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a Departments of Medicine/GI & Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
b Department of Rheumatology, New York University School of Medicine, Hospital for Joint Diseases, New York, New York 10003, USA
c Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI 48109-0680
d Division of Rheumatology, Harvard Medical School, Beth Israel Deaconness Medical Center, Boston, Massachusetts 02215, USA
e Division of Rheumatology, University Hospital Nijmegen. 6500 HB Nijmegen, The Netherlands
f Rheumatic Diseases Division, Harold C. Simmons Arthritis Research Center, The University of Texas Southwestern Medical Center at Dallas, Texas 75235-8884, USA
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCOX-1COX-2REFERENCES |
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Key Words: Prostaglandins • Inflammation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCOX-1COX-2REFERENCES |
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Despite the wide use of NSAIDs over the last century, their mechanism of action was not fully appreciated until 1971, when Vane published his seminal observations proposing that the ability of NSAIDs to suppress inflammation rests primarily on their ability to inhibit the cyclooxygenase (COX) enzyme (1). This would limit the production of proinflammatory prostaglandins (PGs) at a site of injury. Given this, NSAIDs have been used by scientists for the last 25 years to dissect the critical role that both the COX enzyme and the eicosanoids derived from this pathway have in normal and abnormal physiologic states.
The chemistry of the eicosanoid biosynthetic pathway is well known. Prostaglandins are formed by the oxidative cyclization of the central 5 carbons within 20 carbon polyunsaturated fatty acids (2). The key regulatory enzyme of this pathway is COX (COX) (PGH synthase), which catalyzes the conversion of arachidonic acid (or other 20 carbon fatty acids) to prostaglandin (PG) G2 and PGH2. PGH2 is subsequently converted to a variety of eicosanoids that include PGE2, PGD2, PGF2
, PGI2, and thromboxane (TX) A2 (
Fig. 1).
The array of PGs produced varies depending on the downstream enzymatic machinery present in a particular cell type. For example, endothelial cells primarily produce PGI2, whereas platelets mainly produce TXA2 (for general review of this topic, see refs 3, 4). All NSAIDs in clinical use have been shown to inhibit COX, leading to a marked decrease in PG synthesis (5).
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Prostaglandins are found in animals as primitive as the coelenterates and are present in a wide variety of human tissues (2). PGs not only play a central role in inflammation, but also regulate other critical physiological responses. In humans, prostaglandins are involved in diverse functions, including blood clotting, ovulation, initiation of labor, bone metabolism, nerve growth and development, wound healing, kidney function, blood vessel tone, and immune responses. In contrast to hormones such as cortisone or thyroxin, which have broad systemic effects despite being released from a single site in the body, PGs are synthesized in a broad range of tissue types and serve as autocrine or paracrine mediators to signal changes within the immediate environment ( Fig. 2).
Two classes of prostaglandin receptors exist to transduce signals upon binding of ligand, the G-coupled cytoplasmic receptor class (i.e., EP1-4 for PGE2) and the nuclear PPAR receptor class (i.e., PPAR, PPAR
, PPAR
), which acts directly as a transcription factor upon ligand binding (7).
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Given the broad role PGs play in normal human physiology, it is not surprising that systemic suppression of PG synthesis through inhibition of COX can lead to unwanted side effects. In particular, individuals taking NSAIDs for even short periods of time can experience gastrointestinal and renal side effects (8, 9) in addition to effects on other physiological systems. As many as 25% of individuals using NSAIDs experience some type of side effect, and as many as 5% develop serious health consequences.
The different effects of PGs can be explained by considering their varied chemistry, the diversity of PG receptors, and modulation of PG synthesis by local upstream and downstream effects. This review will focus on the role of COX enzymes (COX-1 and COX-2) on the biology of many different organ systems. Since NSAIDs clearly have proven efficacy in treating human disease, while having well-documented deleterious side effects, an intense amount of research over the last 5–10 years has been devoted to distinguishing the role of each type of COX isoform in these two processes. One major goal of this work is the design of an antiinflammatory drug with a wider therapeutic window.
Investigators studying cell growth signaling pathways identified a unique, inducible gene product related to the known COX sequence (see ref 3 for review). Concurrently, investigators looking at PG production in response to cytokines and other inflammatory factors noted increases in COX activity that could only be accounted for by increased expression of another cyclooxygenase (10). Both immunoprecipitation of this COX variant with an anti-COX antibody, as well as the production of an antibody that precipitated only the COX-2 isoform, allowed for the identification of two different COX isoforms. It was subsequently determined that the COX-1 and COX-2 proteins are derived from distinct genes that diverged well before birds and mammals (11).
Taken together, these early studies revealed that while both enzymes carry out essentially the same catalytic reaction and have similar primary protein structures (12), many of the inflammatory, inducible effects of COX appeared to be mediated by the newly discovered COX-2, while many of the ‘housekeeping’ effects of COX appear to be mediated by COX-1. This functional role for each isoform is consistent with their tissue expression patterns: nearly all normal tissues were found to express COX-1 with low to undetectable levels of COX-2. However, COX-2 is constitutively expressed in the brain and kidney of rodents. Other differences between COX-1 and COX-2 include differences in utilization of arachidonic acid substrate pools as well as in mRNA stability (13, 14).
The regions regulating gene expression of COX-1 and COX-2 show little similarity. For example, the promoter and enhancer regions regulating COX-2 contain a variety of response elements that have been shown to explain, at least in part, its inducibility by hormones, growth factors, phorbol esters, cAMP, inflammatory factors, and cytokines. Much less is known about the elements involved in regulating COX-1 gene expression, although studies have reported induction of COX-1 in some circumstances involving differentiation of macrophages (16–19).
COX-1 and COX-2 also show major differences in mRNA splicing, stability, and translational efficiency. Regulation of COX-2 at the mRNA level appears to be an important mechanism by which some physiological mediators, notably the corticosteroids (consistent with their immunosuppresive properties, down-regulate COX-2 expression), act to regulate PG production.
Another major difference between COX-1 and COX-2 appears to be in their ability to use different substrate pools. For example, in both fibroblasts and immune cells, COX-2 was able to utilize endogenous arachidonic acid whereas COX-1 was not. In these systems, COX-1 requires exogenous substrate. Soluble PLA2 can produce an alternative source of substrate for COX-1, and Herschman (3) has suggested that in some tissues the release of sPLA2 from neighboring cells might provide the primary regulation of COX-1 activity. If this is the case, then the regulatory elements responsible for increasing PG production would not involve the COX-1 gene, but rather the sPLA2 gene.
