title: Effects of the kinase inhibitor CGP41251 (PKC 412) on lymphocyte activation and TNF-alpha production.
abstract: CGP41251 is a serine/threonine and tyrosine kinase inhibitor that is a novel anticancer agent. Because the kinases that CGP41251 inhibits play important roles in T lymphocyte activation, we hypothesized that this compound may have useful immunomodulatory properties. Here we characterized the in vitro immunomodulatory effects of CGP41251. The effects of CGP41251 on lymphocyte proliferation, expression of T cell activation surface markers, and intracellular calcium response in peripheral blood mononuclear cells (PBMC's) were measured. Intracellular IL-2, TNF-alpha, IFN-gamma expression in CGP41251-treated T cells stimulated by lectin was measured by flow cytometry. CGP41251 inhibited lectin-induced lymphocyte proliferation and upregulation of activation surface markers with a 50% inhibitory concentration (IC(50)) of 0.1 microM. CGP41251, at micromolar concentrations, blunted the intracellular calcium response during PBMC activation. CGP41251 inhibited TNF-alpha production by T cells with an IC(50) of 0.5 microM and did not significantly inhibit the production of IL-2 or IFN-gamma. In conclusion, CGP41251 potently inhibits T lymphocyte activation and function and interferes with the proximal part of the T cell activation pathway. The ability of CGP41251 to selectively block T cell TNF-alpha production warrants the evaluation of this compound on other, e.g., monocyte, immune cells and in immunological conditions that are characterized by high TNF-alpha levels such as psoriasis and inflammatory bowel diseases.
authors.affiliation: Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5407, United States.
authors.forename: Ming-Sing
authors.initials: MS
authors.lastname: Si
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Reitz
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Borie
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D011990:Receptors, Transferrin; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C068126:CD71 antigen; D047428:Protein Kinase Inhibitors; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin; D002118:Calcium