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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bacterial exotoxins staphylococcal enterotoxin A and B (SEA and SEB) mediate disease through their effects on T lymphocytes. In this manuscript we have demonstrated that both SEA and SEB can directly activate purified T cells in the absence of accessory cells as determined by a transition from G0 to G1 and induction of IL-2 receptor expression. However, neither SEA nor SEB alone was sufficient to result in T-cell proliferation. The induction of T-cell proliferation by SEB or SEA required the addition of a second costimulatory signal. This could be provided by either accessory cells or monoclonal antibody stimulation of CD28. As previously reported, T-cell proliferation induced by enterotoxin in the presence of accessory cells was partially inhibited by a blocking antibody against class II MHC. In contrast, in purified T cells when costimulation was provided through CD28, proliferation was not inhibited by class II antibody, and HLA-DR expression was not detectable. In addition, costimulation through CD28 was partially resistant to the effects of cyclosporin A. These results demonstrate that CD28 costimulation is sufficient to induce proliferation of enterotoxin-activated T cells, and that this effect is independent of class II MHC expression.
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PMID:CD28 and staphylococcal enterotoxins synergize to induce MHC-independent T-cell proliferation. 133 Mar 29

Much remains to be clarified the functional capacities of the two major reciprocal subsets of human CD4+ cells which we interpret to be naive and memory cells. CD4+ naive (CD45RA+, LFA-3-) and memory (CD45R0+, LFA-3+) cells were rigorously purified by immunomagnetic negative selection. Their proliferation was measured in response to four protocols of receptor-mediated activation: soluble anti-CD3 mAb, plastic-immobilized anti-CD3 mAb, activating pairs of anti-CD2 mAb, and "superantigens" staphyloccocal enterotoxins A and B (SEA and SEB). Naive cells proliferated much less than memory cells to each of these four regimens although their capacity to respond was demonstrated by strong PHA-induced proliferation. Although three of the regimens depend on autologous monocytes, poorer naive cell responses are also observed to anti-CD3 mAb immobilized on plastic in the absence of monocytes; this implies an intrinsic hyporesponsiveness of naive cells, independent of their potentially weaker interaction with monocytes. Naive cells proliferated less than memory cells to superantigens SEA and SEB over a wide dose range; this assumes particular importance because such superantigens are believed to more closely mimic antigen-specific stimulation than anti-CD3 mAb. The possibility was explored that hyporesponsiveness of naive cells reflects the fact that naive cells require additional co-stimuli to facilitate their activation. In support of this concept, we observed that proliferation of naive cells to anti-CD3 mAb and SEA or SEB (but not to anti-CD2 mAb pairs) was consistently enhanced by pre-activation of monocytes present in the culture. Naive cell proliferative responses were augmented further in cultures supplemented with interleukin (IL) 1 beta and IL 6 or exposed to the co-stimulating mAb anti-CD28 and anti-CD44. The pattern of augmentation was dependent on the specific triggering regimen: anti-CD44 mAb was particularly effective in augmenting the response to superantigens, anti-CD28 mAb for the anti-CD3 response and IL 1 beta/IL 6 for that induced by anti-CD2 mAb pairs. With particular combinations of stimulus/co-stimuli naive cell proliferation was as strong as that of memory cells. We interpret these findings to indicate that naive cells are capable of responding to antigen, but that such responses are critically dependent on the available co-stimuli in vivo.
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PMID:Hyporesponsiveness of "naive" (CD45RA+) human T cells to multiple receptor-mediated stimuli but augmentation of responses by co-stimuli. 197 79

