title: Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production.
abstract: Regulatory T-cells (Treg) are crucial for immune homeostasis and prevention of immune pathology. Yet, Treg may lose Foxp3 and start secreting IL-17, dependent on environmental cues. Our previous data revealed that Treg from severe psoriasis patients are particularly prone to such conversion. The question of how to maintain Treg stability in the context of inflammation awaits immediate resolution. The pan-protein kinase C (PKC) inhibitor sotrastaurin has shown efficacy in clinical trials of psoriasis. Here, we show that sotrastaurin inhibited effector T-cell responses, whereas the regulatory response was enhanced. Sotrastaurin prevented TCR/CD28-induced T-cell activation and pro-inflammatory cytokine production, but preserved a stable Treg phenotype as evidenced by maintenance of suppressive capacity, high Foxp3 and CD25 expression, and lack of IL-17A and IFNγ production. Moreover, in both circulating and dermal psoriatic Treg, prone to rapid induction of IL-17, sotrastaurin enhanced Foxp3 expression and prevented IL-17A and IFNγ production even when stimulated in the presence of the helper T 17-enhancing cytokines IL-1β or IL-23. Thus, pharmacological inhibition of PKC may serve as a powerful tool to concurrently inhibit effector T cells and to facilitate Treg, thereby showing therapeutic potential for the treatment of psoriasis.
authors.affiliation: Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Xuehui
authors.initials: X
authors.lastname: He
authors.affiliation: Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Hans J P M
authors.initials: HJPM
authors.lastname: Koenen
authors.affiliation: Laboratory of Clinical Chemistry, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ruben L
authors.initials: RL
authors.lastname: Smeets
authors.affiliation: Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: Keijsers
authors.affiliation: Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van Rijssen
authors.affiliation: Department of Dermatology, University of Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koerber
authors.affiliation: Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Peter C
authors.initials: PC
authors.lastname: van de Kerkhof
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Annemieke M H
authors.initials: AMH
authors.lastname: Boots
authors.affiliation: Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: i.joosten@labgk.umcn.nl.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D001706:Biopsy; D018106:CD28 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D011493:Protein Kinase C / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012867:Skin / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508717:IL17A protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D053645:Interleukin-2 Receptor alpha Subunit; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D007371:Interferon-gamma; D011493:Protein Kinase C