1. Rottlerin inhibits human T cell responses.
- Author
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Springael C, Thomas S, Rahmouni S, Vandamme A, Goldman M, Willems F, and Vosters O
- Subjects
- Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Blotting, Western, CD28 Antigens genetics, CD28 Antigens metabolism, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, CD8 Antigens metabolism, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Calcium metabolism, Cell Proliferation drug effects, Cytokines genetics, Cytokines metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Flow Cytometry, Humans, Interleukin-2 antagonists & inhibitors, Interleukin-2 immunology, Interleukin-2 Receptor alpha Subunit genetics, Interleukin-2 Receptor alpha Subunit metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Lectins, C-Type, Propidium metabolism, Protein Kinase C-delta antagonists & inhibitors, Protein Tyrosine Phosphatases genetics, Protein Tyrosine Phosphatases metabolism, Protein Tyrosine Phosphatases, Non-Receptor, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sirolimus pharmacology, Th1 Cells drug effects, Th1 Cells metabolism, Th2 Cells drug effects, Th2 Cells metabolism, Thymidine metabolism, Acetophenones pharmacology, Benzopyrans pharmacology, CD4-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes drug effects
- Abstract
Rottlerin is a pharmacological inhibitor of protein kinase C (PKC) theta, a novel PKC selectively expressed in T lymphocytes. PKC theta is known to regulate T cell receptor (TCR)/CD28 signalling pathways in T lymphocytes, but the impact of PKC theta inhibition on human T cell responses remains undefined. In this work, we describe the effects of rottlerin on the responses of CD4+ and CD8+ human T lymphocytes upon polyclonal activation. We observed a dose-dependent inhibition of CD4+ and CD8+ T cell proliferation in response to anti-CD3/anti-CD28 antibodies stimulation in the presence of rottlerin. This inhibition was associated with impaired CD25 expression and decreased interleukin (IL)-2 production in activated T cells. In contrast, rottlerin did not alter IL-2-induced T cell proliferation. Furthermore, we demonstrated that rottlerin blocked interferon (IFN) gamma, IL-10 and IL-13 mRNA expression in TCR/CD28 activated CD4+ T cells. These findings place rottlerin as a potent immunosuppressive agent for the development of novel therapies in T cell mediated immune disorders.
- Published
- 2007
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