Prostaglandins are involved in many physiologic and cellular processes, such as inflammation. The NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH, type I) is the main enzyme of prostaglandin degradation. ////////Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Zhang Y et al. (2015) Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.//////////////////
NCBI Summary:
This gene encodes a member of the short-chain nonmetalloenzyme alcohol dehydrogenase protein family. The encoded enzyme is responsible for the metabolism of prostaglandins, which function in a variety of physiologic and cellular processes such as inflammation. Mutations in this gene result in primary autosomal recessive hypertrophic osteoarthropathy and cranioosteoarthropathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
General function
Enzyme
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Ovulation, Luteolysis
Comment
Prostaglandin dehydrogenase (PGDH) and prostaglandin levels in periovulatory follicles: Implications for control of primate ovulation by PGE2*
Duffy DM, et al .
Prostaglandin E2 (PGE2) produced by the periovulatory follicle in response to the midcycle LH surge is essential for successful ovulation in primates. Granulosa cells express the PG synthesis enzyme COX-2 in response to the LH surge, but elevated COX-2 mRNA levels precede rising follicular fluid PGE2 levels by 24 h. Therefore, PG metabolism may play a significant role in regulating follicular concentrations of PGE2 during the periovulatory interval. To test this hypothesis, granulosa cells, follicular fluid, and whole ovaries were obtained from adult monkeys receiving exogenous gonadotropins to stimulate development of multiple, large follicles at times spanning the 40 h periovulatory interval. Ovarian expression of the NAD+-dependent 15-hydroxy PG dehydrogenase (PGDH) was assessed by RT-PCR, western blotting, and immunohistochemistry. PGDH mRNA levels were low in granulosa cells obtained 0 h after hCG, rose 10-fold 12 h after hCG, and were not different from 0 h by 24-36 h after hCG administration. Granulosa cell PGDH protein was present 0-12 h after hCG but low/nondetectable 36 h after hCG administration. Follicular fluid PGE2 levels were low at 0-12 h, slightly higher at 24 h, and then rose 10-fold to peak at 36 h hCG. Levels of biologically-inactive PGE2 metabolites (PGEM) in follicular fluid were also low at 0 h but elevated at 12-24 h after hCG, times at which PGE2 levels remain low. Therefore, PGDH is present in the primate periovulatory follicle in a pattern consistent with modulation of follicular PGE2 levels during the periovulatory interval, supporting the hypothesis that gonadotropin-regulated PGDH plays a role in the control and timing of ovulation in primates.
Expression regulated by
LH
Comment
Prostaglandin dehydrogenase (PGDH) in granulosa cells of primate periovulatory follicles is regulated by the ovulatory gonadotropin surge via multiple G proteins. Duffy DM et al. The ovulatory gonadotropin surge increases granulosa cell prostaglandin synthesis as well as prostaglandin dehydrogenase (PGDH), the key enzyme responsible for prostaglandin metabolism. To investigate gonadotropin regulation of PGDH in the primate follicle, monkey granulosa cells were obtained across the 40-h periovulatory interval. PGDH activity was low before the ovulatory hCG stimulus, peaked 12-24h after hCG, and was low again 36h after hCG administration. Granulosa cells maintained in vitro with hCG showed a similar temporal pattern of PGDH. The LH/CG receptor can utilize multiple signaling pathways to regulate intracellular events. Gonadotropin-stimulated cAMP appears to act primarily via the Epacs to increase PGDH mRNA, protein, and activity. In contrast, PLC activation of PKC likely decreases PGDH mRNA, protein, and activity late in the periovulatory interval. Increased, then decreased PGDH activity may delay accumulation of prostaglandins in the follicle until late in the periovulatory interval, contributing to timely ovulation in primates.
Cloning of equine prostaglandin dehydrogenase and its gonadotropin-dependent regulation in theca and mural granulosa cells of equine preovulatory follicles during the ovulatory process. Sayasith K et al. The mammalian ovulatory process is accompanied by a gonadotropin-dependent increase in follicular levels of prostaglandin E2 (PGE2) and PGF2alpha, which are metabolized by 15-hydroxy prostaglandin dehydrogenase (PGDH). Little is known about ovarian PGDH regulation in non-primate species. The objectives of this study were to characterize the structure of equine PGDH and its regulation in follicles during human chorionic gonadotropin (hCG)-induced ovulation. The full-length equine PGDH was obtained by RT-PCR, 5'- and 3'-rapid amplification of cDNA ends (RACE). Its open reading frame encodes a 266-amino acid protein that is 72-95% homologous to other species. Semi-quantitative RT-PCR/Southern blot were used to study PGDH regulation in follicles isolated 0-39 h post-hCG. Results showed that PGDH mRNA expression was low in follicles obtained at 0 h, increased at 12 and 24 h (P < 0.05), and decreased at 36-h post-hCG. This induction of expression was biphasic, with elevated abundance of transcripts at 12 and 33 h post-hCG (P < 0.05) in mural granulosa and theca cells. Immunohistochemistry and immunoblotting confirmed regulated expression of PGHD protein in both cell types of preovulatory follicles after hCG. High levels of PGDH mRNA were observed in corpus luteum and other non-ovarian tissues tested, except kidney, muscle, brain, and heart. Thus, this study is the first to report the gonadotropin-dependent regulation of PGDH during ovulation in a non-primate species. PGDH induction was biphasic in theca and mural granulosa cells differing from primates in which this induction was monophasic and limited to granulosa cells, suggesting species-specific differences in follicular control of PGDH expression during ovulation.