In summary, the COX-1 and COX-2 genes are regulated by two independent and quite different systems even though the enzymatic reaction they catalyze is identical. How these systems function in health and disease, how they are regulated, and how they interact will be addressed in the remainder of this review.
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COX-1 |
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TOPABSTRACTINTRODUCTIONCOX-1COX-2REFERENCES |
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COX-1 appears to function in two other physiological systems leading to vasodilatation in the presence of contractile conditions. In both the kidney and the stomach, normal physiological stimuli are associated with dramatic changes in blood flow. During times of lowered blood volume, the kidney releases angiotensin and other factors to maintain blood pressure by systemic vasoconstriction (22). At the same time, angiotensin provokes PG synthesis in the kidney. COX-1 is expressed in the vasculature, glomeruli, and collecting ducts of the kidney, and it appears to be important in producing the vasodilating PGs, which maintain renal plasma flow and glomerular filtration rate during conditions of systemic vasoconstriction. In the presence of NSAIDs, this protective response fails, leading to renal ischemia and damage in susceptible individuals (23). Similarly, in the gastric antrum, NSAID use leads to ischemia followed by mucosal damage and ulceration (24). The enzyme blocked by NSAIDs is thought to be COX-1 (25) that produces PGs, which alter blood flow in the microcirculation of the gastric mucosa.
So COX-1 acts in a variety of settings to produce homeostatic or maintenance levels of PGs. In some cases, induction of PLA2 is responsible for increased PG synthesis. In others, COX-1 levels are modulated (i.e., macrophages stimulated to differentiate). It is not yet clear whether all cells and tissues with COX-1 rely on exogenous supplies of substrate, but this situation would allow for a variety of cooperative mechanisms tying COX-1 activity to neighboring physiological requirements.
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COX-2 |
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TOPABSTRACTINTRODUCTIONCOX-1COX-2REFERENCES |
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Renal function
Prostaglandins are known to serve as important physiologic modulators of vascular tone and sodium and water homeostasis in the mammalian kidney, including modulation of glomerular hemodynamics, tubular reabsorption of sodium and water, and regulation of renin secretion. While COX-1 has long been recognized to be involved in normal kidney function, COX-2 is now seen to have a distinct role. Localization studies have found COX-2 in both the macula densa of the rat kidney (28) and the interstitial cells of the medulla (29). The macula densa plays an important role in mediating the interaction among glomerular filtration, proximal reabsorption, and regulation of renin release (30), which in turn is responsible for sodium balance and fluid volume. Although, PGE2 has been reported to inhibit chloride reabsorption in the ascending limb of Henle (31), chronic sodium deprivation was found to increase COX-2 levels in the region of the macula densa, and COX-2-generated prostanoids may be important mediators of renin production and tubuloglomerular feedback. The details of interactions between the COX-1 and COX-2 mediated systems in the kidney are not clear. Mapping of PG receptors in the kidney (6) does show differential locations of receptors specific for different PGs, indicating that differential synthesis of specific types of prostaglandins may be responsible for separating the effects of COX-1 and COX-2.
In addition to the multiple roles played by PGs in the adult kidney, COX-2 null mice show severe disruption of kidney development (32, 33). The localization and level of COX-2 expression in the human kidney is currently unknown, but this information will be essential in evaluating the role of COX-2 in human kidney function. NSAIDs are known to have multiple effects on kidney function, and specific COX-2 inhibitors should be useful in dissecting the role of PGs generated from the COX-2 pathway in normal renal physiology.
Nerve and brain function
COX-2 seems to have some role in regulating brain function. PGs have long been known as mediators of fever, of inflammatory reactions in neural tissue, and, more recently, of brain function. The recognition that each of these processes involves induction of PG synthesis has led to an appreciation of the role COX-2 plays in the PG-mediated functions. While NSAIDs are commonly used to control fever, the actual mechanism of fever induction has only recently been de~scribed. Intraperitoneal injection with lipopolysaccharide (LPS) causes a marked fever response in rats. In an elegant dissection of molecular and tissue interactions, Cao and colleagues have shown how COX-2 induction in brain endothelial cells temporally parallels the fever response (34, 35). This leads to the synthesis of PGs, which then act on temperature-sensing neurons in the preoptic area. In turn, COX-2 inhibition by an isoform-specific NSAID can effectively block fever (36). Communication between local inflammatory sites and the brain endothelium is mediated by cytokines such as IL-1, which can directly induce COX-2 expression in these cells (37). These investigators have also shown induction of COX-2 expression in other parts of the brain, but these areas are not directly associated with the fever pathway.
A separate inflammatory pathway is one mediated by microglial cells, a type of tissue-specific macrophage that lies dormant until needed for defense or tissue remodeling (38). While known as a source of PGs during inflammatory states, the microglial cell does not show induction of COX-2 in response to cytokines, in strong contrast with other inflammatory cells. Instead, the microglial COX-2 response is limited to direct LPS exposure, an event that would only occur by direct bacterial infection of the brain. Thus, the microglial defensive response is segregated from systemic inflammation by its limited repertoire of inducers.
This segregation of the brain from systemic inflammatory inducers is important because COX-2 also plays a central role in neural development and adaptation. During earlier stages of brain development, neural genes and proteins are developmentally induced and play a major role in the maturation process. During later stages of maturation, however, environmental influences, as represented by neural responses and synaptic activity, play an increasingly important role in determining brain structure. It is in these final stages of development and brain modeling that COX-2 becomes active in a manner that coincides with the imprinting of environmental influences (39).
COX-2 remains an important modulator of neural response throughout adult life. COX-2 levels increase dramatically after seizures and N-methyl-D aspartate-mediated activity (40). The sites of induction are the postsynaptic dendritic arborizations (41) of specific excitatory neurons located in the major processing centers of the brain. The actual role of COX-2 and PGs in these sites is not yet understood, but associations between COX-2 induction and neural degeneration after glutamate stimulation (42), seizures, and spreading depression waves (43) suggest that COX-2 may play more of a role in the selective loss of neural connections than in their formation.
