MITF is necessary for generation of prostaglandin D2 in mouse mast cells.
Mast cells generate eicosanoids that are linked to asthma and other inflammatory diseases. A basic-helix-loop-helix leucine zipper transcription factor termed MITF is essential for the development of mast cells. Although other substances also linked to inflammatory reactions (such as various proteases and serotonin) require MITF for their expression, the role of MITF in eicosanoid generation has not been studied. We examined eicosanoid generation in bone marrow-derived mast cells (BMMCs) of tg/tg mice that lack MITF. Most eicosanoids generated by BMMCs are either prostaglandin (PG) D2 or leukotriene C4. The former is synthesized via the cyclooxygenase pathway, whereas the latter is synthesized via the 5-lipoxygenase pathway. In response to stimulation with IgE and antigens, BMMCs of tg/tg mice synthesized leukotriene C4 normally. However, neither immediate nor delayed PGD2 production was detected in these BMMCs. This indicates that MITF is a transcription factor that specifically activates the cyclooxygenase pathway, but not the 5-lipoxygenase pathway. Significant decreases in expression of hematopoietic PGD2 synthase (hPGDS, a terminal synthase for PGD2) were observed at both mRNA and protein levels in tg/tg BMMCs. MITF transactivated the hPGDS gene via a CACCTG motif located in the promoter region. MITF appeared to be essential for generation of PGD2 by enhancing expression of the hPGDS gene in BMMCs.
Morii
Eiichi
E
Department of Pathology, Osaka University Medical School, Suita, Osaka 565-0871, Japan. morii@patho.med.osaka-u.ac.jp
Oboki
Keisuke
K
D020816:Amino Acid Motifs; D000818:Animals; D000941:Antigens / Q000737:chemistry; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D015151:Immunoblotting; D007073:Immunoglobulin E / Q000737:chemistry; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D054834:Lipocalins; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism
D000941:Antigens; D004268:DNA-Binding Proteins; D015777:Eicosanoids; D007527:Isoenzymes; D054834:Lipocalins; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D012333:RNA, Messenger; C477240:Rasgrp4 protein, mouse; D014157:Transcription Factors; D020663:ras Guanine Nucleotide Exchange Factors; D017997:Leukotriene C4; D007073:Immunoglobulin E; D001094:Arachidonate 5-Lipoxygenase; D008156:Luciferases; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D001619:beta-N-Acetylhexosaminidases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2