A role for Nuclear Factor Interleukin-3 (NFIL3), a Critical Transcriptional Repressor, in Down-Regulation of Periovulatory Gene Expression. Li F et al. The LH surge triggers dramatic transcriptional changes in genes associated with ovulation and luteinization. The present study investigated the spatiotemporal expression of nuclear factor IL-3 (NFIL3), a transcriptional regulator of the basic leucine zipper transcription factor superfamily, and its potential role in the ovary during the periovulatory period. Immature female rats were injected with pregnant mare's serum gonadotropin, treated with human chorionic gonadotropin (hCG), and ovaries or granulosa cells were collected at various times after hCG. Nfil3 mRNA was highly induced both in intact ovaries and granulosa cells after hCG treatment. In situ hybridization demonstrated that Nfil3 mRNA was highly induced in theca-interstitial cells at 4-8 h after hCG, localized to granulosa cells at 12 h, and decreased at 24 h. Overexpression of NFIL3 in granulosa cells inhibited the induction of prostaglandin-endoperoxide synthase 2 (Ptgs2), progesterone receptor (Pgr), epiregulin (Ereg), and amphiregulin (Areg) and down-regulated levels of prostaglandin E2. The inhibitory effect on Ptgs2 induction was reversed by NFIL3 small interfering RNA treatment. In theca-interstitial cells the expression of hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (Hpgd) was also inhibited by NFIL3 overexpression. Data from luciferase assays demonstrated that NFIL3 overexpression decreased the induction of the Ptgs2 and Areg promoter activity. EMSA and chromatin immunoprecipitation analyses indicated that NFIL3 binds to the promoter region containing the DNA-binding sites of cAMP response element binding protein and CCAAT enhancer binding protein-. In summary, hCG induction of NFIL3 expression may modulate the process of ovulation and theca-interstitial and granulosa cell differentiation by regulating expression of PTGS2, PGR, AREG, EREG, and HPGD, potentially through interactions with cAMP response element binding protein and CCAAT enhancer binding protein- on their target gene promoters.
Ovarian localization
Granulosa, Theca, Luteal cells
Comment
Expression of prostaglandin metabolising enzymes COX-2 and 15-PGDH and VDR in human granulosa cells. Thill M et al. BACKGROUND: Prostaglandins (PGs) within the periovulatory follicle are essential for various female reproductive functions such as follicular development and maturation. In animal models, granulosa cells express the PG synthesizing enzyme cyclooxygenase-2 (COX-2) and the PG inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 (calcitriol) on the expression of COX-2 and 15-PGDH. MATERIALS AND METHODS: The expression of COX-2, 15-PGDH and the vitamin D receptor (VDR) in human granulosa cells (COV434, hGC and HGL5), which were originally isolated from different stages of follicular maturation, was determined by real-time PCR (RT-PCR) and Western blot analysis. RESULTS: A positive correlation of COX-2 and VDR protein was found in the COV434 and HGL5 cells and an inverse correlation of 15-PGDH and VDR protein levels in all the investigated cell types. CONCLUSION: There may be a link between VDR, associated target genes and prostaglandin metabolism in human follicular maturation and luteolysis.
Follicle stages
Preovulatory, Corpus luteum
Comment
The corpus luteum (CL) is a transient ovarian endocrine gland formed from the ovulated follicle. Progesterone (P4) is the primary secretory product of CL and essential for establishment of pregnancy in mammals. In the cyclic female, the life span of CL is characterized by luteal development, maintenance and regression regulated by complex interactions between luteotrophic and luteolytic mediators. It is universally accepted that PGF2a is the luteolysin while PGE2 is considered as a luteotropin in most mammals irrespective of origin either uterus and /or CL. New emerging concepts emphasize the autocrine and paracrine actions of luteal PGs in CL function. However, there is no report on selective biosynthesis and cellular transport of luteal PGE2 and PGF2alpha in the CL of any species. Arosh J et al 2004 have studied the expression of enzymes involved in the metabolism of PGE2 and PGF2alpha, cyclooxygenase (COX) 1 and 2, PG synthases (PGES and PGFS), prostaglandin 15-dehydrogenase (PGDH), and PG transporter (PGT) as well as receptors (EP2, EP3 and FP) throughout the CL life span using a bovine model. COX-1, PGFS and PGDH are expressed at constant levels whereas COX-2, PGES, PGT, EP2, EP3 and FP are highly modulated during different phases of the CL life span. The PG components are preferentially expressed in large luteal cells. The results indicate that PGE2 biosynthesis, transport and signaling cascades are selectively activated during luteal maintenance. By contrast PGF2alpha system is activated during luteal regression.