Abstract Mast cell (MC) granules contain large amounts of proteases of chymase, tryptase and carboxypeptidase A (MC-CPA) type, 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 WT MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation, whereas serglycin-/- MCs totally lacked this ability. Moreover, MCmediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist, suggesting that IL-13 degradation was catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation was 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, suggesting 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. Possibly, reduction of IL-13 levels through this mechanism can provide a protective function in the context of allergic inflammation.