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

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.
PMID: 26590148
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Research group Mécanisme de l'inflammation articulaire (44)
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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. doi: 10.1189/jlb.2A0715-307R https://archive-ouverte.unige.ch/unige:88667

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Deposited on : 2016-11-03

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