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Vesicular Associated Membrane Protein‐8 is required for Mast Cell Degranulation but not Cytokine Secretion.
Author(s) -
Tiwari Neeraj,
Wang ChengChun,
Brochetta Cristiana,
Zabucchi Giuliano,
Rivera Juan,
Hong Wanjin,
Blank Ulrich
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.482
Subject(s) - secretion , microbiology and biotechnology , degranulation , exocytosis , syntaxin , histamine , chemokine , mast cell , cytokine , intracellular , mediator , chemistry , biology , immunology , inflammation , biochemistry , endocrinology , receptor
Mast cell (MC)‐induced inflammatory responses involve massive exocytosis of pre‐stored granular mediators and secretion of numerous cytokines/chemokines. SNARE proteins are crucial for intracellular membrane fusion during secretion in MCs. Here we have analyzed the role of vesicular associated membrane protein‐8 (VAMP‐8), a member of the v‐SNARE family of fusion proteins in MC secretory events. We show that VAMP‐8 partially colocalized with secretory granules and redistributed upon stimulation. Using VAMP‐8‐deficient in bone marrow derived MCs (BMMCs), we observed that release of preformed mediators such as beta‐hexosaminidase and histamine is inhibited (~ 50 %) compared to WT BMMCs. Similarly, we found that VAMP‐8‐deficient mice have reduced plasma histamine levels in passive systemic anaphylaxis experiments. By contrast, VAMP‐8‐deficient BMMCs secreted equal amounts of TNF, IL‐4, IL‐6 and MIP‐1alpha. Upon stimulation, VAMP‐8 engages in SNARE complexes with SNAP‐23 and syntaxin‐4, known to play a role in preformed mediator release. Furthermore, we showed that while externalisation of SGs is blocked in VAMP‐8‐deficient MCs, we can detect unprocessed TNF accumulating at the surface colocalizing with a VAMP‐3‐positive compartmentbut not with VAMP‐8. Our findings demonstrate that VAMP‐8 segregates MC preformed mediator exocytosis from cytokine trafficking pathways.