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.
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.
Murakami
M
M
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Penrose
J F
JF
Urade
Y
Y
Austen
K F
KF
Arm
J P
JP
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D001853:Bone Marrow / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004347:Drug Interactions; D015777:Eicosanoids / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology*; D019089:Stem Cell Factor
D015815:Cell Adhesion Molecules; D016207:Cytokines; D015777:Eicosanoids; D016298:Hematopoietic Cell Growth Factors; D007375:Interleukin-1; D007377:Interleukin-3; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016753:Interleukin-10; D015847:Interleukin-4; D007073:Immunoglobulin E; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D015230:Prostaglandin D2