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Enhanced biosynthesis of prostaglandin (PG)D(2) and subsequent formation of 15-deoxy-Delta(12,14)-PGJ(2) has been suggested to contribute to resolution of inflammation. The primary aim of the present study in mouse heart was, therefore, to determine at the transcriptional level if there is sequential induction of PGE and PGD synthases (S) during inflammation. Expression of interleukin (IL)-1beta in heart was enhanced 4h after systemic inflammation and declined thereafter within 3-5 days to basal levels. In contrast to cyclooxygenase-2 and membrane-bound (m)-PGES-1, which both peaked 4h after endotoxin administration, hematopoietic (H)-PGDS expression was enhanced only >or=48h after endotoxin. The expression of lipocalin-type (L)-PGDS was not significantly influenced. mRNA encoding the putative target of 15-deoxy-Delta(12,14)-PGJ(2), peroxisome proliferator-activated receptor gamma, was enhanced between 4 and 24h after induction of inflammation. Treatment of mice with acetylsalicylic acid or indomethacin at doses effective to cause near-complete inhibition of PGE(2) and PGD(2) biosynthesis in heart ex vivo resulted in enhanced expression of IL-1beta 24h after endotoxin administration. These results provide additional support for the hypothesis of a shift towards PGD(2) biosynthesis during resolution of inflammation.
The inflammatory mediator prostaglandin E(2) (PGE(2)) is implicated in the pathogenesis of chronic inflammatory diseases including periodontitis; it is synthesized by cyclooxygenases (COX) and the prostaglandin E synthases mPGES-1, mPGES-2, and cPGES. The distribution of PGES in gingival tissue of patients with periodontitis and the contribution of these enzymes to inflammation-induced PGE(2) synthesis in different cell types was investigated. In gingival biopsies, positive staining for PGES was observed in fibroblasts and endothelial, smooth muscle, epithelial, and immune cells. To further explore the contribution of PGES to inflammation-induced PGE(2) production, in vitro cell culture experiments were performed using fibroblasts and endothelial, smooth muscle, and mast cells. All cell types expressed PGES and COX-2, resulting in basal levels of PGE(2) synthesis. In response to tumor necrosis factor (TNF-α), IL-1β, and cocultured lymphocytes, however, mPGES-1 and COX-2 protein expression increased in fibroblasts and smooth muscle cells, accompanied by increased PGE(2), whereas mPGES-2 and cPGES were unaffected. In endothelial cells, TNF-α increased PGE(2) production only via COX-2 expression, whereas in mast cells the cytokines did not affect PGE(2) enzyme expression or PGE(2) production. Furthermore, PGE(2) production was diminished in gingival fibroblasts derived from mPGES-1 knockout mice, compared with wild-type fibroblasts. These results suggest that fibroblasts and smooth muscle cells are important sources of mPGES-1, which may contribute to increased PGE(2) production in the inflammatory condition periodontitis.
Although cyclooxygenases (COX) and prostaglandin E synthases (PGES) have been implicated in ischemic stroke injury, little is known about their role in intracerebral hemorrhage (ICH)-induced brain damage. This study examines the expression and cellular localization of COX-1, COX-2, microsomal PGES-1 (mPGES-1), mPGES-2, and cytosolic PGES (cPGES) in mice that have undergone hemorrhagic brain injury.
Interleukin (IL)-1beta is a proinflammatory cytokine expressed in neural tissue following injury and in neurodegenerative states. To understand the consequences of its presence in brain, we carried out intraparenchymal IL-1beta injections and found significant increases in prostaglandin (PG)E2, a critical factor in inflammatory and physiological processes. Elevated mRNA and protein expression of the PGE2-synthetic-related enzymes cyclooxygenase (COX)-2 and membrane-associated PGE synthase (PGES) accompanied local PGE2 production. In addition, IL-1beta stimulated protein expression of cytosolic PGES. Finally, we showed attenuation of these IL-1beta-inductions by COX-2 inhibition, suggesting in vivo regulation of both PGE synthase isoforms in the brain.
