Production of Tumor Necrosis Factor Alpha in Human T Lymphocytes by Staphylococcal Enterotoxin B Correlates with Toxin-Induced Proliferation and Is Regulated through Protein Kinase C

Abstract

The superantigen staphylococcal enterotoxin B (SEB) simultaneously binds both the major histocompatibility complex (MHC) class II receptor on monocytes and the T-cell receptor (TCR) on T lymphocytes, resulting in a range of cell responses including induction of tumor necrosis factor alpha (TNF-α). In this study, we have used mixed cultures of human peripheral blood monocytes and lymphocytes to investigate biochemical events controlling SEB induction of TNF-α. TNF-α production induced by SEB in mixed cultures is more closely associated with T cells than with monocytes: (i) a TCR-binding-site mutant of SEB (N23F) is less active in TNF-α induction than an MHC class II receptor-binding-site mutant (F44R), and (ii) flow cytometric analysis indicated that SEB induced TNF-α production in T cells but not in monocytes. Pretreatment of cells with inhibitors of signal transduction pathways was employed to further define events in SEB-induced TNF-α production. Neither protein kinase A inhibitors nor two protein tyrosine kinase inhibitors altered SEB-induced TNF-α production. In contrast, SEB induced protein kinase C (PKC) translocation, and pretreatment of cultures with inhibitors of PKC blocked TNF-α induction. Alteration of levels of diacylglycerol (DAG), an activator of PKC, by treatment with inhibitors of phospholipase C or DAG kinase also altered SEB-induced TNF-α production. These data suggest that PKC activation plays a critical role in SEB-induced TNF-α production in human T cells.

Cellular and Cytokine Responses in the Circulation and Tissue Reactions in the Lung of Rhesus Monkeys (Macaca mulatta) Pretreated with Cyclosporin A and Challenged with Staphylococcal Enterotoxin B

“…18). TNF is produced by human cells in vitro in response to SEB (33,61). Anti-TNF antibody treatment can protect mice against SEB intoxication (7,21,42,43,45, and our unpublished results).…”

Calcium-sensing receptor-mediated TNF production in medullary thick ascending limb cells

“…These responses also may be elicited by other polyvalent CaR agonists, such as poly-L-arginine (11). Although the precise signaling mechanisms that regulate the expression of TNF and COX-2 in mTAL cells have not yet been determined, the contribution of a PKC-dependent pathway indicates some similarity of the CaR expressed on cultured mTAL cells to those reported for several other cell types (37). The highest levels of the CaR are expressed on the basolateral surface of the cTAL, which reabsorbs divalent minerals in a regulated manner (25).…”

Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood

“…[15][16][17][18] As shown in Figures 2, 3, and 4, ketamine suppresses SEB-induced proinflammatory cytokine production in human whole blood. Recently, Yan et al 19 demonstrated that the cells producing SEB-induced TNF-in human whole blood are mainly T cells, and not monocytes or macrophages, suggesting that ketamine may suppress the proinflammatory cytokine production of T cells.…”