Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse bone marrow-derived mast cells (BMMCs) developed with interleukin 3 (IL-3) can be stimulated by c-kit ligand (KL) and accessory cytokines over a period of hours for direct delayed prostaglandin (PG) generation or over a period of days to prime for augmented IgE-dependent PG and leukotriene (LT) production, as previously reported. We now report that IL-4 is counterregulatory for each of these distinct KL-dependent responses. BMMCs cultured for 4 days with KL + IL-3 or with KL + IL-10 produced 5- to 7-fold more PGD2 and approximately 2-fold more LTC4 in response to IgE-dependent activation than BMMCs maintained in IL-3 alone. IL-4 inhibited the priming for increased IgE-dependent PGD2 and LTC4 production to the level obtained by activation of BMMCs maintained in IL-3 alone with an IC50 of approximately 0.2 ng/ml. IL-4 inhibited the KL-induced increase in expression of cytosolic phospholipase A2 (cPLA2) but had no effect on the incremental expression of PG endoperoxide synthase 1 (PGHS-1) and hematopoietic PGD2 synthase or on the continued baseline expression of 5-lipoxygenase, 5-lipoxygenase activating protein, and LTC4 synthase. BMMCs stimulated by KL + IL-10 for 10 h exhibited a delayed phase of PGD2 generation, which was dependent on de novo induction of PGHS-2. IL-4 inhibited the induction of PGHS-2 expression and the accompanying cytokine-initiated delayed PGD2 generation with an IC50 of approximately 6 ng/ml. IL-4 had no effect on the expression of PGHS-2 and the production of PGD2 elicited by addition of IL-1 beta to the combination of KL + IL-10. IL-4 had no effect on the immediate phase of eicosanoid synthesis elicited by KL alone or by IgE and antigen in BMMCs maintained in IL-3. Thus, the counterregulatory action of IL-4 on eicosanoid generation is highly selective for the induced incremental expression of cPLA2 and the de novo expression of PGHS-2, thereby attenuating time-dependent cytokine-regulated responses to stimulation via Fc epsilon receptor I and stimulation via c-kit, respectively.
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PMID:Interleukin 4 suppresses c-kit ligand-induced expression of cytosolic phospholipase A2 and prostaglandin endoperoxide synthase 2 and their roles in separate pathways of eicosanoid synthesis in mouse bone marrow-derived mast cells. 754 Nov 41

To study cytokine regulation of the 5-lipoxygenase (5-LO)/leukotriene (LT) synthase pathway we have developed mouse bone marrow-derived mast cells (BMMC) that minimally express each protein of the pathway by using a novel culture system, lacking interleukin (IL)-3. When mouse bone marrow cells were cultured for 5 weeks with 100 ng/ml c-kit ligand (KL) and 10 units/ml IL-10, a population of > 95% mast cells was obtained. These cells generated 8.3 +/- 4.5 ng of LTC4/10(6) cells and 8.1 +/- 2.4 ng of prostaglandin (PG) D2/10(6) cells after IgE-dependent activation. When these BMMC were cultured for 2-5 weeks more with 100 units/ml IL-3 in the continued presence of KL and IL-10, the IgE-dependent generation of LTC4 and PGD2 increased to 212 +/- 36 and 25.5 +/- 8.6 ng/10(6) cells, respectively. The dramatic increase in the IgE-dependent generation of LTC4 in response to IL-3 was accompanied by a concomitant increase in expression of 5-LO and 5-LO-activating protein and preceded the increased expression of cytosolic phospholipase A2 and LTC4 synthase. The recognition that IL-3 up-regulates the expression of each protein of the 5-LO pathway for the generation of LTC4 contrasts with our recent finding that KL up-regulates the expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic PGD2 synthase and increases the IgE-dependent generation of PGD2 in BMMC developed from bone marrow with IL-3. Thus, developmentally segregated regulation of the prostanoid and cysteinyl leukotriene pathways in lineage-related committed mast cell progenitors reveals the pleiotropism of this effector cell of allergic inflammation, a cytokine/growth factor basis for preferential expression of pathways of eicosanoid biosynthesis, and the particular role of IL-3 in regulating the expression of the proteins of the 5-LO/LTC4 synthase pathway.
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PMID:Interleukin-3 regulates development of the 5-lipoxygenase/leukotriene C4 synthase pathway in mouse mast cells. 755 81