Murine Bone Marrow-Derived Mast Cells as Potent Producers of IL-9: Costimulatory Function of IL-10 andkitLigand in the Presence of IL-1

Abstract

Recently, the Th2-type cytokine IL-9 was identified by genetic mapping analyses as a key mediator that determines the susceptibility to asthma. This has been further supported by data from IL-9-transgenic mice in which the overexpression of IL-9 in the lung causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. In an accompanying paper, we demonstrate that murine bone marrow-derived mast cells (BMMC) after stimulation with either ionomycin, a combination of ionomycin and IL-1, or via IgE-Ag complexes and IL-1 are very potent producers of IL-9. Herein we show that a dramatic increase of IL-9 production is observed when BMMC activated with ionomycin/IL-1 or with IgE-Ag complexes/IL-1 are treated with either additional kit ligand (KL) or IL-10. Both KL and IL-10 considerably enhance the production of IL-9 mRNA and protein. We were also able to demonstrate that the production of endogenous IL-10 by activated mast cells acts on the production of IL-9. Half-life measurements of IL-9 mRNA revealed no significant effect by KL, but a 2-fold increase of mRNA stability under the influence of IL-10. Reporter gene assays of transfected BMMC showed an enhanced transcriptional activity of the IL-9 promoter in the presence of either IL-10 or KL compared with cells stimulated only with a combination of IL-1 and ionomycin. The influence of KL and IL-10 might be of physiological importance, because it is known that both cytokines are produced by bronchial epithelial cells.

IL-33 can promote survival, adhesion and cytokine production in human mast cells

“…Expression of IL-1R1, IL-18Ra and T1/ST2 by HUCBMCs IL-1 can enhance Th2 cytokine secretion by both human and mouse mast cells in vitro, [10][11][12] and IL-18 can enhance Th2 cytokine secretion by mouse mast cells. 13 In accordance with these results, we detected both IL-1R1 and IL-18Ra on mouse peritoneal mast cells by FACS analysis (data not shown).…”

“…1,2 In IgE-associated allergic disorders, and during infections with certain parasites, crosslinking of IgE bound to the high-affinity IgE receptor (FceRI) on mast cells by multivalent antigens (Ags) promotes FceRI aggregation, which in turn triggers mast cell activation and the secretion of various pro-inflammatory mediators, cytokines and growth factors [3][4][5][6][7][8][9] In vitro studies have shown that certain pro-inflammatory cytokines, including IL-1, can enhance IgE/Ag-FceRI-mediated activation, including the secretion of Th2-type cytokines, in human 10 and mouse 11,12 mast cells. Like IL-1, IL-18 can promote IL-13 production by mouse mast cells and basophils in the presence of IL-3.…”

IL-9: Function, Sources, and Detection

“…Several cytokines have been found to stimulate IL-9 production by mast cells, while IL-9 acts as a growth factor and promotes mast cell expansion [17]. Mast cells are stimulated in an autocrine manner in response to IL-9-induced signals and the cross-linking of IgE molecules on the surface of mast cells triggers release of numerous other cytokines [17,43].…”

“…Several cytokines have been found to stimulate IL-9 production by mast cells, while IL-9 acts as a growth factor and promotes mast cell expansion [17]. Mast cells are stimulated in an autocrine manner in response to IL-9-induced signals and the cross-linking of IgE molecules on the surface of mast cells triggers release of numerous other cytokines [17,43]. Histamine and IL-1β, two cytokines released after mast cell degranulation, have been found to further IL-9 production, and along with IL-9 itself, seem to behave in a positive feedback loop inducing IL-9 production [43].…”

“…Human Th17 cells have been demonstrated to secrete concomitantly IL-9 and IL-17 under TGF-β stimulation [16]. In addition to being the target of IL-9, activated mast cells have also been identified as IL-9 producers [17]. Natural killer T cells are also capable of producing IL-9, initially observed in DX5 + CD3 + T-NK cells derived from murine splenocytes [18], but later was observed in human nasal NKT lymphoma cells [19].…”