Maintenance of gastrointestinal integrity
The intestinal epithelium is a tissue that undergoes constant regeneration in response to both insult and normal use. The use of NSAIDs causes a variety of problems in the gastrointestinal tract (44) including irritation and ulceration of the stomach lining (45). Radiation exposure leads to intestinal epithelial cell death, leaving crypt cells to regenerate the population. In animal studies, COX-2 is not induced after exposure to radiation, and its presence is not essential for crypt cell survival (46). Under these circumstances, COX-1 appears to play a major role, as it does in the stomach, in maintaining proper glandular architecture. For example, indomethacin, which effectively inhibits COX-1, suppressed crypt survival and PGE2 production in intestine after radiation damage. Gastrointestinal epithelium is also the target of numerous infectious and parasitic organisms. In response to infection or invasion, COX-2 expression is induced in epithelial cells (47), which leads to increased PG production. The PGs then stimulate chloride and fluid secretion from the mucosa, which flushes bacteria from the intestine. In addition, COX-2 is expressed during inflammation and wound healing, and in animal models, treatment with COX-2 inhibitors can exacerbate inflammation and inhibit healing. Nevertheless, COX-2 selective inhibitors appear to be associated with less gastrointestinal damage than conventional NSAIDs (48). Clinical trials evaluating compounds that are highly selective for COX-2 are under way, and preliminary results indicate a paucity of gastrointestinal side effects.
Many of the diverse roles of PGs in the intestine have been revealed by studying the effects of indomethacin or other NSAIDs. For example, Giannella et al. (49) found that indomethacin could effectively suppress the rapid intestinal fluid secretion accompanying Salmonella infection of rhesus monkeys. More recently, Eckmann et al. (47) have dissected this effect and shown that Salmonella infection of cultured intestinal epithelial cells gives rise to a rapid induction of COX-2, an associated rise in PGs, and an acceleration in chloride secretion that can be blocked by an anti-PGE antibody. With the response of infected cells, uninfected cells also acquired a state of increased fluid secretion, demonstrating the paracrine nature of the PG response. This model shows the essential features of the PG response: upregulation of COX and PG synthesis, physiological adaptation to infection, and coordination of a protective response.
Ovarian and uterine function
One of the earliest noted sites of PG accumulation was amniotic fluid (50), and one of the first known biological responses to a prostaglandin was the rhythmic contraction of the uterine myometrium. These associations with pregnancy and labor led to the recognition of PGs as a major effector in induction of labor. Indeed, Zuckerman et al. (51) administered indomethacin as a treatment for premature labor with dramatic results. Out of 50 women, 80% experienced cessation of uterine contractions. However, five infants from the treated mothers died because of premature closure of the ductus arteriosus, a circulatory shunt in the fetus that allows the output of the left ventricle to bypass the fetal lungs, which is maintained by PGs (52). Prenatal indomethacin is sufficient to block PG production leading to premature duct closure and disruption of fetal circulation (52).
Ovulation, the process by which oocytes are released from the preovulatory follicle in the ovary is accompanied by induction of prostaglandin synthesis as a consequence of the LH surge. This marked response led to the first observation of COX-2 induction during a normal physiological event (53). One of many molecular events associated with ovulation (54), the induction of COX-2 is necessary for the successful rupture of the follicle, probably mediating directly the generation or activation of proteolytic enzymes necessary for this process (55). Induction of COX-2 can be modulated by the gonadotropins LH and FSH, and by TGF-, IL-1, or other cellular signaling pathways (58).
After fertilization, COX-2 again plays a role, this time during implantation of the embryo in the uterine endometrium. During the pre-implantation period, uterine COX-1 (59) and the PGE2 receptors, EP1, EP3, and EP4 (60), may modulate preparation of the uterus for interaction with the embryo, and COX-2 (59) and the EP2 receptor (61) appear to mediate the embryo-uterine interactions during implantation. COX-2 null mice show multiple failures in reproductive function, including ovulation, fertilization, implantation, and decidualization, underscoring the multiple roles of PGs during these processes (62). Finally, at the completion of pregnancy, PGs again act in the ovary and uterus to help mediate the delivery process. As mentioned above, PGs have long been known to stimulate uterine contraction. In mice, the production of PGF2 by the fetal and/or uterine tissues signals the ovary to induce luteolysis (63), leading to a decline in maternal progesterone and the induction of oxytocin receptors in the myometrium. This induction in turn increases the myometrial response to oxytocin and brings on parturition.
Bone
The role of PGs in bone metabolism is not only complex, but also is apparently contradictory. For example, while PGs were initially characterized by stimulating bone resorption in culture, human and animal responses to PGs often include stimulation of bone formation (64). Collagen synthesis by osteoblasts can be both stimulated (65) or inhibited by PGs. Mechanical stress on bone cells leads to an increase in PG synthesis, suggesting that immobilization would be characterized by low PG levels (66). Nevertheless, immobilization is associated with PG-mediated bone loss, an effect that is slowed by NSAIDs.
PGs act on the modeling of bone in several ways. They stimulate the differentiation of precursors of both the bone resorbing cells (osteoclasts) and the bone-forming cells (osteoblasts), they stimulate bone resorption in vitro, and they stimulate bone growth when given exogenously in vivo (67). While little is known of how PG synthesis effects the balance between bone loss and formation, COX-2 induction in osteoblasts is reported to be essential to the acute stress response in a bone remodeling system (68). Bone loss is associated with inflammation in periodontal disease (69) and NSAIDs can slow this process (70). Cytokines associated with inflammation, including IL-1ß and IL-6 (72), have been found to induce both COX-2 and increase PG production when added to bone marrow cells in culture. In response, osteoclasts are induced to differentiate from their stem cell precursors. Osteoblasts and marrow stromal cells are the site of COX-2 induction and are further activated by the increased production of PGs. Other cytokines, for example IL-4 and IL-13, appear to suppress this response (73). Other inducers of COX-2 include parathyroid hormone (74), an important regulator of calcium metabolism, vibrational forces (75) and pulsating fluid flow (66), both of which are thought to model physical forces associated with mechanical stress on bone. Thus, it appears that stimuli that lead to both breakdown and building of bone use the same basic pathways to activate the bone remodeling system and that in bone PGs are responsible for ensuring that this resorption and formation occur coordinately, preventing an imbalance between these two processes.
