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)

IFN-alpha influences the recirculation and growth of normal and malignant B lymphocytes, although the mechanisms involved are not currently known. Lymphocyte recirculation is fundamentally dependent on cell-to-cell interactions that are mediated by cell surface adhesion molecules. In this report, we examined the relationship between the effect of IFN-alpha on cell-to-cell adhesion processes and induction of the Leu-13 cell surface protein in established human Daudi B lymphoid cell lines that are either sensitive or resistant to the antiproliferative activity of IFN-alpha. IFN-alpha directly triggered homotypic adhesion of IFN-sensitive Daudi B cells in a time- and dose-dependent manner. In contrast, IFN-alpha had no effect on the cell-to-cell adhesion of IFN-resistant Daudi B cells. The capacity of IFN-alpha to trigger homotypic aggregation correlated directly with the level of induction of the cell surface protein Leu-13 and could be potentiated by anti-Leu-13 mAb. Other cytokines also known to influence the proliferation, differentiation, or recirculation of B lymphocytes such as IFN-gamma, IL-2, IL-4, IL-6, TNF-alpha, and low molecular weight B cell growth factor did not induce either Leu-13 expression or homotypic aggregation of Daudi B cells. The adhesion pathway triggered by the IFN-inducible protein Leu-13 required metabolic energy and an intact cytoskeleton but was not dependent on: 1) new protein synthesis; 2) protein kinase C, protein kinase A, or tyrosine kinase activities; or 3) the function of known adhesion molecules including LFA-1, ICAM-1, CD44, or VLA-4. Taken together, these studies demonstrate a fundamental role for IFN-alpha and the IFN-inducible protein Leu-13 in regulating a novel homotypic adhesion pathway in B lymphocytes, and provide insight into the possible mechanisms by which IFN-alpha regulates biologic processes including recirculation.
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PMID:IFN-alpha induces homotypic adhesion and Leu-13 expression in human B lymphoid cells. 842 37

Signal transduction by IL-4 leading to the activation of CD23(Fc epsilon RII) gene expression using human tonsillar B cells was studied. IL-4 stimulated CD23 mRNA transcription within hours (1-4 hr) which preceded the later induction of cell surface CD23. The induction of CD23 gene transcription by IL-4 was not adversely affected by cycloheximide, suggesting that post-translational modifications are accounted for the gene activation. PKC activators (PMA, diacylglycerol, indolactam) were effective inducers of CD23 gene expression, whereas calcium ionophores were not. PMA and IL-4 also displayed similar induction kinetics for CD23 mRNA. However, the signaling pathways utilized by the two agents appear distinct as shown by (1) cotreatment of IL-4 and PMA caused CD23 gene expression over the maximum level inducible by each agent alone and (2) unlike the PMA-induced CD23 expression, the IL-4-induced expression was not affected by PKC inhibitors. These results strongly suggest that IL-4 signals leading to CD23 gene activation are mediated via a PKC-independent pathway. A possible role of tyrosine kinases in the regulation of CD23 expression is discussed.
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PMID:Interleukin-4 signals regulating CD23 gene expression in human B cells: protein kinase C-independent signaling pathways. 842 25

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

The development of B cell tolerance is believed to involve negative signaling to the B cell derived from the binding of Ag to the B cell surface Ig (sIg). B cell clones that receive negative signals via sIg may provide useful models for studying the mechanisms of negative signaling. We have recently identified a previously undescribed mouse B cell clone, CHB3, which receives growth-inhibitory signals through the binding of IL-4 to its IL-4R or through ligation of its sIgM, but not its sIgD, molecules. Data presented here demonstrate that the negative signal delivered by sIgM, but not that delivered by IL-4R, requires protein kinase C activation and elevated intracellular Ca2+, and is associated with the tyrosine phosphorylation of a number of proteins. Thus, the IL-4R signaling pathway appears to be divergent from the sIgM-mediated pathway. However, growth inhibition mediated via both sIgM and IL-4R can be partially counteracted by a signal delivered through the MHC class II molecule.
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PMID:Growth inhibition of a B cell clone mediated by ligation of IL-4 receptors or membrane IgM. 845 43

