UNIGE document Scientific Article
previous document  unige:88667  next document
add to browser collection
Title

SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype

Authors
Published in Journal of Leukocyte Biology. 2016, vol. 99, no. 5, p. 711-721
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.
Identifiers
PMID: 26590148
Full text
Article (Published version) (1.5 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Research group Mécanisme de l'inflammation articulaire (44)
Citation
(ISO format)
LOMBARDI, Maria Stella et al. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. In: Journal of Leukocyte Biology, 2016, vol. 99, n° 5, p. 711-721. https://archive-ouverte.unige.ch/unige:88667

38 hits

0 download

Update

Deposited on : 2016-11-03

Export document
Format :
Citation style :