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- Waern, Ida, et al.
(författare)
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IL-6 and IL-17A degradation by mast cells is mediated by a serglycin : serine protease axis
- 2016
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Ingår i: Immunity, Inflammation and Disease. - : Wiley. - 2050-4527. ; 4:1, s. 70-79
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells contain large amounts of fully active proteases that are stored in complex with serglycin proteoglycan in their secretory granules. Upon degranulation, such serglycin: protease complexes are released to the extracellular space and can potentially have an impact on the local inflammatory reaction, either through direct effects of serglycin proteoglycan or through effects mediated by its bound proteases. The objective of this study was to address this scenario by investigating the possibility that serglycin-associated proteases can regulate levels of pro-inflammatory cytokines. Indeed, we show here that activated cultured peritoneal mast cells from wild type mice efficiently reduced the levels of exogenously administered IL-6 and IL-17A, whereas serglycin-deficient mast cells lacked this ability. Furthermore, our data suggest that the reduction of IL-6 and IL-17A concentrations is due to proteolytic degradation mediated by serglycin-dependent serine proteases. Moreover, we show that activated mast cells have the capacity to release IL-6 and that the levels of this cytokine in supernatants were markedly higher in cultures of serglycin-deficient versus serglycin-sufficient mast cells, suggesting that serglycin-dependent serine proteases also participate in the regulation of endogenously produced IL-6. In summary, although the general consensus is that mast cells have a pathogenic impact on inflammatory settings, this study identifies a role for a mast cell-derived serglycin: serine protease axis in down-regulating levels of major inflammatory cytokines. These findings support the notion that mast cells could have a dual role in inflammatory settings, by both being able to secrete pathogenic compounds and being able to regulate their levels after release.
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| 2. |
- Waern, Ida, et al.
(författare)
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Interleukin-6 degradation by mast cells is mediated by serglycin-dependent serine proteases
- 2013
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Mast cells contain large amounts of fully active proteases, i.e. chymase, tryptase and carboxypeptidase A (CPA3), that are stored together with serglycin (a proteoglycan with heparin side chains) in secretory granules. Hence, mast cell proteases are massively released upon degranulation and they may have a large impact on the local inflammatory reaction, e.g. by degrading various bioactive proteins. The objective of this study was to investigate the possibility if mast cells could regulate the levels of IL-6, a cytokine with a wide variety of biological functions. We found that cultured peritoneal mast cells from wild type mice can efficiently degrade IL-6 upon degranulation, whereas MCs from serglycin-deficient mice totally lacked this ability. Moreover, the addition of a serine protease inhibitor significantly reduced the proteolytic degradation of IL-6. Our data suggest that degradation of IL-6 by mast cells is mediated by serglycin-dependent serine proteases.
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| 3. |
- Waern, Ida, et al.
(författare)
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Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis
- 2012
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Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 393:12, s. 1555-1567
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Tidskriftsartikel (refereegranskat)abstract
- Mast cell (MC) granules contain large amounts of proteases of the chymase, tryptase and carboxypeptidase A (MC-CPA) type that are stored in complex with serglycin, a proteoglycan with heparin side chains. Hence, serglycin-protease complexes are released upon MC degranulation and may influence local inflammation. Here we explored the possibility that a serglycin-protease axis may regulate levels of IL-13, a cytokine involved in allergic asthma. Indeed, we found that wild-type MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation, whereas serglycin(-/-) MCs completely lacked this ability. Moreover, MC-mediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist, which suggests that IL-13 degradation is catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation is dependent on both the serglycin and the protease component of the serglycin-protease complex. Moreover, IL-13 degradation was abrogated in MC-CPA(-/-) MC cultures, but was normal in cultures of MCs with an inactivating mutation of MC-CPA, which suggests that the IL-13-degrading serine proteases rely on MC-CPA protein. Together, our data implicate a serglycin-serine protease axis in the regulation of extracellular levels of IL-13. Reduction of IL-13 levels through this mechanism possibly can provide a protective function in the context of allergic inflammation.
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