Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 Tat has been shown to have an inhibitory effect on the Ag-specific responsiveness of human peripheral T cells. We have previously demonstrated that this retroviral protein binds to and partially inhibits the enzymatic activity of dipeptidyl aminopeptidase type IV (DP IV), also known as CD26, which is expressed on a variety of mammalian tissue, including T lymphocytes. A number of studies have implicated a role for DP IV in the activation of T lymphocytes. By utilizing HIV-1 Tat, as well as ProboroPro, a potent and specific boronic acid analog inhibitor of DP IV, we show here that blocking DP IV partially inactivates Ag and anti-CD3-mediated T cell proliferation. Neither mitogen nor anti-CD2 mediated proliferation of T lymphocytes, however, is impaired by blocking DP IV. The target molecule for the inhibition induced by both compounds was confirmed by the finding that soluble DP IV neutralized the reduced Ag responsiveness. The Ag-specific inhibition could be overcome by the addition of exogenous IL-2, suggesting that blocking or inactivation of DP IV results in a state of anergy, probably by interfering with the delivery or amplification of a signal necessary for IL-2 production. This is further substantiated by the finding that costimulation of human PBMC via the CD28 molecule, which initiates a non-TCR-dependent signaling pathway, overcomes the reduced Ag responsiveness induced by Tat and ProboroPro. The fact that ProboroPro has no impact on stimulation of T cells with PMA and ionomycin implies that blocking DP IV is influencing events before the activation of protein kinase C and Ca2+ flux. These results suggest that DP IV is necessary for amplification of signals generated by the engagement of the TCR-CD3 complex by nominal Ag.
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PMID:Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness. 809 14

TCR (beta-chain) transgenic mice were tolerized with the superantigen staphylococcal enterotoxin B (SEB). Three to 28 days after tolerization with SEB, flow cytometry of peripheral T cells showed the persistence of SEB-unresponsive T cells that did not express reduced levels of the TCR (beta-chain) transgene. Stimulation of the tolerized T cells with a panel of superantigens (SEC1), mitogens (Con A, PHA, and pertussis toxin) and mAb (anti-CD3 epsilon) did not induce T cell proliferation. In contrast to other models, exogenous rIL-2 did not reverse unresponsiveness and induce proliferation. In addition, lymphokines rIL-4 and rIL-6 also did not induce proliferation. However, the unresponsive T cells did respond to the combination of PMA plus ionomycin, but not to PMA or ionomycin alone. Thus, the block in signal transduction in the anergic state occurs between the stimulation of cell surface receptors and the activation of protein kinase C and the increase in intracellular calcium. In addition, these results show that mature T cells tolerized with the superantigen SEB are unresponsive to a wide array of T cell stimuli, indicating a block in a common signal transduction pathway.
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PMID:Superantigen-induced peripheral tolerance inhibits T cell responses to immunogenic peptides in TCR (beta-chain) transgenic mice. 809 52

We have demonstrated earlier that the crosslinkage of the CD3/TCR complex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To further understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purified normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or sn-1,2 dioctanoyl glycerol, was also determined. The emergence of nuclear binding proteins was investigated using interleukin-2 sequence specific oligonucleotide probes in the electrophoretic mobility shift assay. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing the emergence of transcription factors that bind to the NF-AT1, AP-1, and NF-kB sites located in the promoter/enhancer region of the IL-2 gene. Moreover, cyclosporine, at concentrations readily accomplished in clinical practice, was found to inhibit the emergence of these DNA-binding proteins in normal human T cells signaled via cell surface proteins implicated in antigen-dependent T cell activation and in T cells stimulated by mobilization of cellular calcium and activation of protein kinase C.
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PMID:Synergism between the CD3 antigen- and CD2 antigen-derived signals. Exploration at the level of induction of DNA-binding proteins and characterization of the inhibitory activity of cyclosporine. 809 81

