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)

Crosslinking HLA-DR molecules by monoclonal antibodies (moAbs) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic calcium concentrations in activated human T cells. Binding of bacterial superantigens or moAbs to DR molecules on activated T cells was recently reported to induce homotypic aggregation through activation of protein kinase C (PKC) and mediated by CD11a/CD54 (LFA-1/CAM-1) adhesion molecules. Here, we report that moAbs directed against framework DR, but neither DR1, 2- and DRw52- nor DQ- and DP-specific moABs induced homotypic aggregation of antigen- and alloantigen-activated T cells, antigen-specific CD4+ T-cell lines, a CD8+ T-cytotoxic cell line, and T-leukemia cells (HUT78). Protein tyrosine kinase (PTK) inhibitor herbimycin A partly blocked class-II-induced aggregation responses. In contrast, phorbol ester (PMA)-induced aggregation was essentially unaffected. A potent inhibitor of PKC, staurosporin, inhibited both moAb- and PMA-induced aggregation responses. The aggregation responses were completely inhibited by low temperatures, cytochalasins B and E, and partly inhibited by EDTA and CD18 moAbs, but unaffected by aphidicolin, mitomycin C, an adenylate cyclase inhibitor (2'5'-dideoxyadenosine), and moAbs against other adhesion molecules (CD2/CD58 [LFA-3], CD28/CD28 ligand B7, CD4, and CD44). In conclusion, HLA class-II-induced aggregation responses in activated T cells appear to involve PTK and PKC activation and to be mediated through CD11a-dependent and independent adhesion pathways.
 ...
PMID:Signal transduction by HLA class II molecules in human T cells: induction of LFA-1-dependent and independent adhesion. 128 78

Interleukin-1 (IL-1) is believed to be involved in articular destruction in rheumatoid arthritis. HLA-class II antigens are expressed on synovial cells of patients with RA. The relation between the production of IL-1 and expression of HLA-class II antigens was studied. Synovial cells of rheumatoid patients appeared to express HLA-DR and DQ antigens to a significantly greater extent than those of osteoarthritic patients. These cells produced IL-1 following interferon-gamma (IFN-gamma) stimulation and there was synergistic enhancement of production induced by IFN-gamma and monoclonal antibodies to HLA-DR or DQ antigens in combination. In the intracellular signal transduction mechanism for the production of IL-1 beta by these cells following IFN-gamma stimulation, protein kinase C and calmodulin may be involved as second messengers.
 ...
PMID:[Induction of interleukin-1 production in the cultured synovial cells from patients with rheumatoid arthritis]. 141 92

Recent attention has focused on the role keratinocytes (KC) may play in the induction of T cell-mediated inflammatory responses in skin, particularly because KC, when activated by immunologic stimuli, express MHC class II Ag and secrete immunomodulatory cytokines. We tested the capacity of normal human KC that were stimulated with PMA to induce PBMC proliferation. PMA-treated, but not untreated, KC induced proliferation of allogeneic as well as autologous PBMC; in addition, when purified CD4+ or CD8+ T cells were used as responders, each subset proliferated. PBMC proliferation was not due to direct action of PMA on PBMC, nor to contamination of KC cultures with Langerhans cells (LC) or dermal APC. Pretreatment with different protein kinase C inhibitors abrogated the capacity of PMA-stimulated KC to induce proliferation. Paraformaldehyde-fixed PMA-KC stimulated PBMC proliferation, whereas supernatants from PMA-treated KC failed to do so, indicating that a membrane-associated activity on PMA-KC contributes to the induction of PBMC proliferation. PMA induced intercellular adhesion molecule-1 (ICAM-1) expression on KC; furthermore, mAb against ICAM-1 or against its ligand lymphocyte function-associated Ag (LFA-1) (CD11a/CD18) significantly, but incompletely, reduced the stimulatory capacity of PMA-treated KC, indicating that ICAM-1/LFA-1 interaction contributed to PBMC proliferation. IFN-gamma or TNF-alpha also induced ICAM-1 on KC, but these KC failed to stimulate proliferation, suggesting that PMA induces additional signals from KC, which act in concert with ICAM-1 to promote proliferation. Finally, mAb against HLA-ABC or HLA-DR did not inhibit proliferation. We conclude that PMA can activate KC to stimulate T cell proliferation in a MHC-independent fashion. This activation is mediated by protein kinase C and in part by the induction of ICAM-1 expression on KC.
 ...
PMID:Phorbol myristate acetate-activated keratinocytes stimulate proliferation of resting peripheral blood mononuclear lymphocytes via a MHC-independent, but protein kinase C- and intercellular adhesion molecule-1-dependent, mechanism. 167 Sep 43

