Rottlerin inhibits human T cell responses

Biochem Pharmacol. 2007 Feb 15;73(4):515-25. doi: 10.1016/j.bcp.2006.10.034. Epub 2006 Nov 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology*
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Benzopyrans / pharmacology*
  • Blotting, Western
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects*
  • 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

Substances

  • Acetophenones
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Benzopyrans
  • CD28 Antigens
  • CD69 antigen
  • CD8 Antigens
  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • RNA, Messenger
  • Propidium
  • rottlerin
  • Protein Kinase C-delta
  • PTPN7 protein, human
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Calcium
  • Thymidine
  • Sirolimus