Antigen-independent adhesion of CD4+ T lymphocytes to Epstein-Barr virus transformed B cells is mainly mediated by LFA-1 (CD11a/CD18) and CD2 molecules. Low-affinity binding of resting T cells can be transiently upregulated by cross-linking of CD3-TCR (T cell receptor) complexes. This inside-out signaling influences integrin (beta 1 and beta 2) adhesion capacity. Studies using the nonspecific inhibitor staurosporine have suggested that this phenomenon is dependent on protein kinase C activation. We found that the upregulation of anti-CD3-activated CD4+ T cell adhesion was inhibited strongly and in a concentration-dependent manner by GF109203X, a compound described as a potent and selective inhibitor of PKC. Comparative studies showed that GF109203X and staurosporine had similar inhibitory effects on the upregulation of activated CD4+ T cell adhesion. However, staurosporine is a nonselective kinase inhibitor. PMA-activated CD4+ T cell adhesion was also inhibited by GF109203X. In contrast, passive enhancement of adhesion by treatment with the CD11a-specific antibody NKI-L16 was unaffected by GF109203X. Taken together, these results show that PKC is involved in upregulating the adhesion of CD4+ T cells to B cells following activation of the former by CD3 cross-linking. PKC-dependent upregulation of CD4+ T cell adhesion to B cells is exclusively LFA-1-dependent, as GF109203X had no additional inhibitory effect on anti-LFA-1 antibody-pretreated T cells activated by the anti-CD3 antibody OKT3 and had no effect on the adhesion of LFA-1(-) CD4+ T cells. Finally, PKC inhibition did not alter CD2-mediated adhesion. This points to a limited participation of CD2 in T-B cell interactions after TCR/CD3 cross-linking.
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PMID:GF109203X, a specific PKC inhibitor, abrogates anti-CD3 antibody-induced upregulation of CD4+ T cell adhesion to B cells. 810 10

We have studied the TCR mediated signal transduction pathways involved in transcriptional regulation of the mouse IL-4 gene. The sequences extending from base pair -766 to +63 of the IL-4 gene were inserted upstream of a luciferase indicator gene. Transcriptional activity was observed when the construct, [pIL-4(-766)], was transfected into either the IL-4 producing cell line, EL-4, or the IL-4 non-producing T cell hybridoma, 68-41, but not in the L929 fibroblast cell line. By analysis of deletion mutants of pIL-4(-766), we identified a transcriptional regulatory element that is tightly associated with a signal coming from the TCR and which controls inducible activation of the IL-4 promoter. By analysis of deletion mutants of pIL-4(-766), this latter element was found between base pairs -147 to -17. Electrophoretic mobility shift assays indicated that expression of a nuclear binding protein with binding sites between base pairs -84 and -55 could be induced. By competition and mutation analysis, the binding motif of this protein was determined to be AAAATTTTCC. Stimulation with ionomycin alone was sufficient to induce activity in pIL-4(-766). Cyclosporin A inhibited both the IL-4 promoter activity and activation of the inducible nuclear protein. Transient over-expression of a constitutively active form of the Ca2+/calmodulin-regulated protein phosphatase, calcineurin was sufficient to cause activation of pIL-4(-766) without any additional stimulus. These results indicate that the signaling requirements for activation of upstream positive regulatory elements of the IL-4 gene are distinct from those of the IL-2 gene. Ca2+ mobilization is sufficient to activate the IL-4 promoter, whereas IL-2 gene transcription requires both Ca2+ mobilization and protein kinase C activation.
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PMID:The Ca2+/calmodulin-activated, phosphoprotein phosphatase calcineurin is sufficient for positive transcriptional regulation of the mouse IL-4 gene. 815 95

To elucidate Th2 cell clone activation mechanism through TCR-CD3 complex, we examined the reactivity of Th2 cell clones to soluble anti-CD3 in the absence of accessory cells or costimulator. The soluble anti-CD3 stimulated IL-4 production of Th2 cell clones as efficiently as specific Ag. IL-4 production of Th2 cell clones was consistent with the elevation of intracellular free Ca2+ concentration ([Ca2+]i). The elevation was slow and sustained but occurred consistently after the anti-CD3 stimulation in all Th2 cell clones tested. The [Ca2+]i elevation appeared to depend on Ca2+ influx because it could not be observed in Ca(2+)-free medium. Several chemicals such as cholera toxin, neomycin, and herbimycin A, which have been shown to block phosphatidylinositol-4,5-bisphosphate (PIP2) breakdown pathway or protein tyrosine kinase activation, exerted no effect on the IL-4 production. In accordance with these findings, neither PIP2 breakdown nor protein tyrosine phosphorylation was observed in Th2 cell clones stimulated with anti-CD3. The inclusion of anti-CD4 in culture and the depletion of protein kinase C (PKC) did not affect IL-4 production of Th2 cell clones either. These findings support a hypothesis that Th2 cell clones use a signaling pathway for IL-4 production that is independent of protein tyrosine kinase, PIP2 breakdown or PKC, and that the [Ca2+]i elevation is the only pathway common to an IL-2 production of Th1 cell subset.
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PMID:Difference in signal transduction pathway for IL-2 and IL-4 production in T helper 1 and T helper 2 cell clones in response to anti-CD3. 824 50