Interferon gamma (IFN-gamma) is the most potent known lymphokine for activating macrophages and has been shown to induce expression of HLA-DR in THP-1 cells, a monocytic tumor cell line which expresses many of the properties of monocytes, in a dose- and time-dependent manner. Experiments were designed to examine, by FACS analysis and by measurement of messenger RNA levels, the molecular mechanism regulating the expression of HLA-DR molecules. The expression of HLA-DR molecules induced by IFN-gamma was blocked by the protein kinase C (PKC) inhibitors sphingosine, staurosporine, and H7. H7 when added up to 20 hr after the initial stimulation with IFN-gamma prevented the further expression of HLA-DR. The general kinase inhibitors H8, H9, and HA1004, all less potent PKC inhibitors than H7, did not block the IFN-gamma-induced expression of HLA-DR at the concentrations employed. W7, a calmodulin antagonist, but not a PKC inhibitor, was also unable to prevent the IFN-gamma-induced expression of HLA-DR. Treatment of THP-1 with phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, alone or with Ca2+ ionophore A23187, was unable to induce HLA-DR expression. However, pretreatment with PMA for 24 hr prior to IFN-gamma stimulation decreased the IFN-gamma-induced expression of HLA-DR without decreasing IFN-gamma receptor levels. These results suggest that PKC plays a significant role in the IFN-gamma-induced signal transduction pathway leading to the expression of HLA-DR in cells of the mononuclear phagocytic lineage, and that PKC activity is required throughout the course of events leading to the actual expression of HLA-DR.
 ...
PMID:Transduction of the IFN-gamma signal for HLA-DR expression in the promonocytic line THP-1 involves a late-acting PKC activity. 193 72

Ag-dependent activation of human T cells results in high level expression of class II MHC molecules. As part of this process, Ag recognition by TCR generates a series of second signals including protein kinase C, tyrosine kinase, and Ca2+ mobilization. To investigate the role of these second messengers in class II MHC expression, purified T cells were first stimulated by PMA, ionomycin, OKT3 accompanied by IL-2, or the mitogenic anti-CD2 antibodies T112 and T113 and were then stained with FITC-conjugated anti-class I and -class II MHC antibodies for analysis by flow cytometry. OKT3 and IL-2 induced optimal expression of HLA-DR (DR) on 70% of T cells with high density. Despite their high mitogenicity, induction of class II MHC expression by PMA, even with co-stimulation by ionomycin, was reduced to less than 20% of T cells, with an intensity 50-fold lower than in OKT3/IL-2-stimulated T cells. Furthermore, PMA inhibited class II MHC expression by OKT3/IL-2-stimulated T cells in a dose-dependent manner and additional stimuli, such as IL-1, IL-4, IFN-gamma, TCR cross-linkers, or monocytes, did not restore class II MHC expression by PMA-activated T cells. DR beta mRNA analysis showed that the low induction of class II molecules by PMA extends to the transcriptional level. Interestingly, anti-T112 and anti-T113 induced not only proliferation of T cells but also DR expression on more than 90% of T cells. These results indicate that transduction of a specific signal, probably selective phosphorylation of the CD3 molecule, contributes to class II MHC induction in the process of T cell activation.
 ...
PMID:Selective signal transduction through the CD3 or CD2 complex is required for class II MHC expression by human T cells. 197 84