Inflammation and arthritis
Although the importance of COX activity in the production of PGs has been known since 1967 (76), the inducibility of this activity and the central role of this induction in the amplification of inflammation have been fully appreciated only recently (77). Evidence provided by animal models of inflammatory arthritis strongly suggests that increased expression of COX-2 is responsible for increased PG production seen in inflamed joint tissues (78). COX-2 induction has been observed in both human osteoarthritis-affected cartilage (79) as well as in synovial tissue taken from patients afflicted with rheumatoid arthritis (80). Cell culture experiments utilizing primary cells derived from human synovial tissue or cell types (e.g., monocytes) important in inflammatory processes have been critical to an understanding of factors involved in modulating this induction. The pro-inflammatory agents IL-1, TNF-, and LPS, as well as the growth factors TGF-ß, EGF, PDGF, and FGF, have all been shown to induce COX-2 expression in this system. On the other hand, the antiinflammatory cytokines IL-4 and IL-13, as well as the immunosuppresive glucocorticoids, were shown to decrease COX-2 levels (20).
Although the synovial tissues of patients with osteoarthritis express lesser amounts of COX-2, primary explant cultures of human osteoarthritis-affected cartilage spontaneously express large amounts of COX-2 and PGs (79). Nitric oxide, another important inflammatory modulator, has been shown to regulate PG production in osteoarthritic cartilage, though not in synovial cells. Whether this modulation attenuates or enhances COX activity remains controversial (79, 81).
The rapid expansion of knowledge about the role of COX-2 in inflammation led to drug screens attempting to identify antiinflammatory agents selective for COX-2 as well as to the rational design of highly selective COX-2 inhibitors (82). The availability of these COX-2 inhibitors has now allowed for the design of studies that could directly determine the importance of COX-2 in inflammatory disease. COX-2 is reported to be central to the inflammatory process and COX-2 inhibition is sufficient to achieve the same therapeutic endpoints found with less specific inhibitors that also target COX-1(83).
Pain
Local tissue injury and inflammatory diseases like osteoarthritis are associated with increased PGs, and pain receptors are known to be sensitized to lower levels of stimulus by PGs (84). Thus, the action of COX at the site of injury or inflammation is hyperalgesic, and the pain-relieving action of NSAIDs at the local site is easily explained by this mechanism. In addition, PGs are thought to act in the spinal cord to facilitate the transmission of pain responses, though there is little known about how they might do this (85). NSAIDs can also act at these central sites (86–88).
COX-2 is induced in both local and central sites (89), and the question of whether COX-2 mediates pain reception or transmission is being investigated, primarily through the use of COX-2 specific NSAIDs. Intrathecal injection of both the COX-2 specific inhibitor NS-398 and the nonspecific NSAID indomethacin suppressed a formalin-mediated pain response (which measures a central response), but neither suppressed a high temperature-induced pain response (i.e., a local response) (85). In contrast, systematically administered meloxicam, an NSAID more specific for COX-2 than COX-1, suppressed the inflammatory pain response locally (90) without affecting central pain transmission. In neither of these studies was the drug introduced into both sites to allow an internal comparison, but together they show that COX-2 can act both locally and centrally to mediate pain. In fact, the COX-2 specific inhibitor Celecoxib was shown in short-term human studies to effectively suppress the pain associated with dental work, osteoarthritis, or rheumatoid arthritis without causing any significant gastroduodenal lesions (91, 92).
Alzheimer's Disease
NSAID use reduces risk for Alzheimer's Disease (AD), with users of these agents having as little as one half the risk of acquiring AD as those not taking NSAIDs (93–95). A few studies that attempt to identify a role for COX in the etiology of AD have followed up this observation. Evidence of inflammatory mediators and activated microglia at the sites of AD lesions offer the possibility that chronic inflammation could directly cause neural damage, but other evidence contradicts this as the central mechanism (96–97). Tocco et al. (42) have described the appearance during rat brain development of COX-2 induction in response to kainic acid-induced seizures. Notably, the neurons that express COX-2 also show evidence of apoptosis. These links between high NMDA-mediated neural activity, COX-2 induction, and cell death, may prove to be causal in AD. Breitner (97) has pointed out that the A fragment of the amyloid precursor protein found in plaques associated with AD increases the excitotoxicity associated with this pathway.
On the other hand, the anti-thrombotic activity of PGs may be important for protection against AD. For example, de la Torre (98) has hypothesized that AD is caused by the development of tortuous and flow-impeded capillaries in the brain. This would presumably promote intravascular coagulation, leading to ischemic damage in the brain that could promote the development of AD. It seems likely that clinical trials of COX-2 specific NSAIDs will be started before a role of COX-2 in AD is proved, but the mechanistic studies already under way will provide insight and direction for further developments.
Cancer
Several population-based studies have detected a 40–50% decrease in relative risk for colorectal cancer in persons who regularly use aspirin and other NSAIDs (99–103). Clinical trials with NSAIDs in patients with Familial Adenomatous Polyposis have clearly demonstrated that NSAID treatment caused regression of pre-existing adenomas (104). Studies in a variety of animal models (both genetic and carcinogen-induced) of colon cancer have also indicated a significant reduction in tumor multiplicity by NSAID treatment (105). In fact, some of these studies have shown as much as a 80–90% reduction in tumor burden (106).
Initial attempts to determine the molecular basis for these observations found that both human and animal colorectal tumors express high levels of COX-2, whereas the normal intestinal mucosa has low to undetectable COX-2 expression (13, 107–109). These findings led to the hypothesis that COX-2 may be playing a role in colon cancer growth and progression. Subsequent experiments appear to support this view. For example, the effects of a highly selective COX-2 inhibitor (SC-58125) was tested on two different cell lines, only one of which has a high level of COX-2 expression and activity. It was observed that the inhibitor decreased cell growth in both in vitro and in vivo assays only in the COX-2-expressing cell line (110–111). Other work in cell culture models has shown that COX-2 expression contributes significantly to the tumorigenic potential of epithelial cells by increasing adhesion to extracellular matrix and making them resistant to apoptosis (112). These phenotypic changes were shown to be reversible by treatment with a highly selective COX-2 inhibitor (106). Very recent work indicates that cyclooxygenase may play a vital role in the regulation of angiogenesis associated with neoplastic tumor cells (113). Hence, COX inhibitors may block the growth of blood vessels into developing tumors.