We studied the effects of aging on the activities and translocation of Ca-dependent protein kinase C (PKC) in resting mesenteric lymph node (MLN) T and B cells during the activation process induced by T and B cell mitogens and B cell-stimulatory interleukins, including IL-4, IL-5 and IL-6. The activation process in senescent, resting (high density (HD)) MLN T cells is impaired, when these cells are stimulated with T cell mitogen, Con A. The defect in activation is associated with a reduction in both the new production of inositol-1,4,5-triphosphate (IP3) (an indicator for the production of intracellular free Ca) and the induction of Ca-dependent PKC. In contrast, the activation of the aged B cells with LPS plus/minus interleukins (IL-4, IL-5 and IL-6) is not impaired, being at least associated with a Ca-independent pathway of PKC activation. The elevated IP3 content and total (cytosol plus membrane) PKC activity in both resting T and B cells from aged MLN along with the greater difference in T cells than in B cells suggest that the in vivo Go cell cycle status of these cells may differ from that of the young, involving more in T cells. Finally, the MLN and splenic T cell Ca-dependent and B cell Ca-independent PKC activation do not differ between both age groups.
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PMID:Activation of calcium (Ca)-dependent protein kinase C in aged mesenteric lymph node T and B cells. 845 34

The effects of PMA and staurosporine (PKC depletor/antagonist) and IL-2/IL4 were used to determine the role of PKC and cytokine on alpha CD3-induced activated killer cells (CD3-AK). The present study examines their effects on the production of BLT-esterase and on the effector function of CD3-AK cells as well as the cytolytic granules. The production of BLT-esterase generally correlated with the cytolytic activity of CD3-AK cells and was reduced by PKC depletor/inhibitor but increased by IL-4. In studying the effector function of CD3-AK cells, we found that adding PMA or SSP at the effector phase inhibited the PKC-dependent slow lysis. PMA, but not SSP, also reduced fast lysis, which was shown to be a PKC-independent event. Additional experiments were performed to determine the effect of PKC on the lytic granules and to ascertain whether PMA has other effects on the effector-to-target relationship unrelated to PKC. It was found that neither PMA nor SSP affects the function of cytolytic granules, as measured by hemolytic assay against anucleated target (SRBC). These findings indicate that PKC has no direct effect on the granules. During testing against the nucleated tumor target through a novel approach using non-cytolytic surrogate killers, the lytic activity of the granules was inhibited by PMA, suggesting that exocytosis or delivery of granules to nucleated target cells may require mobilization of intracellular Ca2+ in the killer cells, and this process is inhibited by PMA. Our findings indicate that PKC and cytokines regulate the production but not the lytic activity of cytolytic granules. Nonetheless, delivery of cytolytic granules from killer cells to the nucleated tumor target appears to be a Ca(2+)-dependent event unrelated to PKC.
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PMID:Role of protein kinase C and cytokines on the function and production of cytolytic granules in alpha CD3-activated killer-cell-mediated killing of tumor cells. 847 55

Activation of individual CD4+ T cells results in differential lymphokine expression: interleukin 2 (IL-2) is preferentially produced by T helper type 1 (TH1) cells, which are involved in cell-mediated immune responses, whereas IL-4 is synthesized by TH2 cells, which are essential for humoral immunity. The Ca(2+)-dependent factor NF-ATp plays a key role in the inducible transcription of both these lymphokine genes. However, while IL2 expression requires the contribution of Ca(2+)- and protein kinase C-dependent signals, we report that activation of human IL4 transcription through the Ca(2+)-dependent pathway is diminished by protein kinase C stimulation in Jurkat T cells. This phenomenon is due to mutually exclusive binding of NF-ATp and NF-kappa B to the P sequence, an element located 69 bp upstream of the IL4 transcription initiation site. Human IL4 promoter-mediated transcription is downregulated in Jurkat cells stimulated with the NF-kappa B-activating cytokine tumor necrosis factor alpha and suppressed in RelA-overexpressing cells. In contrast, protein kinase C stimulation or RelA overexpression does not affect the activity of a human IL4 promoter containing a mouse P sequence, which is a higher-affinity site for NF-ATp and a lower-affinity site for RelA. Thus, competition between two general transcriptional activators, RelA and NF-ATp, mediates the inhibitory effect of protein kinase C stimulation on IL4 expression and may contribute to differential gene expression in TH cells.
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PMID:Inhibition of NF-AT-dependent transcription by NF-kappa B: implications for differential gene expression in T helper cell subsets. 852 16

