Decreased IL‐10 expression in stefin B‐deficient macrophages is regulated by the MAP kinase and STAT‐3 signaling pathways

Maher, Katarina; Završnik, Janja; Jerič-Kokelj, Barbara; Vasiljeva, Olga; Turk, Boris; Kopitar-Jerala, Nataša

doi:10.1016/j.febslet.2014.01.015

Cited by 30 publications

(46 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this context, it is interesting that other studies have shown that cystatin B interacts with cathepsin L in the nucleus (80), and that cathepsin L can play a role in NF-κB activation (81). Moreover, cystatin B-deficient macrophages have lower IL-10 expression (82), and IL-10 transcriptionally downregulates IL-1β synthesis (83). …”

Section: Discussionmentioning

confidence: 99%

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Orlowski

Colbert

Sharma

et al. 2015

The Journal of Immunology

224

201

View full text Add to dashboard Cite

Sterile particles induce robust inflammatory responses that underlie the pathogenesis of diseases like silicosis, gout and atherosclerosis. A key cytokine mediating this response is IL-1β. The generation of bioactive IL-1β by sterile particles is mediated by the NLRP3 inflammasome, although exactly how this occurs is incompletely resolved. Prior studies have found that the cathepsin B inhibitor, Ca074Me, suppresses this response, supporting a model whereby ingested particles disrupt lysosomes and release cathepsin B into the cytosol, somehow activating NLRP3. However, reports that cathepsin B-deficient macrophages have no defect in particle-induced IL-1β generation have questioned cathepsin B’s involvement. Here, we examine the hypothesis that multiple redundant cathepsins (not just cathepsin B) mediate this process by evaluating IL-1β generation in murine macrophages, singly or multiply deficient in cathepsins B, L, C, S and X. Using an activity-based probe, we measure specific cathepsin activity in living cells, documenting compensatory changes in cathepsin-deficient cells, and Ca074Me’s dose-dependent cathepsin inhibition profile is analyzed in parallel with its suppression of particle-induced IL-1β secretion. Also, we evaluate endogenous cathepsin inhibitors, cystatins C and B. Surprisingly, we find that multiple redundant cathepsins, inhibited by Ca074Me and cystatins, promote pro-IL-1β synthesis, and we provide the first evidence that cathepsin X plays a non-redundant role in non-particulate NLRP3 activation. Finally, we find cathepsin inhibitors selectively block particle-induced NLRP3 activation, independently of suppressing pro-IL-1β synthesis. Altogether, we demonstrate that both small molecule and endogenous cathepsin inhibitors suppress particle-induced IL-1β secretion, implicating roles for multiple cathepsins in both pro-IL-1β synthesis and NLRP3 activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Orlowski

Colbert

Sharma

et al. 2015

The Journal of Immunology

224

201

View full text Add to dashboard Cite

show abstract

“…They reported that stefin B interacted with several different proteins in HIV-1-infected macrophages; among others the two proteins were involved in JAK/STAT signaling pathway (54). In our recent work, we showed significantly lower STAT3 signaling in LPS-stimulated StB KO BMDMs, which resulted in decreased IL-10 expression (55). Therefore, we propose that stefin B interferes with the signaling pathway upstream of STAT1 and STAT3.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 68%

A Role for Stefin B (Cystatin B) in Inflammation and Endotoxemia

Maher

Kokelj

Butinar

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:The lack of cysteine cathepsin inhibitor, stefin B (cystatin B), results in progressive myoclonus epilepsy, type 1. Results: Stefin B deficiency in macrophages resulted in increased inflammasome activation. Conclusion: Stefin B-deficient mice are significantly more sensitive to e LPS-induced sepsis due to increased caspase-11 expression and mitochondrial damage. Significance: Stefin B has an important role in limiting the inflammatory response during LPS-induced sepsis.

show abstract

“…However, the mechanism of EPCs affected by IL-10 remains unclear. There are numerous studies that exhibit the association between IL-10 and STAT3 (24,25). STAT3 is known to be involved in the development and progression of a number of different types of tumor.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 overexpression improves the function of endothelial progenitor cells stimulated with TNF-α through the activation of the STAT3 signaling pathway

Wáng

Chen

Zhang

et al. 2014

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Decreased IL‐10 expression in stefin B‐deficient macrophages is regulated by the MAP kinase and STAT‐3 signaling pathways

Cited by 30 publications

References 39 publications

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

A Role for Stefin B (Cystatin B) in Inflammation and Endotoxemia

Interleukin-10 overexpression improves the function of endothelial progenitor cells stimulated with TNF-α through the activation of the STAT3 signaling pathway

Contact Info

Product

Resources

About