Genetic evidence supporting a role for COX-2 in the development of intestinal neoplasia has also been reported. Oshima et al. (114) assessed the development of intestinal adenomas in Apc
716 mice (a model in which a targeted truncation deletion in the tumor suppresser gene APC causes intestinal polyposis) in a wild-type and homozygous null COX-2 genetic background. The number and size of polyps were reduced dramatically (six- to eightfold) in the COX-2 null mice compared with COX-2 wild-type mice. In addition, treatment of the Apc716 mice with a novel COX-2 inhibitor, Merck Frosst tricyclic, reduced polyp number more significantly than the non-selective NSAID, sulindac (114).
Whether NSAIDs block tumor progression solely by blocking PG synthesis is a matter still being debated. Several studies have shown that NSAIDs can act through mechanisms that are independent of their ability to inhibit COX (115–117). Most of this work has been done in cell culture models where effects are only seen at fairly high concentrations of drug (200–1000 µM). Recently, animal studies have been reported that demonstrate the ability of sulindac sulfone to have protective effects against mammary tumors (116). Sulindac sulfone is a metabolite of the NSAID sulindac, which lacks the ability to inhibit COX directly. Therefore, some evidence indicates that COX-independent pathways also play an important role in the cancer chemopreventive properties of NSAIDs, and it is likely that both COX-dependent and -independent pathways are involved.
CONCLUSION
This discussion highlights the many physiological systems in which the COX enzymes play functional roles. The precise mechanisms by which this biosynthetic pathway can mediate such diverse functions is largely unknown and will likely remain so until researchers can more fully characterize the biology of the various PG synthases and receptors downstream of COX. Nevertheless, identifying an inducible COX was a major breakthrough in this area. What evolved from this discovery was a paradigm in which one isoform, COX-1, was mainly responsible for the biosynthesis of PGs involved in homeostatic regulation, while the second isoform, COX-2, was primarily involved in producing PGs in response to a wide spectrum of environmental insults and internal stimuli. Such a mechanism appears to explain, at least in part, both the therapeutic and toxic effects of NSAIDs in humans. The major side effects of NSAIDs, gastroduodenal erosion and disruption of normal renal function, appear to caused by the inhibition of COX-1, while the antiinflammatory and analgesic activity of these drugs rests largely on their ability to inhibit COX-2.
Investigations into the role of COX-2 in disease have suggested that chronic activation of this enzyme may be pathological in the colon, where there is strong evidence to suggest that inhibition of COX-2 can limit the progression of colorectal cancer. Thus, a little more than a century after the discovery of aspirin, the potential clinical indications for NSAID use appear to be widening from their original purpose as analgesic agents. Ongoing studies to more clearly delineate the role of each COX isoform in both health and disease will be crucial in defining the use of these drugs in the next century.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations: NSAIDs, nonsteroidal antiinflammatory drugs; COX, cyclooxygenase; PGs, proinflammatory prostaglandins; TX, thromboxane.
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REFERENCES |
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716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2). Cell 87, 803–809[Medline]
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 L. Yu, W. K. K. Wu, Z. J. Li, H. P. S. Wong, E. K. K. Tai, H. T. Li, Y. C. Wu, and C. H. Cho E Series of Prostaglandin Receptor 2-Mediated Activation of Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Is Required for the Mitogenic Action of Prostaglandin E2 in Esophageal Squamous-Cell Carcinoma J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 258 - 267. [Abstract] [Full Text] [PDF]
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 J. Zhang and C. Chen Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation J. Biol. Chem., August 15, 2008; 283(33): 22601 - 22611. [Abstract] [Full Text] [PDF]
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 C.-C. Ho, Y.-C. Ling, L. W. Chang, H.-T. Tsai, M.-H. Tsai, and P. Lin 17-Beta Estradiol and Hydroxyestradiols Interact via the NF-Kappa B Pathway to Elevate Cyclooxygenase 2 Expression and Prostaglandin E2 Secretion in Human Bronchial Epithelial Cells Toxicol. Sci., August 1, 2008; 104(2): 294 - 302. [Abstract] [Full Text] [PDF]
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 T. Bryn, S. Yaqub, M. Mahic, K. Henjum, E. M. Aandahl, and K. Tasken LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism Int. Immunol., February 1, 2008; 20(2): 235 - 245. [Abstract] [Full Text] [PDF]
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 Y.-S. Piao, Y.-C. Du, H. Oshima, J.-C. Jin, M. Nomura, T. Yoshimoto, and M. Oshima Platelet-type 12-lipoxygenase accelerates tumor promotion of mouse epidermal cells through enhancement of cloning efficiency Carcinogenesis, February 1, 2008; 29(2): 440 - 447. [Abstract] [Full Text] [PDF]
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 J.-Y. Qian, P. Harding, Y. Liu, E. Shesely, X.-P. Yang, and M. C. LaPointe Reduced Cardiac Remodeling and Function in Cardiac-Specific EP4 Receptor Knockout Mice With Myocardial Infarction Hypertension, February 1, 2008; 51(2): 560 - 566. [Abstract] [Full Text] [PDF]
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H. E. Hollingshead, M. G. Borland, A. N. Billin, T. M. Willson, F. J. Gonzalez, and J. M. Peters Ligand activation of peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms Carcinogenesis, January 1, 2008; 29(1): 169 - 176. [Abstract] [Full Text] [PDF]
