Prostaglandin endoperoxide synthase-1 and -2 couple to different transmembrane stimuli to generate prostaglandin D2 in mouse bone marrow-derived mast cells.
The view that the two isoforms of prostaglandin-endoperoxide synthase (cyclooxygenase), PGHS-1 and PGHS-2, mediate physiologic and inflammatory processes, respectively, implies separate pathways of arachidonic acid metabolism with different benefits to the host. Functional segregation of these steps in endogenous arachidonic acid metabolism in a single cell in response to different stimuli is now demonstrated. When mouse bone marrow-derived mast cells developed in interleukin-3 (IL-3)-containing medium were cultured with c-kit ligand in combination with IL-10 and IL-1 beta, transient expression of PGHS-2 mRNA and protein occurred in a dose- and time-dependent fashion, accompanied by substantial release of prostaglandin D2 (PGD2) into the culture medium from 2 to 10 h. In contrast, induction of PGHS-2 did not mediate an increase in PGD2 generation in response to stimulation with IgE and antigen. After a longer period of culture, from 24 to 48 h, the expression of PGHS-1 increased, as did the increase in IgE/antigen-dependent generation of PGD2. Dexamethasone, which inhibited the induction of PGHS-2 but not PGHS-1, and a PGHS-2-selective inhibitor suppressed cytokine-induced PGD2 generation but not IgE-dependent PGD2 generation. Thus, at a time when both PGHS-1 and PGHS-2 are present in bone marrow-derived mast cells, they function independently by coupling to different stimulus-initiated pathways to PGD2 generation from endogenously derived arachidonic acid.
Murakami
M
M
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
Matsumoto
R
R
Austen
K F
KF
Arm
J P
JP
D000818:Animals; D001853:Bone Marrow / Q000201:enzymology / Q000378:metabolism*; D001854:Bone Marrow Cells; D002462:Cell Membrane / Q000378:metabolism; D007073:Immunoglobulin E / Q000502:physiology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D007378:Interleukins; D007527:Isoenzymes; D007073:Immunoglobulin E; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2