Peripheral inflammation causes upregulation of cyclooxygenase in the spinal cord and subsequent increase in prostaglandin biosynthesis. However, prostaglandin synthases, which are downstream of cyclooxygenase control the type of prostaglandin that is formed predominantly. Since there is little known about the regulation of prostaglandin synthases, the present study was conducted in order to determine the effect of endotoxin treatment on the expression of messenger RNA encoding interleukin 1beta, cyclooxygenase-2, and prostaglandin synthases mediating the formation of prostaglandin E(2) (membrane bound prostaglandin E synthase) and prostaglandin D(2) (lipocalin prostaglandin D synthase) in spinal cord, dorsal root ganglia and skin of rats. Endotoxin (2 mg/kg i.p.) induced the expression of interleukin-1beta, cyclooxygenase-2, and membrane bound prostaglandin E synthase messenger RNA in spinal cord, dorsal root ganglia, and skin as determined by reverse transcription polymerase chain reaction. In contrast, basal expression of lipocalin prostaglandin D synthase messenger RNA in spinal cord and dorsal root ganglia was not significantly altered by endotoxin. Dexamethasone (1 mg/kg s.c. at -18 h and -1 h) attenuated the effect endotoxin on the expression of interleukin-1beta, cyclooxygenase-2, and membrane bound prostaglandin E synthase messenger RNA in all tissues investigated, but did not significantly influence expression of lipocalin prostaglandin D synthase mRNA in spinal cord and dorsal root ganglia. In situ hybridisation histochemistry showed endotoxin-induced expression of cyclooxygenase-2 and membrane bound prostaglandin E synthase messenger RNA throughout gray and white matter of spinal cord sections. In dorsal root ganglia, expression of membrane bound prostaglandin E synthase seemed primarily located to non-neuronal cells, while cyclooxygenase-2 messenger RNA was not detectable. The results show that the immune response elicited by endotoxin induced cyclooxygenase-2 and membrane bound prostaglandin E synthase, but not lipocalin prostaglandin D synthase messenger RNA in spinal cord and dorsal root ganglia of rats. The distribution of cyclooxygenase-2 and membrane bound prostaglandin E synthase messenger RNA expressing cells suggests major involvement of non-neuronal cells in spinal prostaglandin biosynthesis. Determination of the regulation of enzymes downstream of cyclooxygenase at the messenger RNA level may represent a valuable tool to investigate effects of analgesic/anti-inflammatory drugs on the regulation of spinal prostaglandin biosynthesis.
Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and prostacyclin (PGI2) synthase (PGIS) are PG terminal synthases that work downstream of cyclooxygenase and synthesize PGE2 and PGI2, respectively. Although the involvement of PG receptors in acquired cutaneous immune responses was recently shown, the roles of these PG terminal synthases remain unclear. To identify the pathophysiological roles of mPGES-1 and PGIS in cutaneous immune systems, we applied contact hypersensitivity (CHS) to mPGES-1 and PGIS knockout (KO) mice as a model of acquired immune responses. Mice were treated with 1-fluoro-2,4-dinitrobenzene (DNFB) and evaluated for ear thickness and histopathological features. The results showed that the severity of ear swelling in both gene-deficient mice was much lower than that in wild-type (WT) mice. Histological examination of DNFB-treated ears showed that inflammatory cell infiltration and edema in the dermis were also less apparent in both genotypic mice. LC-MS analysis further showed that the increment in PGE2 levels in DNFB-treated ear tissue was reduced in mPGES-1 KO mice, and that 6-keto PGF1α (a stable metabolite of PGI2) was not detected in PGIS KO mice. Furthermore, we made bone marrow (BM) chimera and found that transplantation of WT mouse-derived BM cells restored the impaired CHS response in mPGES-1 KO mice but did not restore the response in PGIS KO mice. These results indicated that mPGES-1 in BM-derived cells and PGIS in non-BM-derived cells might play critical roles in DNFB-induced CHS. mPGES-1-derived PGE2 and PGIS-derived PGI2 might coordinately promote acquired cutaneous immune responses.
