identified as a p97 tyrosine-phosphorylated protein band which exhibited identical gel mobility to the mammary STAT5. Because v-mpl, a truncated form of the TPO receptor c-mpl, was shown to be oncogenic, we tested the activity of v-mpl on STAT5 and found STAT5 constitutively activated in two different v-mpl-expressing cells, the transiently transfected Cos7 cells and the stable v-mpl-UT7 transfectants. Overall, our data indicate that STAT5 is widely expressed in hematopoietic cells and activated by a number of cytokines, including TPO, GM-CSF and EPO, but not by IFN-gamma or SCF.
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PMID:Thrombopoietin activates a STAT5-like factor in hematopoietic cells. 779 11

TGF-beta is a widely expressed immunoregulatory protein that exerts a diverse range of effects on many types of cells. One of the effects of TGF-beta is the inhibition of both constitutive and cytokine-inducible class II MHC gene expression. In this study, we demonstrate that TGF-beta inhibits expression of class II MHC surface protein, mRNA, and promoter activity in primary astrocytes, and that this inhibition is both dose and time dependent. TGF-beta does not act to inhibit IFN-gamma-induced gene expression in a global fashion, as induction of ICAM-1 and IRF-1 gene expression by IFN-gamma is unaffected by treatment with TGF-beta. Furthermore, TGF-beta does not affect events that are involved in IFN-gamma-induced intracellular signaling such as tyrosine phosphorylation of JAK1, JAK2, and STAT1 alpha, nor does it affect IFN-gamma induction of the class II X2 box binding protein IFN-gamma enhanced factor X. We speculate that TGF-beta may be exerting its effects by modulating the expression or function of constitutively expressed factors responsible for regulation of class II MHC gene expression in astrocytes.
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PMID:TGF-beta suppression of IFN-gamma-induced class II MHC gene expression does not involve inhibition of phosphorylation of JAK1, JAK2, or signal transducers and activators of transcription, or modification of IFN-gamma enhanced factor X expression. 781 71


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