Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

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...

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Veröffentlicht in:Biological chemistry 2012-12, Vol.393 (12), p.1555-1567
Hauptverfasser: Waern, Ida, Karlsson, Iulia, Thorpe, Michael, Schlenner, Susan M., Feyerabend, Thorsten B., Rodewald, Hans-Reimer, Åbrink, Magnus, Hellman, Lars, Pejler, Gunnar, Wernersson, Sara
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Sprache:eng
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Zusammenfassung: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.
ISSN:1431-6730
1437-4315
1437-4315
DOI:10.1515/hsz-2012-0189