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 M. Yamashita, T. Shinohara, S. Tsuji, Q. N. Myrvik, A. Nishiyama, R. A. Henriksen, and Y. Shibata Catalytically Inactive Cyclooxygenase 2 and Absence of Prostaglandin E2 Biosynthesis in Murine Peritoneal Macrophages following In Vivo Phagocytosis of Heat-Killed Mycobacterium bovis Bacillus Calmette-Guerin J. Immunol., November 15, 2007; 179(10): 7072 - 7078. [Abstract] [Full Text] [PDF]
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M. Joo, M. Kwon, R. T. Sadikot, P. J. Kingsley, L. J. Marnett, T. S. Blackwell, R. S. Peebles Jr, Y. Urade, and J. W. Christman Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity J. Immunol., August 15, 2007; 179(4): 2565 - 2575. [Abstract] [Full Text] [PDF]
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 A. S.J. Yeoh, R. J. Gibson, E. E.K. Yeoh, J. M. Bowen, A. M. Stringer, K. A. Giam, and D. M.K. Keefe A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-{kappa}B, COX-1, and COX-2 Mol. Cancer Ther., August 1, 2007; 6(8): 2319 - 2327. [Abstract] [Full Text] [PDF]
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 S. Donnini, F. Finetti, R. Solito, E. Terzuoli, A. Sacchetti, L. Morbidelli, P. Patrignani, and M. Ziche EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways FASEB J, August 1, 2007; 21(10): 2418 - 2430. [Abstract] [Full Text] [PDF]
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L. W. Chang, Y.-C. Chang, C.-C. Ho, M.-H. Tsai, and P. Lin Increase of carcinogenic risk via enhancement of cyclooxygenase-2 expression and hydroxyestradiol accumulation in human lung cells as a result of interaction between BaP and 17-beta estradiol Carcinogenesis, July 1, 2007; 28(7): 1606 - 1612. [Abstract] [Full Text] [PDF]
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M. Yamashita, S. Tsuji, A. Nishiyama, Q. N. Myrvik, R. A. Henriksen, and Y. Shibata Differential subcellular localization of COX-2 in macrophages phagocytosing heat-killed Mycobacterium bovis BCG Am J Physiol Cell Physiol, July 1, 2007; 293(1): C184 - C190. [Abstract] [Full Text] [PDF]
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 L. S. Aroeira, A. Aguilera, J. A. Sanchez-Tomero, M. A. Bajo, G. del Peso, J. A. Jimenez-Heffernan, R. Selgas, and M. Lopez-Cabrera Epithelial to Mesenchymal Transition and Peritoneal Membrane Failure in Peritoneal Dialysis Patients: Pathologic Significance and Potential Therapeutic Interventions J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2004 - 2013. [Abstract] [Full Text] [PDF]
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S. S. Barbieri and B. B. Weksler Tobacco smoke cooperates with interleukin-1{beta} to alter {beta}-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo FASEB J, June 1, 2007; 21(8): 1831 - 1843. [Abstract] [Full Text] [PDF]
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E. M. Weinheimer, B. Jemiolo, C. C. Carroll, M. P. Harber, J. M. Haus, N. A. Burd, J. K. LeMoine, S. W. Trappe, and T. A. Trappe Resistance exercise and cyclooxygenase (COX) expression in human skeletal muscle: implications for COX-inhibiting drugs and protein synthesis Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2241 - R2248. [Abstract] [Full Text] [PDF]
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J. M. Bock, S. G. Menon, L. L. Sinclair, N. S. Bedford, P. C. Goswami, F. E. Domann, and D. K. Trask Celecoxib Toxicity Is Cell Cycle Phase Specific Cancer Res., April 15, 2007; 67(8): 3801 - 3808. [Abstract] [Full Text] [PDF]
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J.-Y. Liou, D. Ghelani, S. Yeh, and K. K. Wu Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3{varepsilon} Cancer Res., April 1, 2007; 67(7): 3185 - 3191. [Abstract] [Full Text] [PDF]
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L. Xu, C. Han, and T. Wu A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor-{delta} and Prostaglandin E2 Signaling Pathways for Human Cholangiocarcinoma Cell Growth J. Biol. Chem., November 10, 2006; 281(45): 33982 - 33996. [Abstract] [Full Text] [PDF]
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F. Cianchi, C. Cortesini, L. Magnelli, E. Fanti, L. Papucci, N. Schiavone, L. Messerini, A. Vannacci, S. Capaccioli, F. Perna, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2716 - 2726. [Abstract] [Full Text] [PDF]
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M. Tong, Y. Ding, and H.-H. Tai Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells Carcinogenesis, November 1, 2006; 27(11): 2170 - 2179. [Abstract] [Full Text] [PDF]
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 M. R. Hill, A. Papafili, H. Booth, P. Lawson, M. Hubner, H. Beynon, C. Read, G. Lindahl, R. P. Marshall, R. J. McAnulty, et al. Functional Prostaglandin-Endoperoxide Synthase 2 Polymorphism Predicts Poor Outcome in Sarcoidosis Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 915 - 922. [Abstract] [Full Text] [PDF]
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H. Oshima, M. M. Taketo, and M. Oshima Destruction of Pancreatic beta-Cells by Transgenic Induction of Prostaglandin E2 in the Islets J. Biol. Chem., September 29, 2006; 281(39): 29330 - 29336. [Abstract] [Full Text] [PDF]
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S. F. G. van Helden, D. J. E. B. Krooshoop, K. C. M. Broers, R. A. P. Raymakers, C. G. Figdor, and F. N. van Leeuwen A Critical Role for Prostaglandin E2 in Podosome Dissolution and Induction of High-Speed Migration during Dendritic Cell Maturation J. Immunol., August 1, 2006; 177(3): 1567 - 1574. [Abstract] [Full Text] [PDF]
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R. A. Davies, B. Knight, Y. W. Tian, G. C.T. Yeoh, and J. K. Olynyk Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor Carcinogenesis, August 1, 2006; 27(8): 1607 - 1616. [Abstract] [Full Text] [PDF]
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R. Martin-Venegas, S. Roig-Perez, R. Ferrer, and J. J. Moreno Arachidonic acid cascade and epithelial barrier function during Caco-2 cell differentiation J. Lipid Res., July 1, 2006; 47(7): 1416 - 1423. [Abstract] [Full Text] [PDF]
