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S Miron

Publications and source records attributed to S Miron.

12 recordsLinked to original sources
PubMed1992

Involvement of a protein kinase C and protein phosphatases in adhesion of CD4+ T cells to and detachment from extracellular matrix proteins.

For immune surveillance and function to be effective, T lymphocytes constantly recirculate via lymph and blood between lymphoid organs and body tissues. To enable efficient cell movement and migration, cell adhesion to components of the basement membrane and the extracellular matrix (ECM) must be a rapid and transitory process. Whether phosphorylation and dephosphorylation of cellular proteins are involved in this phenomena was explored by monitoring the adhesion of T cells to immobilized ECM proteins. A short exposure of 51Cr-labeled human CD4+ T cells to phorbol esters in vitro induced a rapid beta 1-integrin-mediated adhesion to both fibronectin and laminin, as determined by inhibition with anti-integrin antibodies. Adhesion was reversible; detachment from the immobilized ECM ligands occurred between 20 and 120 min without further intervention. This T cell adhesion was regulated by the activation of protein kinase C because (a) staurosporine and H-7 inhibitors of protein kinase C suppressed T cell adhesion, and (b) PMA-induced down-regulation of intracellular levels of protein kinase C was associated with the abrogation of the T cell adhesiveness to fibronectin and laminin. Furthermore, inhibition of protein phosphatases activity by okadaic acid delayed the detachment of the T cells from fibronectin or laminin. Thus, we suggest that T cell-ECM interactions such as adhesion and detachment are regulated, respectively, by protein kinase C and protein phosphatases.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

T lymphocyte adhesion to the fibronectin and laminin components of the extracellular matrix is regulated by the CD4 molecule.

The adhesion of T cells to components of the extracellular matrix (ECM) is mediated by the beta 1 subfamily of integrin receptors, designated VLA. It has been recently demonstrated that the binding of VLA receptors to protein components of the ECM is rapidly augmented by the activation of the T cells without, however, any actual change in the level of expression of the VLA receptors for fibronectin (FN) or laminin (LN). Thus, it is likely that activation of existing VLA receptors is required for binding. The activation must be regulated by T cell surface molecules capable of transducing signals into the cell. We studied the role of the CD4 molecule in the binding of rat CD4+ T cells to the FN and LN components of the ECM. We now report that the CD4 molecule appears to play a major role in regulating T cell interactions with ECM. This conclusion is based on the following observations: (a) monoclonal antibodies directed against the CD4 molecule inhibited T cell adhesion to both FN and LN; (b) down-regulation of the CD4 molecule resulted in partial loss of the ability of CD4+ T cells to adhere to FN and LN; (c) a CD4+ T cell clone adhered to both FN and LN while a CD4-CD8- clone expressing an identical T cell receptor bound weakly to both proteins and (d) treatment of the CD4+ T cells with an inhibitor of the CD4-associated tyrosine protein kinase activity inhibited T cell adhesion to both ECM proteins.

Animals↗
PubMed1992

Delineation of tissue damage mechanisms in experimental autoimmune encephalomyelitis (EAE). II. Characteristics of astrocyte detachment mediated by myelin basic protein (MBP) specific CD4+ T lymphocytes.

We have shown that encephalitogenic, myelin basic protein (MBP)-specific CD4+ T cells can cause astrocyte and oligodendrocyte detachment in vitro. Similar processes may damage the central nervous system (CNS) in vivo by causing disorganization and destruction of brain tissue structure. The finding that 'bystander' allogeneic fibrosarcoma cells were detached by MBP-specific CD4+ T cells only when syngeneic astrocytes were present, suggested that a soluble cell-detaching factor (CDF) is released during the specific astrocyte-CD4+ effector interaction. In this study, CDF activity was detected in the supernatants of MBP-reactive CD4+ T cells incubated with concanavalin A or astrocytes. Lymphocyte-induced astrocyte lysis, but not detachment, was inhibited by the protein synthesis inhibitors, cycloheximide and puromycin, indicating that de novo protein synthesis is required for this type of lysis, but not for detachment. Astrocyte detachment was not inhibited, but rather augmented, by the trypsin inhibitors, soybean trypsin inhibitor (SBTI) and alpha-1-antitrypsin (alpha 1), suggesting that the CDF activity is not due to tryptic serine proteases, although it may be protease susceptible. The heparanase inhibitor, heparin, inhibited CD4+ T cell-mediated astrocyte detachment at low doses, but augmented detachment at higher doses, indicating that detaching activity is not due to heparanases. The actin microfilament disrupting agent, cytochalasin B (CB), inhibited astrocyte detachment induced by MBP-specific CD4+ T cells. CB pretreatment of the target astrocytes, but not of the effector CD4+ T cells, inhibited astrocyte detachment, suggesting that the integrity of the target's, but not the effector's, cytoskeleton is required for astrocyte detachment. The results herein suggest that during astrocyte interaction with MBP-specific CD4+ T cells, soluble factors are released that trigger an intrinsic astrocyte detachment mechanism.

Animals↗
PubMed1991

Nonencephalitogenic CD4-CD8- V alpha 2V beta 8.2+ anti-myelin basic protein rat T lymphocytes inhibit disease induction.

Recently there has been a number of reports suggesting that CD4-CD8- T cells participate in the processes of inflammatory reaction. In an attempt to delineate the distinctive functions of double negative (DN) T lymphocytes in an autoimmune-induced disease, we isolated and cloned such T cells, along with control CD4+ cells, from Lewis rats immunized with guinea-pig myelin basic protein in CFA. Both clones proliferated in response to the guinea-pig myelin basic protein and its synthetic encephalitogenic peptide, and expressed the same TCR V genes homologous to the mouse V alpha 2 and V beta 8.2 families that appear to be the defining entity of experimental autoimmune encephalomyeltis (EAE). Moreover, the TCR D and J region gene products of the DN cell were found to be similar to another encephalitogenic rat T cell clone. The two T clones did not differ markedly in their ability to produce TNF and IL-2 and to adhere to vascular wall-derived extracellular matrix- and laminin-coated plates. Surprising, therefore, was the finding that, although the CD4+ T lymphocytes were capable of inducing EAE, the DN cells did not elicit disease but rather inhibited subsequent EAE induction. Thus, TCR V alpha 2V beta 8.2 and its junctional region gene products are not the only prerequisite segment for a T cell to become encephalitogenic. We suggest that the important determinants of the T cell ability to induce disease are features of the T cell, other than or in addition to, the T cell receptor.

Animals↗
PubMed1990

Tumor necrosis factor-alpha/cachectin activates the O2(-)-generating system of human neutrophils independently of the hydrolysis of phosphoinositides and the release of arachidonic acid.

We have investigated the mechanisms of transmembrane signalling implicated in the activation of the respiratory burst of adherent neutrophils by tumor necrosis factor-alpha/cachectin (TNF). The activation of the respiratory burst by TNF is insensitive to pertussis toxin and weakly sensitive to protein kinase C inhibitors. Cytochalasin B and dibutyryl cyclic AMP have an inhibitory effect. The activation of the respiratory burst by TNF takes place in the absence of formation of 3H-inositol phosphates, 32P-phosphatidic acid, and 3H-arachidonic acid. These results demonstrate that the activation of the respiratory burst by an endogenous, physiologic stimulus can be independent of the formation of messengers derived from hydrolysis of phosphoinositides.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