IFN-gamma enhances many monocyte functions, including oxidative metabolism and Ag presentation. IFN-gamma has been reported to increase the intracellular concentration of calcium ([Ca2+]i) and modulate protein kinase C activity in murine macrophages, but the signal transduction pathways induced by IFN-gamma in human cells and their functional significance are poorly understood. Our study examined the hypothesis that an increases in [Ca2+]i and protein kinase C activation are required for functional responses to IFN-gamma. The U937 cell line was used as a model of an IFN-gamma responsive cell. IFN-gamma caused a rapid and concentration-dependent increase in [Ca2+]i, which was partly inhibited by calcium-free medium, diltiazem, and TMB-8. IFN-gamma induced a fourfold increase in the concentration of inositol 1,4,5-trisphosphate. Induction of HLA-DR, Fc gamma R, CR3, and Mo3e Ag expression by IFN-gamma was blocked by concentrations of TMB-8 that inhibited an increase in [Ca2+]i, but not by protein kinase C inhibition by H-7 or inhibition of calmodulin with W-7. Ionomycin did not enhance Ag expression and PMA induced the expression of only the Mo3e Ag. We conclude that IFN-gamma induces antigenic expression on human U937 cells by a mechanism dependent on, but not limited to, an increase in intracellular calcium, which is likely due to inositol 1,4,5-trisphosphate generation.
 ...
PMID:Role of intracellular calcium concentration and protein kinase C activation in IFN-gamma stimulation of U937 cells. 214 Mar 94

These studies examined the role of the MHC class II Ag in signal transduction using human B lymphocytes. Early events in signal transduction were considered including the intracellular calcium [Ca2+)i) flux, the activation of phospholipase C, and induction of protein phosphorylation. The (Ca2+)i was enhanced after incubation of B lymphocytes with several mAb anti-HLA class II and cross-linking with rabbit anti-mouse-F(ab')2. We have also demonstrated an enhancement of the (Ca2+)i in response to a suboptimal concentration of a monoclonal anti-IgM either in the presence of or after preincubation with a mAb anti-HLA class II. The activation of phospholipase C was assessed by measuring the generation of inositol phosphates in permeabilized B lymphocytes. mAb anti-HLA-class II of two different epitopes were used to demonstrate both the (Ca2+)i flux and the generation of inositol phosphates. Two-dimensional gel electrophoresis was used to investigate the phosphorylation pattern of resting B lymphocytes and the changes in the pattern after stimulation with soluble mAb anti-HLA-DR, immobilized mAb anti-HLA-DR, and PMA. In addition to the augmentation of phosphorylation observed with regard to phosphoproteins already present in resting B lymphocytes, new phosphorylations were observed after stimulation by any one of the reagents. Furthermore, stimulation by PMA did not result in an identical pattern to that observed after stimulation by mAb anti-HLA class II. An inhibition of the proliferative response to PMA was demonstrated after prestimulation of cells with immobilized mAb anti-HLA-DR, supporting the notion of a shared pathway of activation. In summary, these data demonstrate signal transduction via MHC class II Ag as assessed by three different measures of early events in human B lymphocyte activation and suggest that a protein kinase C pathway is at least partly involved.
 ...
PMID:Early biochemical events after MHC class II-mediated signaling on human B lymphocytes. 239 73

The ability of small molecules such as urushiol, present as a wax on the poison ivy leaf surface, to cause allergic contact dermatitis (rhus dermatitis) has fascinated immunologists for decades. Current dogma suggests that these epicutaneously applied catechol-containing molecules serve as haptens to conjugate with larger proteins via reactive o-quinone intermediates. These complexes are then recognized as foreign antigens by the immune system and elicit a hypersensitivity reaction. Phorbol ester can directly induce cultured keratinocyte (KC) intercellular adhesion molecule-1 (ICAM-1) expression via a protein kinase C (PK-C)-dependent mechanism. As urushiol is also a known PK-C agonist, we asked if topical application of a poison ivy/oak mixture could directly induce epidermal KC ICAM-1 expression. During the pre-erythematous phase of this reaction (4 to 20 hours), epidermal KCs expressed ICAM-1; this "initiation phase" preceded the appearance of activated memory T lymphocytes in the papillary dermis, and thus appeared to be nonlymphokine mediated. A near-contiguous cellular-adhesion molecular network was identified by ICAM-1 staining of basal KCs, dermal dendrocytes, and endothelial cells. During the second 24-hour period with the onset of erythema and edema, there was an "amplification phase" of more intense KC ICAM-1 expression coupled with relatively weak KC HLA-DR expression that coincided with dermal and epidermal T-cell infiltration. This suggests the presence of lymphokines, such as gamma interferon, during the amplification phase because of KC HLA-DR expression. On cultured KCs, urushiol directly induced ICAM-1 expression but not HLA-DR. Thus, in addition to functioning as an antigenic hapten, urushiol directly induces KC ICAM-1 expression. The KC ICAM-1 expression may then alter the dynamic trafficking of memory T cells in the epidermis, so as to initiate cutaneous inflammation in a nonantigen specific manner. This initiation phase is followed by T-cell infiltration and consequent lymphokine production that significantly amplifies the original stimulus. Thus much can still be learned about the molecular pathophysiology of this common type of cutaneous inflammation.
 ...
PMID:Keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis). 257 36