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J. R. Mann, M. G. Backlund, F. G. Buchanan, T. Daikoku, V. R. Holla, D. W. Rosenberg, S. K. Dey, and R. N. DuBois Repression of Prostaglandin Dehydrogenase by Epidermal Growth Factor and Snail Increases Prostaglandin E2 and Promotes Cancer Progression. Cancer Res., July 1, 2006; 66(13): 6649 - 6656. [Abstract] [Full Text] [PDF]
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J Mrena, J-P Wiksten, S Nordling, A Kokkola, A Ristimaki, and C Haglund MMP-2 but not MMP-9 associated with COX-2 and survival in gastric cancer. J. Clin. Pathol., June 1, 2006; 59(6): 618 - 623. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, N. K. Narayanan, L. Davis, and D. Nargi RNA interference-mediated cyclooxygenase-2 inhibition prevents prostate cancer cell growth and induces differentiation: modulation of neuronal protein synaptophysin, cyclin D1, and androgen receptor Mol. Cancer Ther., May 1, 2006; 5(5): 1117 - 1125. [Abstract] [Full Text] [PDF]
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J. Huh, A. Liepins, J. Zielonka, C. Andrekopoulos, B. Kalyanaraman, and A. Sorokin Cyclooxygenase 2 Rescues LNCaP Prostate Cancer Cells from Sanguinarine-Induced Apoptosis by a Mechanism Involving Inhibition of Nitric Oxide Synthase Activity. Cancer Res., April 1, 2006; 66(7): 3726 - 3736. [Abstract] [Full Text] [PDF]
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B. Miller, V. A. Patel, and A. Sorokin Cyclooxygenase-2 Rescues Rat Mesangial Cells from Apoptosis Induced by Adriamycin via Upregulation of Multidrug Resistance Protein 1 (P-Glycoprotein) J. Am. Soc. Nephrol., April 1, 2006; 17(4): 977 - 985. [Abstract] [Full Text] [PDF]
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A. Castells, A. Paya, C. Alenda, F. Rodriguez-Moranta, R. Agrelo, M. Andreu, V. Pinol, S. Castellvi-Bel, R. Jover, X. Llor, et al. Cyclooxygenase 2 expression in colorectal cancer with DNA mismatch repair deficiency. Clin. Cancer Res., March 15, 2006; 12(6): 1686 - 1692. [Abstract] [Full Text] [PDF]
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T. Chen, H. Hwang, M. E. Rose, R. G. Nines, and G. D. Stoner Chemopreventive Properties of Black Raspberries in N-Nitrosomethylbenzylamine-Induced Rat Esophageal Tumorigenesis: Down-regulation of Cyclooxygenase-2, Inducible Nitric Oxide Synthase, and c-Jun. Cancer Res., March 1, 2006; 66(5): 2853 - 2859. [Abstract] [Full Text] [PDF]
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R. Suzuki, H. Kohno, M. Suzui, N. Yoshimi, H. Tsuda, K. Wakabayashi, and T. Tanaka An animal model for the rapid induction of tongue neoplasms in human c-Ha-ras proto-oncogene transgenic rats by 4-nitroquinoline 1-oxide: its potential use for preclinical chemoprevention studies Carcinogenesis, March 1, 2006; 27(3): 619 - 630. [Abstract] [Full Text] [PDF]
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A. J. Tyson-Capper and G. N. Europe-Finner Novel Targeting of Cyclooxygenase-2 (COX-2) Pre-mRNA Using Antisense Morpholino Oligonucleotides Directed to the 3' Acceptor and 5' Donor Splice Sites of Exon 4: Suppression of COX-2 Activity in Human Amnion-Derived WISH and Myometrial Cells Mol. Pharmacol., March 1, 2006; 69(3): 796 - 804. [Abstract] [Full Text] [PDF]
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G. D'Orazi, M. G. Sciulli, V. Di Stefano, S. Riccioni, M. Frattini, R. Falcioni, L. Bertario, A. Sacchi, and P. Patrignani Homeodomain-Interacting Protein Kinase-2 Restrains Cytosolic Phospholipase A2-Dependent Prostaglandin E2 Generation in Human Colorectal Cancer Cells Clin. Cancer Res., February 1, 2006; 12(3): 735 - 741. [Abstract] [Full Text] [PDF]
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I. Csiki, K. Yanagisawa, N. Haruki, S. Nadaf, J. D. Morrow, D. H. Johnson, and D. P. Carbone Thioredoxin-1 Modulates Transcription of Cyclooxygenase-2 via Hypoxia-Inducible Factor-1{alpha} in Non-Small Cell Lung Cancer Cancer Res., January 1, 2006; 66(1): 143 - 150. [Abstract] [Full Text] [PDF]
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S. Martin, D. C. Phillips, K. Szekely-Szucs, L. Elghazi, F. Desmots, and J. A. Houghton Cyclooxygenase-2 Inhibition Sensitizes Human Colon Carcinoma Cells to TRAIL-Induced Apoptosis through Clustering of DR5 and Concentrating Death-Inducing Signaling Complex Components into Ceramide-Enriched Caveolae Cancer Res., December 15, 2005; 65(24): 11447 - 11458. [Abstract] [Full Text] [PDF]
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H. Dalwadi, K. Krysan, N. Heuze-Vourc'h, M. Dohadwala, D. Elashoff, S. Sharma, N. Cacalano, A. Lichtenstein, and S. Dubinett Cyclooxygenase-2-Dependent Activation of Signal Transducer and Activator of Transcription 3 by Interleukin-6 in Non-Small Cell Lung Cancer Clin. Cancer Res., November 1, 2005; 11(21): 7674 - 7682. [Abstract] [Full Text] [PDF]
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A. Ferrario, A. M. Fisher, N. Rucker, and C. J. Gomer Celecoxib and NS-398 Enhance Photodynamic Therapy by Increasing In vitro Apoptosis and Decreasing In vivo Inflammatory and Angiogenic Factors Cancer Res., October 15, 2005; 65(20): 9473 - 9478. [Abstract] [Full Text] [PDF]
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Y. Lu and L. M. Wahl Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E2 through Enhancement of NF-{kappa}B Activity in Lipopolysaccharide-Activated Human Primary Monocytes J. Immunol., October 15, 2005; 175(8): 5423 - 5429. [Abstract] [Full Text] [PDF]
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J. Mrena, J.-P. Wiksten, A. Thiel, A. Kokkola, L. Pohjola, J. Lundin, S. Nordling, A. Ristimaki, and C. Haglund Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR Clin. Cancer Res., October 15, 2005; 11(20): 7362 - 7368. [Abstract] [Full Text] [PDF]
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K. P. Townsend and D. Pratico Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs FASEB J, October 1, 2005; 19(12): 1592 - 1601. [Abstract] [Full Text] [PDF]
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K. J. Sales, T. List, S. C. Boddy, A. R.W. Williams, R. A. Anderson, Z. Naor, and H. N. Jabbour A Novel Angiogenic Role for Prostaglandin F2{alpha}-FP Receptor Interaction in Human Endometrial Adenocarcinomas Cancer Res., September 1, 2005; 65(17): 7707 - 7716. [Abstract] [Full Text] [PDF]