Cyclooxygenase (COX)-2 expression and release of prostaglandins (PGs) by macrophages are consistent features of lipopolysaccharide (LPS)-induced macrophage inflammation. The two major PGs, PGE(2) and PGD(2), are synthesized by the prostanoid isomerases, PGE synthases (PGES) and PGD synthases (PGDS), respectively. Since the expression profile and the individual role of these prostanoid isomerases-mediated inflammation in macrophages has not been defined, we examined the LPS-stimulated PGs production pattern and the expression profile of their synthases in the primary cultured mouse bone marrow derived macrophages (BMDM). Our data show that LPS induced both PGE(2) and PGD(2) production, which was evident by ∼8 hrs and remained at a similar ratio (∼1∶1) in the early phase (≤12 hrs) of LPS treatment. However, PGE(2) production continued increase further in the late phase (16-24 hrs); whereas the production of PGD(2) remained at a stable level from 12 to 24 hrs post-treatment. In response to LPS-treatment, the expression of both COX-2 and inducible nitric oxide synthase (iNOS) was detected within 2 to 4 hrs; whereas the increased expression of microsomal PGES (mPGES)-1 and a myeloid cell transcription factor PU.1 did not appear until later phase (≥12 hrs). In contrast, the expression of COX-1, hematopoietic-PGDS (H-PGDS), cytosolic-PGES (c-PGES), or mPGES-2 in BMDM was not affected by LPS treatment. Selective inhibition of mPGES-1 with either siRNA or isoform-selective inhibitor CAY10526, but not mPGES-2, c-PGES or PU.1, attenuated LPS-induced burst of PGE(2) production indicating that mPGES-1 mediates LPS-induced PGE(2) production in BMDM. Interestingly, selective inhibition of mPGES-1 was also associated with a decrease in LPS-induced iNOS expression. In summary, our data show that mPGES-1, but not mPGES-2 or c-PGES isomerase, mediates LPS-induced late-phase burst of PGE(2) generation, and regulates LPS-induced iNOS expression in BMDM.
Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects.
Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT.
We have recently reported that cyclooxygenase (COX)-2-deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E2 (PGE2), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A2 enzymes (cPLA2 and sPLA2), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and - 2) in wild type and COX-1(-/-) mice. We found that brain PGE2 concentration was significantly increased, whereas thromboxane B2 (TXB2) concentration was decreased in COX-1(-/-) mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-kappaB pathway, and also an increase in the upstream cPLA2 and sPLA2 enzymes. The mechanism of NF-kappaB activation in the COX-1(-/-) mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-kappaB, as well as the increased protein levels of phosphorylated IkappaBalpha and of phosphorylated IKKalpha/beta. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE2 production being metabolically coupled with COX-2 and TXB2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca2+ -dependent PLA2, and terminal mPGES-2, to overcome defects in brain AA cascade.
Prostaglandin E2 (PGE2) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor alpha (TNFalpha) induces PGE2 synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNFalpha-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE2-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE2 production.
The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant Braf(V600E) mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways. This mouse COX-dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing for COX activity as a driver of immune suppression across species. Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients.
Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%-30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.
Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans.
Keel fracture has negative effects on the health and welfare of laying hens. We investigated effects of keel fracture on stress, inflammation, and the orexin system in laying hens. Ninety 17-week-old Lohmann white laying hens were palpated and euthanatized at 42 weeks old, and marked as normal keel (NK)/fractured keel (FK) from absence/presence of keel fracture. Serum, brain, liver, and abdominal-muscle samples were collected from 10 NK and 10 FK hens to determine the stress and inflammatory responses and the activity of orexin systems by corticosterone content, expression of heat shock proteins (TNF-α 60, 70, 90), and inflammatory factors (tumor necrosis factor (TNF)-α, nuclear factor-kappa Bp65 (NF-κBp65), inducible nitric oxide synthase (iNOS), prostaglandin E synthases (PTGEs), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β)), orexin (ORX), and orexin-receptor 1/2 (ORXR1/ORXR2). The FK hens had higher serum corticosterone content, Hsps, and inflammatory factor mRNA expression levels than NK hens, although levels of iNOS in the liver and TNF-α in the muscle were similar. Protein levels of Hsp70 and Hsp90 in the brain and liver, iNOS and COX-2 in the liver, NF-κBp65, iNOS, and COX-2 in the brain of FK hens were increased compared with NK hens. Furthermore, FK hens had lower mRNA expression of ORX, ORXR1, and ORXR2 than NK hens. Therefore, keel fracture causes stress and inflammation, and inhibits the expression of the orexin system in laying hens.
