Cytokines and chemokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation, and are produced when mast cells are stimulated with interleukin-33 (IL-33). Here we establish that the Salt-Inducible Kinases (SIKs) are required for the IL-33-stimulated transcription of il13, gm-csf and tnf and hence the production of these cytokines. The IL-33-stimulated secretion of IL-13, GM-CSF and TNF was strongly reduced in foetal liver-derived mast cells from mice expressing a kinase-inactive mutant of SIK3 and abolished in cells expressing kinase-inactive mutants of SIK2 and SIK3. The IL-33-dependent secretion of these cytokines and several chemokines was also abolished in SIK2/3 double knock-out (KO) bone marrow-derived mast cells (BMMC), reduced in SIK3 KO cells but little affected in BMMC expressing kinase-inactive mutants of SIK1 and SIK2 or lacking SIK2 expression. In SIK2 KO BMMC the expression of SIK3 was greatly increased. Our studies identify essential roles for SIK2 and SIK3 in producing inflammatory mediators that trigger airway inflammation. The effects of SIKs were independent of IKKβ, IKKβ-mediated NF-κB-dependent gene transcription and activation of the MAP kinase family members p38α and JNKs. Our results suggest that dual inhibitors of SIK2 and SIK3 may have therapeutic potential for the treatment of mast cell-driven diseases.
Nicola J. Darling, J. Simon C. Arthur, Philip Cohen