title: SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype.
abstract: Macrophage polarization into a phenotype producing high levels of anti-inflammatory IL-10 and low levels of proinflammatory IL-12 and TNF-α cytokines plays a pivotal role in the resolution of inflammation. Salt-inducible kinases synergize with TLR signaling to restrict the formation of these macrophages. The expression and function of salt-inducible kinase in primary human myeloid cells are poorly characterized. Here, we demonstrated that the differentiation from peripheral blood monocytes to macrophages or dendritic cells induced a marked up-regulation of salt-inducible kinase protein expression. With the use of 2 structurally unrelated, selective salt-inducible kinase inhibitors, HG-9-91-01 and ARN-3236, we showed that salt-inducible kinase inhibition significantly decreased proinflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-12p40) and increased IL-10 secretion by human myeloid cells stimulated with TLR2 and-4 agonists. Differently than in mouse cells, salt-inducible kinase inhibition did not enhance IL-1Ra production in human macrophages. Salt-inducible kinase inhibition blocked several markers of proinflammatory (LPS + IFN-γ)-polarized macrophages [M(LPS + IFN-γ)] and induced a phenotype characterized by low TNF-α/IL-6/IL-12p70 and high IL-10. The downstream effects observed with salt-inducible kinase inhibitors on cytokine modulation correlated with direct salt-inducible kinase target (CREB-regulated transcription coactivator 3 and histone deacetylase 4) dephosphorylation in these cells. More importantly, we showed for the first time that salt-inducible kinase inhibition decreases proinflammatory cytokines in human myeloid cells upon IL-1R stimulation. Altogether, our results expand the potential therapeutic use of salt-inducible kinase inhibitors in immune-mediated inflammatory diseases.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland maria.lombardi@unige.ch.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Lombardi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Corine
authors.initials: C
authors.lastname: Gilliéron
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Damien
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland cem.gabay@hcuge.ch.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D016764:Cell Polarity / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines; D034741:RNA, Small Interfering / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C495791:CRTC3 protein, human; C577044:HG-9-91-01; C508609:IL10 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010671:Phenylurea Compounds; D011743:Pyrimidines; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D012097:Repressor Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: dendritic cells; inflammation; macrophages; monocytes