Contradictory Functions (Activation/Termination) of Neutrophil Proteinase 3 Enzyme (PR3) in Interleukin-33 Biological Activity

Bae, Sang Rak; Kang, Tae-Bong; Hong, Jaewoo; Lee, Siyoung; Choi, Jida; Jhun, Hyunjhung; Kwak, Areum; Hong, Kwang Won; Kim, Eunsom; Jo, Seunghyun; Kim, Soohyun

doi:10.1074/jbc.m111.295055

Cited by 57 publications

(41 citation statements)

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“…However, evidence suggests that the caspase-1 cleavage site is similar to the consensus sequence for caspase-3 and that the intracellular IL-33 precursor is also a substrate for caspase-3 (48). Neutrophil proteinase 3 (PR3) can process the precursor IL-33 into an active mature form as IL-33, but increasing PR3 incubation time downregulates the biological activity of IL-33 (49). In addition, neutrophil elastase and cathepsin G can cleave the IL-33 precursor, which results in the maturation of precursor IL-33 (50).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Xie

Shen

Zhong

et al. 2014

International Journal of Molecular Medicine

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Abstract. The NOD-like receptor family, pyrin domaincontaining 3 (NLRP3) inflammasome plays pivotal roles in inflammation and autoimmunity. The NLRP3 inflammasome is activated in response to various signals, including pathogenassociated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). However, its role in inflammation remains unclear. In this study, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to simulate an inflammatory environment as the testing model. We found that the exposure of RAW264.7 cells to LPS/ATP triggered the activation of caspase-1 (P<0.01) and the cleavage of interleukin (IL)-1β (P<0.01), as well as the release of other cytokines, such as IL-18 (P<0.01) and IL-33 (P<0.01). Extracellular potassium chloride at a high concentration (150 mM) abrogated the secretion of IL-1β and IL-18 (P<0.01), but did not reduce the processing of IL-33 (P>0.05). In addition, the silencing of NLRP3 with small interfering RNA (siRNA) suppressed the generation of proinflammatory cytokines, such as IL-1β (P<0.01), IL-18 (P<0.01), but not IL-33 (P>0.05), along with the decreased mRNA and protein expression of NLRP3 and caspase-1 (P<0.05). However, extracellular potassium at a high concentration and NLRP3 siRNA did not affect the level of apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC; P>0.05). Our results suggest that the NLRP3/ASC/caspase-1 axis participates in the regulation of pro-imflammatory cytokine secretion in RAW264.7 cells, particularly the generation of IL-1β and IL-18.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Xie

Shen

Zhong

et al. 2014

International Journal of Molecular Medicine

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“…Importantly, processing of extracellular IL-33 has been detected in bronchoalveolar lavage fluid from mice with neutrophil-dominated acute lung injury, suggesting a physiological role for neutrophil-derived proteases in the regulation of IL-33 activity (Lefranç ais et al, 2012). Another neutrophil protease, PR-3, also processes IL-33 at multiple sites (Bae et al, 2012). However, only brief incubation (5 min) of IL-33 with PR-3 produces biologically active fragments, whereas prolonged exposure results in IL-33 degradation, suggesting that PR-3 might actually dampen the inflammatory response by inactivating IL-33 (Bae et al, 2012).…”

Section: Proteases Derived From Neutrophils and Mast Cellsmentioning

confidence: 99%

Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme

et al. 2015

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Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease.

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“…Full-length human IL-33 consists of 270 residues and is biologically active (17,18). It is also a substrate of serine proteases released by inflammatory cells recruited to the site of injury (18,19). The proteases elastase, cathespin G, and proteinase 3 cleave fulllength IL-33 to release N-terminal-truncated mature forms containing the IL-1-like cytokine domain: IL-33 95-270 , L-33 99-270 , and IL-33 109-270 (18).…”

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confidence: 99%

Structural insights into the interaction of IL-33 with its receptors

Liu

Hammel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

170

193

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Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 Å. Coupled with structure-based mutagenesis and binding assay, the structural results define the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from smallangle X-ray-scattering analysis resembles IL-1β-IL-1RII-IL-1RAcP and IL-1β-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand-receptor assembly and activation in the IL-1 family.protein-protein interaction | X-ray crystallography | SAXS | cytokine signaling I nterleukin (IL)-33 has important roles in initiating a type 2 immune response during infectious, inflammatory, and allergic diseases (1-5). It was initially identified as a nuclear factor in endothelial cells and named NF-HEV (nuclear factor from high endothelial venules) (6, 7). In 2005, it was rediscovered as a new member of the IL-1 family and an extracellular ligand for the orphan IL-1 receptor family member ST2 (8). As an extracellular cytokine, IL-33 is involved in the polarization of Th2 cells and activation of mast cells, basophils, eosinophils, and natural killer cells (1-3). Recent studies also discovered that the type 2 innate lymphoid cells (ILC2s) are major target cells of IL-33 (9, 10). ILC2s express a high level of ST2 and secrete large amounts of Th2 cytokines, most notably IL-5 and IL-13, when stimulated with . Activation of ILC2s is essential in the initiation of the type 2 immune response against helminth infection and during allergic diseases such as asthma (9, 10).IL-33 does not have a signal peptide and is synthesized with an N-terminal propeptide upstream of the IL-1-like cytokine domain. It is preferentially and constitutively expressed in the nuclei of structural and lining cells, particularly in epithelial and endothelial cells (14,15). Tissue damage caused by pathogen invasio...

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Contradictory Functions (Activation/Termination) of Neutrophil Proteinase 3 Enzyme (PR3) in Interleukin-33 Biological Activity

Abstract: Background:The maturation process of IL-33 (IL-1F11) remains unclear. Results: IL-33 ligand affinity column isolates neutrophil proteinase 3. Conclusion: PR3 is an IL-33-processing enzyme. Significance: PR3 has a dual function in IL-33 biological activity.

Cited by 57 publications

References 47 publications

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme

Structural insights into the interaction of IL-33 with its receptors

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