PubMed · 1901450
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
P A Arns. 1991. Misoprostol.. https://doi.org/10.1097/00000441-199102000-00008
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
In a recent communication, we demonstrated that prostaglandin E2 (PGE2) lowers basal while it ablates interleukin-1beta((IL-1beta) and transforming growth factor-beta (TGFbeta) upregulated lysyl oxidase (LO) mRNA levels. Correspondingly, PGE2 increases cyclooxygenase-1 (COX1) mRNA in diploid, human embryo lung fibroblasts (IMR90) [Roy et al., 19961. We now report that these actions by PGE2 are routed through cAMP via the PGE2, EP2 receptor. Among the PGE2 receptor types, the IMR90 predominantly express the EP2 mRNA. These cells also express EP3 and EP4 mRNA at comparatively low levels. Northern blot analyses show that 11-deoxy PGE1, an EP2/EP4 agonist, emulates the action of PGE2. In a similar manner to PGE2, 11-deoxy PGE1 decreases basal and TGF-beta induced type I collagen alpha1 (COL) mRNA, basal and IL-1beta induced LO mRNA while it increases COX1 mRNA. Sulprostone, an EP3/EP1 agonist, has no effect on the expression of these three genes. Forskolin, an adenylate cyclase activator, acts in a very similar manner to PGE2 or 11-deoxy PGE1. It suppresses both basal and TGF-beta induced COL mRNA levels. Both PGE2 and 11-deoxy PGE1 increase cAMP to a level comparable with forskolin. The role of the EP2 receptor in controlling collagen production is further underscored in the immortalized Rat-1 fibroblasts, derived from Fischer rat embryos, which do not express detectable EP2 mRNA. In these cells, PGE2 has little effect on COL mRNA level, whereas forskolin increases it. Furthermore, forskolin increases cAMP level in Rat-1 cells, whereas PGE2 does not. Overall, these results illustrate that much of the PGE2 action on the expression of COL, LO, and COX1 genes is mediated through the EP2 receptor and a subsequent increase in intracellular cAMP.
We previously reported that prostaglandin (PG)E1 and PGF2alpha induce the synthesis of interleukin-6 (IL-6) via activation of protein kinase (PK)A and PKC, respectively, in osteoblast-like MC3T3-E1 cells. In addition, we have shown that basic fibroblast growth factor (bFGF) elicits IL-6 synthesis through intracellular Ca2+ mobilization in these cells and that tumor necrosis factor-alpha (TNF) induces IL-6 synthesis through sphingosine 1-phosphate produced by sphingomyelin hydrolysis. In the present study, among sphingomyelin metabolites, we examined the effect of sphingosine on IL-6 synthesis induced by various agonists in MC3T3-E1 cells. Sphingosine inhibited the IL-6 synthesis induced by PGF2alpha or 12-O-tetradecanoylphorbol-13-acetate, an activator of PKC. Sphingosine suppressed the PGE1-induced IL-6 synthesis. The IL-6 synthesis induced by cholera toxin, forskolin, or dibutyryl cAMP was inhibited by sphingosine. Sphingosine inhibited the IL-6 synthesis induced by bFGF or A23187. However, sphingosine did not affect the IL-6 synthesis induced by interleukin-1. On the contrary, sphingosine enhanced the TNF-induced IL-6 synthesis. DL-threo-Dihydrosphingosine, an inhibitor of sphingosine kinase, reduced the enhancement by sphingosine as well as the TNF-effect. These results indicate that sphingosine modulates the IL-6 synthesis stimulated by various agonists in osteoblasts.
BACKGROUND: To assess whether prostaglandin E1 analogs have a role in either reducing renal allograft rejection or improving renal function among both transplant and nontransplant patients. METHODS: Studies were identified through Ovid MEDLINE between 1981 and December 1997 using multiple MeSH headings and text words related to renal or liver transplantation, as well as renal insufficiency. These items were crossed with MeSH headings and text words related to prostaglandins and prostaglandin E1. All abstracts were read, in addition to review articles, and their bibliographies were searched for further references. Articles were limited to those published in the English language. Studies were selected based on the following criteria: (1) a randomized control clinical trial; (2) administration of any form of prostaglandin; (3) publication of primary data; and (4) reporting on either renal transplant rejection or renal dysfunction after transplant or, for both transplant and nontransplant studies, objectively comparing a change in renal function from before to after prostaglandin E1 therapy. From the 217 articles that were retrieved, 19 met all inclusion criteria. Data were extracted on study design, nature of the study subjects, and the principal therapeutic intervention. Among the transplant studies, the rate of acute renal graft rejection or renal dysfunction was calculated for each study and then pooled using a random effects model. In addition, the mean change in renal glomerular filtration rate was compared between prostaglandin E1 and controls among both transplant and nontransplant studies and then pooled using an inverse variance-weighted method. Using the Breslow-Day method, statistical heterogeneity was defined at a two-sided P value less than 0.10. RESULTS: Within the 10 transplant trials, all patients were on cyclosporine; oral or intravenous prostaglandin E1 was generally started within 24 hr of transplantation. Renal transplant rejection or renal dysfunction was not significantly reduced with prostaglandin E1 (odds ratio 0.91, 95% confidence interval [CI] 0.64 to 1.28, two-sided P value=0.58; weighted control event 66.9%, 95% CI 50.5 to 80.0). The glomerular filtration rate was estimated within nine transplant studies, with a minimal positive gain in renal function with prostaglandin E1 (mean difference 2.3 ml/min, 95% CI 1.6 to 3.1). Nine other randomized, double-blinded trials evaluated the effect of prostaglandin E1 on renal function among a variety of nontransplant patients. These patients were generally selected based on their susceptibility to renal injury, with a concomitant exposure to nonsteroidal anti-inflammatory drugs. No significant change in the glomerular filtration rate was observed between prostaglandin E1 and placebo arms (mean difference 0.5 ml/min in favor of placebo, 95% CI -2.8 to 1.8). However, these studies were very heterogeneous. CONCLUSIONS: Among both transplant and nontransplant populations, prostaglandin E1 does not seem to preserve or improve renal function. Further research is unlikely to demonstrate superiority of prostaglandin E1 in the context of cyclosporine or nonsteroidal anti-inflammatory drug use.