Prostaglandin E2 impairs CD4+ T cell activation by inhibition of lck: implications in Hodgkin's lymphoma.
Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E(2) (PGE(2)), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE(2) in T cells from healthy individuals. These data strongly suggest that PGE(2) is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma.
Chemnitz
Jens M
JM
Molecular Tumor Biology and Tumor Immunology, Department of Internal Medicine I, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany.
Driesen
Julia
J
Classen
Sabine
S
Riley
James L
JL
Debey
Svenja
S
Beyer
Marc
M
Popov
Alexey
A
Zander
Thomas
T
Schultze
Joachim L
JL
D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation
D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D015232:Dinoprostone