Staphylococcus enterotoxins bind class II MHC molecules on antigen-presenting cells (APC) and stimulate T cells expressing appropriate V beta gene products. Although the role of non-TcR-associated costimulatory receptors during antigen-specific T cell stimulation has been clearly established, the involvement of costimulatory activity in T cell activation by superantigens (SAgs) has been the matter of controversy. The aim of this study was to evaluate the role of the costimulatory-receptor ligand molecules CD28/B7 on bacterial SAg-mediated activation of naive murine T cells. We demonstrate in this report that a combination of monoclonal antibodies to murine B7.1 and B7.2 molecules inhibits the in vitro response of naive T cells to SAgs SEA, SEB, and TSST-1. The inhibition of T cell responses required simultaneous blocking of B7.1 and B7.2, suggesting that either B7.1 or B7.2 is sufficient to provide costimulatory signals to naive T cells in response to bacterial exotoxins. Inhibition of T cell activation by antibodies to B7-related molecules can be overcome by antibodies to CD28, a finding in agreement with the hypothesis that CD28-mediated signals participate in T cell activation by bacterial SAgs. These observations suggest that, as demonstrated for conventional antigen, T cell activation by SAgs requires the coordinated participation of TcR- and CD28-derived signals.
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PMID:Activation of murine T cells by bacterial superantigens requires B7-mediated costimulation. 753 50

The interaction of CD28 with its counter-receptor, B7, induces a cosignal in T cells required to prevent clonal anergy and to promote antigen-dependent interleukin-2 production. The molecular basis of the CD28 cosignal is not well understood but involves the activation of protein tyrosine kinase(s) (PTK). In this report we demonstrate that CD28 cross-linking on Jurkat T leukemic cells causes the activation of at least two PTK pathways. A CD28-induced, p56lck kinase-independent pathway causes tyrosine-phosphorylation of a 110-kDa substrate while recruitment of p56lck kinase activity is apparently required for CD28-induced tyrosine-phosphorylation of 97- and 68-kDa substrates as well as CD28-induced increases in intracellular calcium. The tyrosine phosphorylation of p110, but not p97 or p68, correlated with CD28 calcium-independent costimulatory activity. The pp110 molecule was tentatively identified as the catalytic subunit of phosphoinositide (PI)-3 kinase based upon its coimmunoprecipitation with the p85 regulatory subunit of PI-3 kinase. PI-3 kinase protein and catalytic activity were found complexed with the CD28 receptor if the receptor was "activated" by cross-linking on the surface of intact cells prior to detergent solubilization. The kinetics of association of PI-3 kinase with the "activated" CD28 receptor was rapid, occurring within 30 s of receptor cross-linking and was stable for at least 30 min. Analysis of the CD28 cytoplasmic peptide sequence revealed a putative PI-3 kinase src homology 2 binding motif and CD28 tyrosine phosphorylation site, DYMNM. Tyrosine phosphorylation of CD28 was detected in pervanadate-treated Jurkat B2.7 cells, but not untreated cells. Pervanadate-induced tyrosine phosphorylation of CD28 correlated with receptor association of PI-3 kinase in the absence of CD28 cross-linking, suggesting that CD28 association with PI-3 kinase uses a tyrosine phosphorylation-dependent mechanism. These data provide a model for CD28 signal transduction and support a role for PI-3 kinase in mediating the CD28 calcium-independent, cyclosporin A-insensitive costimulatory signal.
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PMID:CD28 signal transduction: tyrosine phosphorylation and receptor association of phosphoinositide-3 kinase correlate with Ca(2+)-independent costimulatory activity. 795 66

