IgE-dependent activation of cytokine-primed mouse cultured mast cells induces a delayed phase of prostaglandin D2 generation via prostaglandin endoperoxide synthase-2.
Mouse bone marrow-derived mast cells (BMMC) developed with IL-3 generate prostaglandin D2 (PGD2) through the utilization of prostaglandin endoperoxide synthase (PGHS)-1 within several minutes of cross-linking the high affinity Fc receptor for IgE (Fc epsilon RI) by hapten-specific IgE and Ag. We now report that this immediate generation of PGD2 is followed by a 15-fold induction of steady-state transcripts for PGHS-2, with a maximum at 30 min, accompanied by transient expression of PGHS-2 protein. When BMMC were pretreated with c-kit ligand (KL) in combination with IL-10 for 2 h, sensitized with IgE, and activated with Ag, their expression of steady-state transcripts for PGHS-2 increased 111-fold and their expression of PGHS-2 protein was markedly enhanced, with maximal expression at 1 h and 5 h, respectively, after activation. These events were accompanied by PGD2 generation from 1 to 10 h after activation that accounted for approximately 50% of total PGD2 generation. The expression of PGHS-1 protein did not change during this period. The optimal priming interval for the effect of KL plus IL-10 on the IgE-dependent induction of PGHS-2 was 2 h, at which time only this particular cytokine combination acted synergistically with activation by IgE and Ag. In contrast, at 2 days the accessory cytokines that could provide priming with KL included IL-3 and IL-9 in addition to IL-10. Dexamethasone, which inhibited the expression of PGHS-2 but not PGHS-1, and NS-398, a selective inhibitor of PGHS-2, each suppressed the delayed phase but not the immediate phase of PGD2 generation. Conversely, valeryl salicylate, a selective inhibitor of PGHS-1, suppressed the immediate but not the delayed phase of PGD2 generation after cell priming and IgE-dependent activation.
Murakami
M
M
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Bingham
C O
CO
Matsumoto
R
R
Austen
K F
KF
Arm
J P
JP
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007073:Immunoglobulin E / Q000502:physiology*; D016753:Interleukin-10 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D016906:Interleukin-9 / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology
D007377:Interleukin-3; D016906:Interleukin-9; D011448:Prostaglandin Antagonists; D019089:Stem Cell Factor; D016753:Interleukin-10; D007073:Immunoglobulin E; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2