Salt-inducible kinases are required for the IL-33–dependent secretion of cytokines and chemokines in mast cells

Darling, Nicola J.; Arthur, J. Simon C.; Cohen, Philip

doi:10.1016/j.jbc.2021.100428

Cited by 17 publications

(27 citation statements)

References 49 publications

(70 reference statements)

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“…The lack of any effect on cytokine production in SIK2 KO mast cells may be explained by the greatly increased expression of SIK3 in these cells. The IL-33-dependent secretion of chemokines was also abolished in SIK2/3 double KO mast cells [54]. In summary SIK2 and SIK3 play a critical role in mediating the IL-33 stimulated secretion of cytokines and chemokines in mast cells, however the underlying molecular mechanisms have yet to be defined.…”

Section: The Role Of Siks In Regulating Mast Cell Functionmentioning

confidence: 94%

“…Subsequently, it was found to enhance the secretion of the anti-inflammatory cytokine interleukin (IL)-10 and to suppress the production of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated monocytes and macrophages, which led to the discovery that these effects were mediated by inhibition of the SIKs [17]. The closely related compound MRT199665 (Figure 3) is an equally potent inhibitor of the SIKs, which does not inhibit TBK1 and IKKε, and is therefore an improved version of MRT67307 [17,54]. However, while MRT199665 is a relatively specific SIK inhibitor it also inhibits other AMPK-related kinases, and for this reason should be used in conjunction with HG-9-91-01 (Figure 3); the latter is a structurally unrelated SIK inhibitor that does not inhibit any other AMPK-related kinase family member [17].…”

Section: Development and Exploitation Of Small Molecule Sik Inhibitorsmentioning

confidence: 99%

“…SIK inhibitors may also suppress other aberrant inflammatory responses driven by myeloid cells, such as those seen in rheumatoid arthritis, psoriatic arthritis and psoriasis, or in inflammatory bowel diseases where inflammatory myeloid cells are recruited to the gut and drive the production of inflammatory cytokines [55,[131][132][133]. Since SIK inhibition suppresses the secretion of inflammatory cytokines and chemokines in mast cells [54], SIK-inhibiting drugs may also prove beneficial for the treatment of mast cell driven diseases, including asthma. However, as the normal function of cytokines is to co-ordinate the clearance of pathogens, the possibility that SIK-inhibiting drugs will increase the risk of microbial infection cannot be discounted.…”

Section: Sik-inhibiting Drugs For the Treatment Of Diseasementioning

confidence: 99%

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Nuts and bolts of the salt-inducible kinases (SIKs)

Darling

Cohen

2021

Biochemical Journal

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The salt-inducible kinases, SIK1, SIK2 and SIK3, most closely resemble the AMP-activated protein kinase (AMPK) and other AMPK-related kinases, and like these family members they require phosphorylation by LKB1 to be catalytically active. However, unlike other AMPK-related kinases they are phosphorylated by cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 14-3-3 proteins and inactivation. The most well-established substrates of the SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 14-3-3s, preventing them from regulating their nuclear binding partners, the transcription factors CREB and MEF2. This process is reversed by PKA-dependent inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a HDACs and their re-entry into the nucleus. Through the reversible regulation of these substrates and others that have not yet been identified, the SIKs regulate many physiological processes ranging from innate immunity, circadian rhythms and bone formation, to skin pigmentation and metabolism. This review summarises current knowledge of the SIKs and the evidence underpinning these findings, and discusses the therapeutic potential of SIK inhibitors for the treatment of disease.

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Section: The Role Of Siks In Regulating Mast Cell Functionmentioning

confidence: 94%

Section: Development and Exploitation Of Small Molecule Sik Inhibitorsmentioning

confidence: 99%

Section: Sik-inhibiting Drugs For the Treatment Of Diseasementioning

confidence: 99%

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Nuts and bolts of the salt-inducible kinases (SIKs)

Darling

Cohen

2021

Biochemical Journal

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“…Bone marrow-derived mast cells (BMMC) were generated from the bone marrow of mice aged 3-6 months and their purity was analysed as described previously [23]. Cytokine concentrations in cell free culture medium or serum samples were measured using the Bio-Plex Pro Assay System (Bio-Rad Laboratories) [23]. Serum IgE concentrations were measured using an ELISA kit (Biolegend) according to the manufacturer's instructions.…”

Section: Mast Cell Culture Purity and Cytokine Secretionmentioning

confidence: 99%

“…In addition, polymorphisms in human IL-33 or the IL-33 receptor subunit have been linked to the incidence of asthma [20]. IL-33 stimulates ILC2s and mast cells to secrete IL-13 and other cytokines, such as granulocyte-macrophage colony stimulating factor (GM-CSF) [21][22][23][24][25]. IL-13 promotes airway hyper-responsiveness, the overproduction of mucus and infiltration of eosinophils into the lungs, resulting in airway obstruction [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

Gijsel-Bonnello

Darling

McDonald

et al. 2021

Preprint

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Interleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJ et al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in the Alternaria alternata-induced model of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.

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Deficiency of salt‐inducible kinase 2 (SIK2) promotes immune injury by inhibiting the maturation of lymphocytes

Zhu,

Li,

Wang

et al. 2023

MedComm

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Salt‐inducible kinase 2 (SIK2) belongs to the serine/threonine protein kinases of the AMPK/SNF1 family, which has important roles in cell cycle, tumor, melanogenesis, neuronal damage repair and apoptosis. Recent studies showed that SIK2 regulates the macrophage polarization to make a balance between inflammation and macrophage. Macrophage is critical to initiate immune regulation, however, whether SIK2 can be involved in immune regulation is not still well understood. Here, we revealed that the protein of SIK2 was highly expressed in thymus, spleen, lung, and brain. And SIK2 protein content increased in RAW264.7 and AHH1 cells with a time and dose‐dependent after‐ionizing radiation (IR). Inhibition of SIK2 could promote AHH1 cells apoptosis Moreover, we used the Cre‐LoxP system to construct the SIK2+/− mice, and the research on function suggested that the deficiency of SIK2 could promote the sensitivity of IR. The deficiency of SIK2 promoted the immune injury via inhibiting the maturation of T cells and B cells. Furthermore, the TCRβ rearrangement was inhibited by the deficiency of SIK2. Collectively, this study demonstrated that SIK2 provides an essential function of regulating immune injury, which will provide new ideas for the treatment of immune injury‐related diseases.

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Salt-inducible kinases are required for the IL-33–dependent secretion of cytokines and chemokines in mast cells

Cited by 17 publications

References 49 publications

Nuts and bolts of the salt-inducible kinases (SIKs)

Nuts and bolts of the salt-inducible kinases (SIKs)

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

Deficiency of salt‐inducible kinase 2 (SIK2) promotes immune injury by inhibiting the maturation of lymphocytes

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