1,25-Dihydroxyvitamin-D3 (1,25-D3) is known to inhibit DNA synthesis, immunoglobulin and lymphokine production [interleukin-2 (IL-2), gamma interferon (G-IFN), and granulocyte-monocyte colony-stimulating factor (GM-CSF)] by mitogen-stimulated human peripheral blood mononuclear cells (PBMCs). Recent data suggest these inhibitory effects are mediated at the gene level through inhibition of mRNA accumulation of specific lymphokines in the activated cells. In previous studies, we have demonstrated the CD8+ T cell population was less sensitive to the anti-proliferative actions of 1,25-D3 than CD4+ T cells. The purpose of this investigation was to further assess ability of 1,25-D3 to regulate CD4+ and CD8+ T cell functions. Initial experiments showed that 1,25-D3 inhibited both IL-2 production and mRNA accumulation in mitogen-stimulated PBMC. However, IL-2 receptor (IL-2R) expression and mRNA accumulation in stimulated PBMC was not affected by 1,25-D3. Both FACS sorted CD4+ and CD8+ T cells expressed IL-2R equally upon stimulation and neither showed an inhibitory effect on this expression by 1,25-D3. Human CD4+ and CD8+ T cells showed a stimulus-specific production of IL-2. CD4+ cells stimulated with mitogen and HLA-DR positive accessory cells produced measurable levels of IL-2 that were completely inhibited by 1,25-D3. CD8+ T cells did not generate measurable amounts of IL-2 in this system. However, CD4+ and CD8+ T cells produced large amounts of IL-2 when stimulated with mitogen and a protein kinase C activator, phorbol myristate acetate (PMA). Under these circumstances, both CD4+ and CD8+ T cell IL-2 production was inhibited completely by 1,25-D3. These data suggest that IL-2R expression in PBMCs and T cell subsets is equal and unaffected by 1,25-D3 while IL-2 production in T cell subsets is stimulus-specific and completely inhibited by 1,25-D3.
 ...
PMID:1,25-Dihydroxyvitamin-D3 regulation of interleukin-2 and interleukin-2 receptor levels and gene expression in human T cells. 259 16

The proliferative responses of natural killer (NK) cells to 12-O-tetradecanoylphorbol-13-acetate (TPA), which directly activates protein kinase c(PKC), and to the Ca2+ ionophores A23817 and ionomycin, known to enhance the intracellular calcium, have been investigated. Highly purified large granular lymphocytes (LGL) were cultured for 12-30 hr in the presence of TPA, ionomycin, or A23817. TPA alone (1-20 ng/ml) triggered rapid LGL proliferation, whereas the calcium ionophores were ineffective. The addition of either calcium ionophore to suboptimal doses or TPA (0.1-0.5 ng/ml) resulted in a synergistic effect on LGL proliferation. Under these conditions high levels of IL-2 activity were released by the LGL. Phenotypic analysis revealed the rapid loss of the Fc gamma receptors (CD16) on LGL and the induction of the expression of IL-2 (CD25) and transferrin receptors and of HLA-DR, but not of CD3. Removal of extracellular Ca2+ by addition of EGTA at the beginning of the culture greatly depressed LGL proliferation and IL-2 production, and blocked phenotypic changes, such as the expression of Tac antigen. Finally, progression to the proliferative phase of LGL, activated by TPA alone or with ionomycin, was completely abrogated by a hyperimmune anti-IL-2 antiserum.
 ...
PMID:Proliferative effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophores on human large granular lymphocytes (LGL). 283 70


1 2 3 4 5 Next >>