Abstract
A characteristic feature of tissue resident human mast cells (MCs) is their hTryptase-beta-rich cytoplasmic granules. Mouse MC protease-6 (mMCP-6) is the ortholog of hTryptase-beta, and we have shown that this tetramer-forming tryptase has beneficial roles in innate immunity but adverse roles in inflammatory disorders like experimental arthritis. Because the key tissue factors that control tryptase expression in MCs have not been identified, we investigated the mechanisms by which fibroblasts mediate the expression and granule accumulation of mMCP-6. Immature mouse bone marrow-derived MCs (mBMMCs) co-cultured with fibroblast-like synoviocytes (FLS) or mouse 3T3 fibroblasts markedly increased their levels of mMCP-6. This effect was caused by an undefined soluble factor whose levels could be increased by exposing FLS to tumor necrosis factor-alpha or interleukin (IL)-1beta. Gene expression profiling of mBMMCs and FLS for receptor.ligand pairs of potential relevance raised the possibility that IL-33 was a sought after fibroblast-derived factor that promotes tryptase expression and granule maturation via its receptor IL1RL1/ST2. MCs lacking IL1RL1 exhibited defective fibroblast-driven tryptase accumulation, whereas recombinant IL-33 induced mMCP-6 mRNA and protein accumulation in wild-type mBMMCs. In agreement with these data, synovial MCs from IL1RL1-null mice exhibited a marked reduction in mMCP-6 expression. IL-33 is the first factor shown to modulate tryptase expression in MCs at the mRNA and protein levels. We therefore have identified a novel pathway by which mesenchymal cells exposed to inflammatory cytokines modulate the phenotype of local MCs to shape their immune responses.
Highlights
Mast cells (MCs)2 are granulated cells of the myeloid lineage that reside within connective tissues [1]
A Soluble fibroblast-like synoviocytes (FLS)-derived Factor Induces Immature mouse bone marrow-derived MCs (mBMMCs) to Increase Their Expression of mouse MC protease (mMCP)-6—Using WT B6 mBMMCs [40], we examined whether FLS induced this nontransformed immature population of MCs to undergo granule maturation by measuring their levels of Mouse MC protease-6 (mMCP-6)
We found that the transcripts that encode 59 of these 229 candidate proteins were constitutively expressed in mouse 3T3 fibroblasts at a level that exceeded 1% of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and -actin transcripts
Summary
Mast cells (MCs)2 are granulated cells of the myeloid lineage that reside within connective tissues [1]. The development of all MCs in vivo is highly dependent on mesenchymal cell-derived kit ligand (Kitl)/stem cell factor [1, 24, 25], exposure of mBMMCs to recombinant Kitl does not result in a significant increase in mMCP-6 mRNA and/or protein levels [26].
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