| Mast cells are immune effector cells that cause allergic symptoms and regulate innate and acquired immunity. Mast cells induce allergic symptoms partially through release of pre-formed mediators such as histamine in a process termed degranulation. We show that when stimulated with the neuropeptide substance P (SP), human leukemic LAD2 mast cells have a heterogeneous response in which not all cells degranulate. By sorting LAD2 cells based on the degranulation marker CD63 and performing a gene microarray analysis, we demonstrate that a number of genes are differentially expressed in responding and non-responding cells.;One differentially expressed gene is Ucp2, which encodes a mitochondrial protein that inhibits reactive oxygen species (ROS) production. Ucp2-/- mice have greater skin plasma extravasation in response to intradermal SP compared to wild-type mice, although they have a normal distribution of skin mast cells and normal response to intradermal histamine. However, the skin of Ucp2-/- mice and bone marrow mast cells (BMMCs) derived from Ucp2-/- mice have greater histamine content compared to wild-type controls. BMMC and LAD2 cell histamine content is reduced by either overexpression of UCP2 or treatment with the superoxide dismutase (SOD)-mimetic TBAP. Ucp2 -/- BMMCs also exhibit enhanced degranulation and prostaglandin D2 (PGD2) production compared to wild-type BMMCs in response to either IgE/antigen or compound 48/80 (C48/80), which acts like SP. Although Ucp2-/- BMMCs have greater IL-6 and TNF-alpha release in response to lipopolysaccharide (LPS), they unexpectedly have less TNF-alpha release in response to IgE/antigen.;15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) is an endogenous ligand of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), which is known to inhibit mast cell degranulation. We hypothesized that 15d-PGJ2 inhibits degranulation through induction of UCP2. 15d-PGJ2 induces UCP2 in BMMCs and does not have an inhibitory effect on histamine release from Ucp2-/- BMMCs, indicating that expression of UCP2 is critical for 15d-PGJ2 to inhibit degranulation. UCP2 is also induced by SP, indicating that UCP2 expression may be part of a negative feedback loop. UCP2 is a novel regulator of mast cell activation, and may be targeted as a treatment for allergic and inflammatory diseases. |