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J. Moreno, A. V. Krishnan, S. Swami, L. Nonn, D. M. Peehl, and D. Feldman Regulation of Prostaglandin Metabolism by Calcitriol Attenuates Growth Stimulation in Prostate Cancer Cells Cancer Res., September 1, 2005; 65(17): 7917 - 7925. [Abstract] [Full Text] [PDF]
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S. I. Abdalla, I. R. Sanderson, and R. C. Fitzgerald Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells Carcinogenesis, September 1, 2005; 26(9): 1627 - 1633. [Abstract] [Full Text] [PDF]
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S.-G. Hwang, S.-S. Yu, H. Poo, and J.-S. Chun c-Jun/Activator Protein-1 Mediates Interleukin-1{beta}-induced Dedifferentiation but Not Cyclooxygenase-2 Expression in Articular Chondrocytes J. Biol. Chem., August 19, 2005; 280(33): 29780 - 29787. [Abstract] [Full Text] [PDF]
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D. Pratico and J.-M. Dogne Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine Circulation, August 16, 2005; 112(7): 1073 - 1079. [Full Text] [PDF]
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 J. Shi, N. L. A. Misso, D. L. Duffy, B. Bradley, R. Beard, P. J. Thompson, and M-A. Kedda Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy Eur. Respir. J., August 1, 2005; 26(2): 249 - 256. [Abstract] [Full Text] [PDF]
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 M. Lantz, T. Vondrichova, H. Parikh, C. Frenander, M. Ridderstrale, P. Asman, M. Aberg, L. Groop, and B. Hallengren Overexpression of Immediate Early Genes in Active Graves' Ophthalmopathy J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4784 - 4791. [Abstract] [Full Text] [PDF]
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K. Krysan, K. L. Reckamp, H. Dalwadi, S. Sharma, E. Rozengurt, M. Dohadwala, and S. M. Dubinett Prostaglandin E2 Activates Mitogen-Activated Protein Kinase/Erk Pathway Signaling and Cell Proliferation in Non-Small Cell Lung Cancer Cells in an Epidermal Growth Factor Receptor-Independent Manner Cancer Res., July 15, 2005; 65(14): 6275 - 6281. [Abstract] [Full Text] [PDF]
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K. B. Kilunga, T. Inoue, Y. Okano, Z. Kabututu, S. K. Martin, M. Lazarus, M. Duszenko, Y. Sumii, Y. Kusakari, H. Matsumura, et al. Structural and Mutational Analysis of Trypanosoma brucei Prostaglandin H2 Reductase Provides Insight into the Catalytic Mechanism of Aldo-ketoreductases J. Biol. Chem., July 15, 2005; 280(28): 26371 - 26382. [Abstract] [Full Text] [PDF]
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 E. Y. Fukuda, S. P. Lad, D. P. Mikolon, M. Iacobelli-Martinez, and E. Li Activation of Lipid Metabolism Contributes to Interleukin-8 Production during Chlamydia trachomatis Infection of Cervical Epithelial Cells Infect. Immun., July 1, 2005; 73(7): 4017 - 4024. [Abstract] [Full Text] [PDF]
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 P. A. Konstantinopoulos and D. F. Lehmann The Cardiovascular Toxicity of Selective and Nonselective Cyclooxygenase Inhibitors: Comparisons, Contrasts, and Aspirin Confounding J. Clin. Pharmacol., July 1, 2005; 45(7): 742 - 750. [Abstract] [Full Text] [PDF]
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J. Parent and M. A. Fortier Expression and Contribution of Three Different Isoforms of Prostaglandin E Synthase in the Bovine Endometrium Biol Reprod, July 1, 2005; 73(1): 36 - 44. [Abstract] [Full Text] [PDF]
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W. Dou, S. Thompson-Jaeger, S. J. F. Laulederkind, J. W. Becker, J. Montgomery, E. Ruiz-Bustos, D. L. Hasty, L. R. Ballou, P. S. Eastman, B. Srichai, et al. Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections Am J Physiol Renal Physiol, July 1, 2005; 289(1): F49 - F60. [Abstract] [Full Text] [PDF]
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M. Joo, Y. S. Hahn, M. Kwon, R. T. Sadikot, T. S. Blackwell, and J. W. Christman Hepatitis C Virus Core Protein Suppresses NF-{kappa}B Activation and Cyclooxygenase-2 Expression by Direct Interaction with I{kappa}B Kinase {beta} J. Virol., June 15, 2005; 79(12): 7648 - 7657. [Abstract] [Full Text] [PDF]
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H. Kim, S. H. Rhee, E. Kokkotou, X. Na, T. Savidge, M. P. Moyer, C. Pothoulakis, and J. T. LaMont Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK J. Biol. Chem., June 3, 2005; 280(22): 21237 - 21245. [Abstract] [Full Text] [PDF]
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 X. Zhang and A. H. Neufeld Activation of the Epidermal Growth Factor Receptor in Optic Nerve Astrocytes Leads to Early and Transient Induction of Cyclooxygenase-2 Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 2035 - 2041. [Abstract] [Full Text] [PDF]
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 E. M. Sievers, R. D. Bart, L. M. Backhus, Y. Lin, M. Starnes, R. Castanos, V. A. Starnes, and Ross. M. Bremner Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1242 - 1249. [Abstract] [Full Text] [PDF]
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Y. Denkins, D. Kempf, M. Ferniz, S. Nileshwar, and D. Marchetti Role of {omega}-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma J. Lipid Res., June 1, 2005; 46(6): 1278 - 1284. [Abstract] [Full Text] [PDF]
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 V. Mollace, C. Muscoli, E. Masini, S. Cuzzocrea, and D. Salvemini Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors Pharmacol. Rev., June 1, 2005; 57(2): 217 - 252. [Abstract] [Full Text] [PDF]
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M Fornai, C Blandizzi, R Colucci, L Antonioli, N Bernardini, C Segnani, B Baragatti, S Barogi, P Berti, R Spisni, et al. Role of cyclooxygenases 1 and 2 in the modulation of neuromuscular functions in the distal colon of humans and mice Gut, May 1, 2005; 54(5): 608 - 616. [Abstract] [Full Text] [PDF]
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