title: Rottlerin inhibits human T cell responses.
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.
authors.affiliation: Institute for Medical Immunology (IMI), Université Libre de Bruxelles (ULB), Rue Adrienne Bolland, 8, B-6041 Gosselies, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Springael
authors.forename: Séverine
authors.initials: S
authors.lastname: Thomas
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Arnaud
authors.initials: A
authors.lastname: Vandamme
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Fabienne
authors.initials: F
authors.lastname: Willems
authors.forename: Olivier
authors.initials: O
authors.lastname: Vosters
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type; D011419:Propidium / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000098:Acetophenones; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001578:Benzopyrans; D018106:CD28 Antigens; D016827:CD8 Antigens; D002118:Calcium; D016207:Cytokines; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011419:Propidium; D051745:Protein Kinase C-delta; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012333:RNA, Messenger; D020123:Sirolimus; D013936:Thymidine; D000099192:CD69 Antigens; C085746:rottlerin; C502159:PTPN7 protein, human