title: Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients.
abstract: Spleen tyrosine kinase (SYK) is a protein kinase involved in cell proliferation and the regulation of inflammatory pathways. Due to the increasing evidence that kinase inhibitors have potential as specific anti-inflammatory drugs, we have investigated the potential for SYK inhibition as a therapeutic target in autoimmune diseases, particularly cutaneous lupus erythematosus (CLE). Skin samples of patients with different CLE subtypes and appropriate controls were analysed for the expression of SYK and SYK-associated pro-inflammatory mediators via gene expression analysis and immunohistochemistry. The functional role of SYK in keratinocytes was investigated in vitro, using LE-typical pro-inflammatory stimuli and a selective inhibitor of SYK. SYK-associated genes are strongly upregulated in CLE skin lesions. Importantly, phosphorylated SYK (pSYK) is strongly expressed by several immune cell types and also keratinocytes in CLE skin. In vitro, immunostimulatory nucleic acids are capable of inducing SYK phosphorylation in keratinocytes leading to the induction of pro-inflammatory cytokines, while small-molecule SYK inhibition decreases the expression of these proteins. The results demonstrate that pSYK is expressed by immune cells and keratinocytes in skin lesions of CLE patients. LE-typical stimuli induce the expression of pSYK in vitro. Small-molecule SYK inhibition leads to a reduction of pSYK expression and downregulation of pro-inflammatory cytokines in keratinocytes. We therefore believe that pSYK provides a potential future drug target for the treatment of patients who suffer from CLE and related skin disorders. Specifically, our study reveals evidence supporting the use of topical SYK inhibitors in treating lupus.
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Braegelmann
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Ludbrook
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: Dickson
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: Nil
authors.initials: N
authors.lastname: Turan
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ferring-Schmitt
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sternberg
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.affiliation: Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Kuhn
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wenzel
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000201:enzymology*; D010766:Phosphorylation; D000072377:Syk Kinase / Q000378:metabolism*
chemical_list: D016207:Cytokines; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: cutaneous lupus erythematosus; innate immunity; kinase inhibition; targeted therapy