We have previously demonstrated that activation of cAMP-dependent protein kinase (cAK) type I (cAKI, RI alpha 2-C beta 2) mediates the inhibitory effects of cAMP on T-cell replication induced through the TCR/CD3 complex. In the present study we have investigated the effect of cAMP on T-cell DNA synthesis, tyrosine phosphorylation of a 100 kDa protein (pp100) and IL2 mRNA expression, induced through stimulation of the TCR/CD3- and/or the CD28 molecules. Our results demonstrate that tyrosine phosphorylation of pp100 stimulated by anti-CD3 is inhibited by cAMP both in the presence and absence of the phorbol ester PMA, and reflects the changes seen in IL2 mRNA expression and T-cell replication. Combined stimulation with anti-CD3 and anti-CD28, which gives a synergistic response in T-cell replication, gave pp100 phosphorylation and IL2 mRNA expression sensitive to cAMP-dependent inhibition. When PMA was added in addition to anti-CD3 and anti-CD28, the inhibitory effect of cAMP on both T-cell replication and pp100 phosphorylation was completely abolished. The fact that pp100 phosphorylation in response to TCR/CD3-, CD28- and PMA stimulation and cAMP mediated inhibition are identical to the effects of the same stimuli on T-cell proliferation, makes this protein an interesting candidate in downstream signalling from these receptors. In addition, our results are compatible with a model where cAMP, through activation of cAKI, eliminates both the PTK and PKC activating capability of the T-cell receptor at a site(s) proximal to PKC activation. Furthermore, the CD28 molecule which activates PTKs, enters the PTK cascade at a point distal to the target(s) for cAKI action. Therefore, during CD28 signalling PKC activation can be achieved either by TCR/CD3 stimulation (inhibited by cAMP), or directly by PMA (not inhibited by cAMP).
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PMID:Cyclic AMP sensitive signalling by the CD28 marker requires concomitant stimulation by the T-cell antigen receptor (TCR/CD3) complex. 804 42

T lymphocytes require two signals for activation. Recognition of antigen/MHC complexes by the T cell receptor delivers the first signal, while a second signal, delivered by the cell surface receptors CD80 and/or CD86 binding to the T cell surface molecule CD28, has been shown to be effective for the initiation of effective T cell responses. While some of the cytoplasmic effector molecules involved in T cell receptor signaling is known, little is known regarding those involved in the co-stimulation of T cells by CD28. Using the T cell leukemic cell line Jurkat as a model for T cell activation, we demonstrate that cross-linking CD28 using monoclonal antibodies causes tyrosine phosphorylation and activation of MAP kinase/ERK. This activation was rapid, peaking at approximately 5 minutes post CD28 cross-linking, and transient. Activation of MAP kinase/ERK occurred 3 fold less efficiently in a Jurkat line lacking functional p56lck (JCAM.1), and was almost undetectable in a line lacking CD45 (J45.01). These results suggest that CD28 cross-linking can activate intracellular signaling pathways via several different tyrosine kinases. Thus CD28 signaling can activate src family kinases lck and fyn, as well as the Tec family kinase emt/itk. Activation of any one or a combination of these tyrosine kinases may be sufficient for the activation of MAPK following CD28 cross-linking. Activation of MAPK has been shown to cause activation of AP-1 and other transcription factors via serine and/or threonine phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of extracellular signal-regulated protein kinase (ERK/MAP kinase) following CD28 cross-linking: activation in cells lacking p56lck. 852 74

We investigated interleukin-10 (IL-10) production in freshly isolated mononuclear cells and purified T cells in response to stimulation with monoclonal antibodies (mAb) recognizing CD3, CD2 and CD28, or with the bacterial products Staphylococcus aureus cells (SAC), staphylococcal enterotoxin (SEA) and lipopolysaccharide (LPS). IL-10 production was compared with that of IL-2, IL-4 and interferon-gamma (IFN-gamma). Similar to the other cytokines, in peripheral blood mononuclear cells (PBMC) from adult donors the highest IL-10 levels were produced in response to CD2 plus CD28 stimulation, within 72-96 hr of stimulation. Levels of IL-10 in response to CD2 plus CD28 stimulation (1.9 +/- 1 ng/ml) exceeded those in response to SEA (0.25 +/- 0.16 ng/ml), SAC (0.43 +/- 0.42 ng/ml), or LPS (0.19 +/- 0.14 ng/ml) stimulation. With adult purified T cells, high levels of IL-10 and IL-4 were measured following CD3 plus CD28 stimulation, and the amounts of both T-helper type-2 (Th2) cytokines decreased following the addition of phorbol myristate acetate (PMA), whereas the synthesis of the Th1 cytokines IL-2 and IFN-gamma was enhanced. When PBMC were stimulated with a CD3 mAb and different other cytokines were added, strong enhancement of IL-10 production was seen upon the addition of IL-2, IL-4, IL-7, IL-12 and IFN-gamma, whereas inhibition was found with transforming growth factor-beta 1 (TGF-beta 1). These data illustrate that in freshly isolated PBMC large amounts of IL-10 can be induced rapidly by appropriate mAb stimulation, and that even in freshly isolated cells IL-4 and IL-10 show signs of parallel regulation.
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PMID:High-level IL-10 production by monoclonal antibody-stimulated human T cells. 855 72

