Fever, a hallmark of disease, is elicited by exogenous pyrogens, that is, cellular components, such as lipopolysaccharide (LPS), of infectious organisms, as well as by non-infectious inflammatory insults. Both stimulate the production of cytokines, such as interleukin (IL)-1beta, that act on the brain as endogenous pyrogens. Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis, it is thought that a prostaglandin is important in fever generation. Prostaglandin E2 (PGE2) may be a neural mediator of fever, but this has been much debated. PGE2 acts by interacting with four subtypes of PGE receptor, the EP1, EP2, EP3 and EP4 receptors. Here we generate mice lacking each of these receptors by homologous recombination. Only mice lacking the EP3 receptor fail to show a febrile response to PGE2 and to either IL-1beta or LPS. Our results establish that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP3 receptor.

Prostaglandin E 2 (PGE 2 ) and prostaglandin I 2 (PGI 2 ) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA-and PKC-dependent pathways. PGE 2 or PGI 2 increased or sensitized TRPV1 responses through EP 1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE 2 or PGI 2 , the temperature threshold for TRPV1 activation was reduced below 35°C, so that temperatures near body temperature are sufficient to activate TRPV1.

Mice lacking the gene encoding the receptor for prostaglandin F2alpha (FP) developed normally but were unable to deliver normal fetuses at term. Although these FP-deficient mice showed no abnormality in the estrous cycle, ovulation, fertilization, or implantation, they did not respond to exogenous oxytocin because of the lack of induction of oxytocin receptor (a proposed triggering event in parturition), and they did not show the normal decline of serum progesterone concentrations that precedes parturition. Ovariectomy at day 19 of pregnancy restored induction of the oxytocin receptor and permitted successful delivery in the FP-deficient mice. These results indicate that parturition is initiated when prostaglandin F2alpha interacts with FP in ovarian luteal cells of the pregnant mice to induce luteolysis.

Female mice lacking the gene encoding the prostaglandin (PG) E 2 receptor subtype EP 2 (EP 2 ؊͞؊ ) become pregnant and deliver their pups at term, but with a much reduced litter size. A decrease in ovulation number and a much reduced fertilization rate were observed in EP 2 ؊͞؊ females without difference of the uterus to support implantation of wild-type embryos. Treatment with gonadotropins induced EP 2 mRNA expression in the cumulus cells of ovarian follicles of wild-type mice. The immature cumuli oophori from wildtype mice expanded in vitro in response to both folliclestimulating hormone and PGE 2 , but the response to PGE 2 was absent in those from EP 2 ؊͞؊ mice. Cumulus expansion proceeded normally in preovulatory follicles but became abortive in a number of ovulated complexes in EP 2 ؊͞؊ mice, indicating that EP 2 is involved in cumulus expansion in the oviduct in vivo. No difference in the fertilization rate between wild-type and EP 2 ؊͞؊ mice was found in in vitro studies using cumulusfree oocytes. These results indicate that PGE 2 cooperates with gonadotropin to complete cumulus expansion for successful fertilization.Ovulation and fertilization are key processes in mammalian female reproduction, which is highly regulated by pituitary gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone. These hormones induce a number of preovulatory processes, including follicular development, oocyte maturation, cumulus expansion, and rupture of antral follicles (1). The ovulated eggs move to the oviducts, and timely interaction between an egg and a sperm then leads to successful fertilization (2). Undoubtedly, these processes are initiated by the gonadotropins, but how gonadotropins regulate these processes remains unclear. It is known that some gonadotropin actions are mediated by other mediators. Prostanoids, the cyclooxygenase (COX)-metabolites of arachidonate, likely mediate the ovulatory actions of gonadotropins (3) because aspirin-like drugs that inhibit COX have been reported to inhibit spontaneous and gonadotropin-primed ovulation in many species (4). Prostaglandin E 2 (PGE 2 ), a dominant prostanoid in the ovary, can reverse the inhibitory effect of aspirin-like drugs, when administered simultaneously. These results suggest that some of the steps of ovulation are mediated by this prostanoid (5). Indeed, luteinizing hormone surge leads to high expression of COX-2 in granulosa cells (6, 7), and a large amount of PGE 2 is produced and released into the antral fluid (8). Recently, the importance of prostanoids in early pregnancy has been definitely shown in mice deficient in COX-2. The COX-2 Ϫ͞Ϫ animals showed a reduction in ovulation number and severe failure in fertilization as well as defects in the ability of the uterus to receive implants and to undergo decidualization (9). The result that not only ovulation but fertilization was also severely affected indicates that prostanoids play a role in one of a series of preovulatory processes that are required for both ovulation and fert...