Granzyme B is a novel interleukin-18 converting enzyme

Omoto, Youichi; Yamanaka, Keiichi; Tokime, Kazuya; Kitano, Shigehisa; Kakeda, Masato; Akeda, Tomoko; Kurokawa, Ichiro; Gabazza, Esteban C.; Tsutsui, Hiroko; Katayama, Naoyuki; Yamanishi, Kiyofumi; Nakanishi, Kenji; Mizutani, Hitoshi

doi:10.1016/j.jdermsci.2010.05.004

Cited by 113 publications

(80 citation statements)

References 48 publications

(49 reference statements)

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“…27,28,[31][32][33] GzmB can also regulate inflammation by cleaving and activating cytokines such as IL-18 and IL-1a. 34,35 Interestingly, it is also known that GzmB-mediated cleavage of IL-1a can occur extracellularly by GzmB derived from NK cells, 35 further highlighting the potential importance of perforin-independent GzmB activity in health and disease. In fact, both cytotoxic and non-cytotoxic activities of GzmB are suggested to have a role in many inflammatory disorders such as diabetes, cancer, transplant rejection, autoimmunity, cardiovascular and pulmonary diseases (reviewed in refs [36][37][38][39][40] ).…”

Section: Discussionmentioning

confidence: 99%

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Hiebert

Granville

2013

Cell Death Differ

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Chronic inflammation and excessive protease activity have a major role in the persistence of non-healing wounds. Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-established role in initiating apoptotic cell death. GzmB is also capable of acting extracellularly, independent of perforin and can degrade several extracellular matrix (ECM) proteins that are critical during wound healing. We used apolipoprotein E (ApoE) knockout (AKO) mice as a novel model of chronic inflammation and impaired wound healing to investigate the role of GzmB in chronic wounds. Wild-type and AKO mice were grown to 7 weeks (young) or 37 weeks (old) of age on a regular chow or high-fat diet (HFD), given a 1-cm diameter full thickness wound on their mid dorsum and allowed to heal for 16 days. Old AKO mice fed a HFD exhibited reduced wound closure, delayed contraction, chronic inflammation and altered ECM remodeling. Conversely, GzmB/ApoE double knockout mice displayed improved wound closure and contraction rates. In addition, murine GzmB was found to degrade both fibronectin and vitronectin derived from healthy mouse granulation tissue. In addition, GzmB-mediated degradation of fibronectin generated a fragment similar in size to that observed in non-healing mouse wounds. These results provide the first direct evidence that GzmB contributes to chronic wound healing in part through degradation of ECM.

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Section: Discussionmentioning

confidence: 99%

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Hiebert

Granville

2013

Cell Death Differ

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“…A role for human GrB in the processing of proinflammatory cytokines also has been described. GrB cleaves pro-IL-18 in vitro and ex vivo, at the same position as caspase-1, although with slower kinetics (51,52). Furthermore, hGrB cleaves the 31-kDa precursor of IL-1a, which enhances the biological activity of the cytokine several fold, an in vitro result that was confirmed in mice (50).…”

Section: Grs Trigger Cytokine Release and Activationmentioning

confidence: 93%

Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

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Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

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“…Pro-IL-18 is expressed constitutively (26) and is stored preformed in the DC cytoplasm (23). The processing of pro-IL-18 and the release of the active IL-18 cytokine are generally considered to depend on inflammasome assembly (61), although alternative mechanisms were suggested by previously reported in vitro studies (53). Consequently, we hypothesize that following immunization, FWPV directly infects pDCs and drives inflammasome assembly by the cytosolic recognition of FWPV OVA -derived dsDNA, putatively via AIM2 (57), which in turn triggers the release of active IL-18, thus facilitating T-cell adaptive immune responses to FWPV-encoded antigens.…”

Section: Vol 85 2011mentioning

confidence: 99%

“…In addition, the proinflammatory cytokines pro-IL-1␤ and pro-IL-18 generally require further processing by caspase-1, which is itself controlled by PRR-regulated inflammasome assembly, to produce biologically active cytokines (61); however, recently reported evidence suggests that pro-IL-1␤ can also be cleaved by granzyme B (53). Subsequently, these soluble mediators orchestrate antiviral effector responses, which include the recruitment of effector cells such as macrophages and neutrophils and the activation of the specific dendritic cell (DC) subsets required to drive productive T-cell responses (70).…”

mentioning

confidence: 99%

Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition

Lousberg

Diener

Fraser

et al. 2011

J Virol

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Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV OVA ), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV OVA in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPVderived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.

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Granzyme B is a novel interleukin-18 converting enzyme

Cited by 113 publications

References 48 publications

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Granzymes Regulate Proinflammatory Cytokine Responses

Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition

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