The present study explores a model for tumor cell-induced immunosuppression and reversal of suppression by cytokines and other pharmacological agents. To simulate tumor-cell-induced suppression, a panel of suppressor agents which included CsA (cyclosporin A), SSP (staurosporine), BSO (L-buthionine-[S,R]-sulfoximine) and PMA, and a panel of anti-suppressor agents which included IL-2, IL-4, GSH (glutathione) and amiloride, were tested. These suppressor/anti-suppressor agents acted differently on four specific sites of the immune arm that affected the alpha CD3-induced T cell proliferative and cytotoxic responses. They included (1) IL-2 production, (2) PKC-regulated cytolytic granule production, (3) GSH-regulated maturation of functional granules, and (4) granule exocytosis. When a single suppressor agent was used, all the suppressor agents tested in this study inhibited the generation of alpha CD3-induced activated killer cells (CD3-AK), whereas alpha CD3-induced proliferation was inhibited by CsA, BSO, and EL-4 tumor cells. Except for EL-4, suppression induced by a single suppressor agent could be corrected by an appropriate single anti-suppressor agent. Multiple suppressor agents induced profound suppression of CD3-AK response. In most cases, multiple anti-suppressor agents were required to correct the immune defects induced by multiple suppressor agents. Finally, EL-4 tumor-cell-induced immunosuppression could not be corrected by any single anti-suppressor agent tested, but a combination of IL-4, GSH and amiloride fully restored the CD3-AK response. These results suggest that tumor cells may induce multiple immune defects that require multiple anti-suppressor agents for correcting the defects to restore the host immunocompetence.
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PMID:Reversal of multiple-site tumor cell-induced immunosuppression by specific cytokines and pharmacological agents. 853 Feb 53

A subset of type 2, but not type 1, CD4 T cell clones expresses IL-3R and can be stimulated by IL-3. Expression of IL-3R on these type 2 T cell clones is induced by TCR stimulation, and subsequent stimulation by IL-3 augmented the proliferation of and IL-4 production by these cells. This augmented response is inhibited by anti-IL-4 mAb, suggesting the involvement of IL-4 in this response. In place of TCR stimulation, treatment of these type 2 CD4 T cell clones with PMA rendered them responsive to further stimulation of proliferation by IL-3, indicating the cooperation between the IL-3R-elicited signals and PKC-mediated signals in stimulating proliferation. Although the augmentation of the TCR-mediated proliferative response by IL-3 was mainly due to the increased production of IL-4, we also demonstrated the presence of IL-4-independent mechanism mediating the response to IL-3. In situ, we found that splenic T cells could be induced to respond to Il-3 by TCR stimulation. Thus, IL-3 can stimulate a specific population of T cells and influence the immune response.
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PMID:IL-3 augments TCR-mediated responses of type 2 CD4 T cells. 859 73

Optimal activation of T cells to clonally expand requires at least two distinct biological signals; one is generated by the interaction of the T cell receptor (TcR) with peptides bound to MHC molecules. The other signal(s) is (are) generated by a functionally defined event called the co-stimulatory pathway. We have characterized the co-stimulatory property of a murine B lymphocyte membrane protein (155-160 kD) on resting CD4+ T cells. The study involved the isolation of a 155-160 kD protein (B1) from the membranes of LPS-stimulated B cells. When reconstituted into lipid vesicles, B1 exerted a dose-dependent proliferative response to CD4+ T cells, resulting in the predominant secretion of IL-4 and IL-5 after cross-linking receptors with anti-CD3 mAb. This protein is a phosphoglycoprotein which gives a single spot on two-dimensional gel electrophoresis under reducing conditions and as a distinct peak on reverse phase-HPLC. The B1 binds to the T cell surface as is demonstrated by electron microscopic autoradiography and scanning electron microscopy, as well as competitive binding assays. It does not cross-react with antibodies directed against ICAM-1, LFA-1 alpha, B7, HSA and VCAM-1, suggesting the novelty of the protein. Activation of CD4+ T cells with B1 in the presence of anti-CD3 resulted in the translocation of protein kinase C (PKC). The B1 is barely detectable on the surface of resting B cells and digestion of this protein with V8 protease and peptide N-glycosidase F resulted in distinct protein bands on an autoradiogram.
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PMID:Characterization of a novel co-stimulatory molecule: a 155-160kD B cell surface protein provides accessory help to CD4+ T cells to proliferate and differentiate. 860 18


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