Germinal centers (GC) are well-defined areas in lymphoid organs were B cells proliferate and differentiate in response to T-cell-dependent antigens. The GC comprises B cells, follicular dendritic cells, tangible body macrophages, and a low number of CD4+ T cells. A large portion of these T cells expresses CD57. We have examined the ability of the CD4+ CD57+ GC T cells to become activated and to take part in B cell activation processes. These T cells coexpress CD45RO, CD69, CD28, and upon mitogenic stimulation CD25. The cell population was found neither to contain nor to be able to produce any specific mRNA for IL-2, IL-4, and IFN-gamma upon activation. Levels of mRNA encoding CD40 ligand was also undetectable under similar conditions. Furthermore, in contrast to ordinary CD4+ T cells, this population expressing CD57 was unable to induce B cells to Ig production in the presence of pokeweed mitogen or SEA unless IL-2 was added to the cultures. However, despite their apparent lack of function CD4+ CD57+ GC T cells were found to rescue GC B cells from cell death in vitro to the same extent as CD4+ CD57+ Th cells. The phenotypical and functional differences found between these Th cells and regular Th-cells suggest that they either represent a T cell subset with distinct properties within the GC yet to be determined or that they represent T cells, late in the immune response, having lost most of their original functions and capabilities.
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PMID:Immunoglobulin production induced by CD57+ GC-derived helper T cells in vitro requires addition of exogenous IL-2. 862 May 44

T cells activated by antigen receptor stimulation in the absence of accessory cell-derived costimulatory signals lose the capacity to synthesize the growth factor interleukin-2 (IL-2), a state called clonal anergy. An analysis of CD3- and CD28-induced signal transduction revealed reduced ERK and JNK enzyme activities in murine anergic T cells. The amounts of ERK and JNK proteins were unchanged, and the kinases could be fully activated in the presence of phorbol 12-myristate 13-acetate. Dephosphorylation of the calcineurin substrate NFATp (preexisting nuclear factor of activated T cells) also remained inducible. These results suggest that a specific block in the activation of ERK and JNK contributes to defective IL-2 production in clonal anergy.
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PMID:Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. 863 2

Working with the murine epidermal-derived dendritic cell (DC) line XS52, we have observed previously that antigen-specific interaction with T cells stimulates their "terminal maturation" into fully professional DC. In this study we examined the impact of dexamethasone (DEX) on this T cell-induced event. When added to cocultures of XS52 DC and the KLH-specific Th1 clone HDK-1 in the presence of antigen, DEX at relatively low concentrations (10(-9)-10(-7) M) prevented substantially or completely each of the changes that typify terminal maturation, including (a) secretion of relatively large amounts of IL-1beta, IL-6, and TNFalpha; (b) loss of CD115 (colony-stimulating factor-1 receptor) expression and proliferative responsiveness to colony-stimulating factor-1; and (c) elevated expression of CD86 (B7-2). XS52 cells also underwent terminal maturation upon exposure to lipopolysaccharide alone, and DEX also inhibited effectively each of the same changes, indicating that DC can serve as the direct target of DEX. By contrast, DEX inhibited XS52 DC-stimulated IL-2 secretion by HDK-1 T cells, but not other changes that accompany T cell activation, including the secretion of IFNgamma and TNFalpha and the elevated expression of CD25, CD28, and CD44. These results reveal a new immunosuppressive mechanism of glucocorticoid action, that is, direct inhibition of T cell-mediated terminal maturation by DC.
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PMID:A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line. 869 Jul 86


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