A B cell line, B6-1710, expressing murine AIDS virus superantigen stimulates T cell hybridomas derived from a Ld-specific CTL clone to produce IL-2 regardless of their CD4/CD8 phenotype. However, B6-1710 cell did not stimulate the original CTL clone, L3, in either proliferation or cytolytic assays. Both B6-1710 and Ld+ P815 cells stimulated a significant Ca2+ influx in the T cell hybridomas. In contrast, only P815 stimulated tyrosine phosphorylation of a 19-kDa protein in the T cell hybridoma. The addition of the nonspecific protein kinase C activator PMA restored the proliferative response of L3 cells to B6-1710. PMA did not induce the lysis of B6-1710 cells by L3. These results suggest that murine AIDS virus encoded superantigen elicits a TCR-mediated signal different from that caused by nominal Ag. This different signaling by viral superantigen may be important for the development of viral pathogenesis in vivo.
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PMID:Defective T cell receptor-mediated signaling and differential induction of T cell functions by murine AIDS virus superantigen. 838 46

Human alpha-thrombin stimulated five different T lymphoblastoid cell lines to increase intracellular free Ca2+ concentrations, whereas five B cell lines did not similarly respond. The T cell intracellular free Ca2+ increased rapidly, plateaued within 10 to 20 s, and then declined without any measurable sustained intracellular free Ca2+ elevation. Liberation of inositol trisphosphate peaked within 60 s, and a rapid and sustained activation of protein kinase C was induced. The thrombin-specific inhibitor, hirudin, completely blocked the response to alpha-thrombin. Catalytically inactivated forms of alpha-thrombin failed to stimulate the T cells, whereas trypsin, gamma-thrombin (which lacks fibrinogen clotting activity), or the synthetic 14-amino acid thrombin receptor-activation peptide stimulated T cells, but required approximately 10-, approximately 15-, or approximately 100-fold higher concentrations, respectively, when compared to alpha-thrombin. Stimulation by thrombin receptor-activation peptide was desensitized by alpha-thrombin, and vice versa, but alpha-thrombin did not desensitize stimulation by mAb to the TCR/CD3 Ag. The presence of the receptor on T but not on B cells was confirmed by flow-cytometric analysis using a mAb against the human thrombin receptor. These findings demonstrate functional thrombin receptors on T lymphoblastoid cells that may be capable of activating the cells, independently of an ongoing immune response.
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PMID:Functional thrombin receptors on human T lymphoblastoid cells. 838 23

Interleukins play a role in the process of T-cell development and, like other cytokines, seem able to modulate apoptosis. Interleukin-2 has been reported to inhibit apoptotic cell death of thymocytes induced in vitro by either activation of CD3/TCR complex or treatment with glucocorticoid hormone. We demonstrate here that IL-2 can provoke DNA fragmentation and cell death of CD4+ CD8+ mouse thymocytes by activating an endogenous apoptotic pathway. Thymocytes, incubated with high IL-2 concentrations in vitro, showed the morphological characteristics of apoptotic cells, including reduction in nuclear size, derangement in chromatin structure, and DNA fragmentation in oligonucleosomal subunits. Inhibition of mRNA and protein synthesis and addition of the PKC-inhibitor H-7, Zn2+ ions, and IL-4 counteracted the IL-2 effect. These data suggest that high IL-2 concentrations may induce an active process of cell death on mouse thymocytes in vitro.
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PMID:Interleukin-2 induces apoptosis in mouse thymocytes. 842 30

In T cells, signals initiated at the TCR, and in particular activation of protein kinase C (PKC), can activate the p21ras proteins. Triggering of the TCR and PKC is required for the efficient production of the T cell growth factor, IL-2. IL-2 gene transcription is controlled by a 275-bp enhancer that is known to contain binding sites for many transcription factors including the octamer family of proteins, NF kappa B, AP-1, and a T cell-specific factor, NFAT (nuclear factor of activated T cells). NFAT binds to a region of the IL-2 enhancer that has been defined as a TCR response element (ARRE-2), and is induced in response to increases in intracellular calcium, stimulation of PKC, or triggering of the TCR. To determine whether p21ras is involved in the signals that regulate NFAT, we examined the effect of expression of a constitutively active p21ras mutant, v-Ha-ras, and a dominant inhibitory mutant of p21ras, c-Ha-ras(asn)17, on the induction of a NFAT-driven reporter gene (NFAT CAT) during T cell activation. The constitutively active Ras mutant could synergize with the calcium ionophore ionomycin to induce NFAT. In addition, expression of p21v-Ha-ras could enhance NFAT CAT induction in response to TCR and PKC agonists. The dominant inhibitory mutant of p21ras could prevent NFAT CAT expression in response to PKC or TCR triggering. These data show that Ras regulates NFAT, and that p21ras function is important for the TCR- and PKC-regulated pathways that regulate NFAT.
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PMID:p21ras function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. 847 36


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