Cyclooxygenases (COX), prostaglandin E(2) (PGE(2)) and nitric oxide (NO) are believed to be some of the most important factors related to colon cancer growth and metastasis. In this study, we aimed to investigate the associations between COX-2, PGE(2) and NO in co-cultures of human colon cancer spheroids obtained from different tumor grades with normal human colonic epithelium and myofibroblast monolayers. L-arginine (2 mM), a substrate for nitric oxide synthases (NOS), decreased COX-2 and PGE(2) levels, while N( G )-nitro-L-arginine methyl ester (L-NAME) (2 mM), a NOS inhibitor, had no influence on COX-2 and PGE(2) levels but limited tumor cell motility. NS398 (75 μM), a selective COX-2 inhibitor, had no significant influence on NO level but decreased motility of tumor cells. COX-2, PGE(2) and NO levels depended on the tumor grade of the cells, being the highest in Duke's stage III colon carcinoma. Summing up, we showed that addition of L-arginine at doses which did not stimulate NO level caused a significant decrease in COX-2 and PGE(2) amounts in co-cultures of colon tumor spheroids with normal epithelial cells and myofibroblasts. Any imbalances in NO level caused by exogenous factors influence COX-2 and PGE(2) amounts depending on the kind of cells, their reciprocal interactions and the local microenvironmental conditions. The knowledge of these effects may be useful in limiting colon carcinoma progression and invasion.
Dermal exposure to sulfur mustard causes inflammation and tissue injury. This is associated with changes in expression of antioxidants and eicosanoids which contribute to oxidative stress and toxicity. In the present studies we analyzed mechanisms regulating expression of these mediators using an in vitro skin construct model in which mouse keratinocytes were grown at an air-liquid interface and exposed directly to 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. CEES (100-1000 microM) was found to cause marked increases in keratinocyte protein carbonyls, a marker of oxidative stress. This was correlated with increases in expression of Cu,Zn superoxide dismutase, catalase, thioredoxin reductase and the glutathione S-transferases, GSTA1-2, GSTP1 and mGST2. CEES also upregulated several enzymes important in the synthesis of prostaglandins and leukotrienes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), prostaglandin D synthase (PGDS), 5-lipoxygenase (5-LOX), leukotriene A(4) (LTA(4)) hydrolase and leukotriene C(4) (LTC(4)) synthase. CEES readily activated keratinocyte JNK and p38 MAP kinases, signaling pathways which are known to regulate expression of antioxidants, as well as prostaglandin and leukotriene synthases. Inhibition of p38 MAP kinase suppressed CEES-induced expression of GSTA1-2, COX-2, mPGES-2, PGDS, 5-LOX, LTA(4) hydrolase and LTC(4) synthase, while JNK inhibition blocked PGDS and GSTP1. These data indicate that CEES modulates expression of antioxidants and enzymes producing inflammatory mediators by distinct mechanisms. Increases in antioxidants may be an adaptive process to limit tissue damage. Inhibiting the capacity of keratinocytes to generate eicosanoids may be important in limiting inflammation and protecting the skin from vesicant-induced oxidative stress and injury.
Ammonia (NH3), a toxic gas, has deleterious effects on chicken health in intensive poultry houses. MicroRNA can mediate inflammation. The complex molecular mechanisms underlying NH3 inhalation-caused inflammation in animal kidneys are still unknown. To explore the mechanisms, a broiler model of NH3 exposure was established. Kidney samples were collected on day 14, 28, and 42, and meat yield was evaluated on day 42. We performed histopathological examination, detected miR-6615-5p and mothers against decapentaplegic homolog 7 (Smad7), and determined inflammatory factors and cytokines in kidneys. The results showed that excess NH3 reduced breast weight and thigh weight, which indicated that excess NH3 impaired meat yield of broilers. Besides, kidney tissues displayed histopathological changes after NH3 exposure. Meanwhile, the increases of inducible nitric oxide synthase (iNOS) activity and nitric oxide content were obtained. The mRNA and protein expression of inflammatory factors, including nuclear factor-κB (NF-κB), cyclooxygenase-2, prostaglandin E synthases, and iNOS increased, indicating that NF-κB pathway was activated. T-helper (Th) 1 and regulatory T (Treg) cytokines were downregulated, whereas Th2 and Th17 cytokines were upregulated, suggesting the occurrence of Th1/Th2 and Treg/Th17 imbalances. In addition, we found that Smad7 was a target gene of miR-6615-5p in chickens. After NH3 exposure, miR-6615-5p expression was elevated, and Smad7 mRNA and protein expression were reduced. In summary, our results suggest that NH3 exposure negatively affected meat yield; and miR-6615/Smad7 axis and immune imbalance participated in NH3-induced inflammatory injury via the NF-κB pathway in broiler kidneys. This study is helpful to understand the mechanism of NH3-induced kidney injury and is meaningful to poultry health and breed aquatics.
In sheep, the uterus produces luteolytic pulses of prostaglandin F2alpha (PGF) on Days 15 to 16 of estrous cycle to regress the corpus luteum (CL). These PGF pulses are produced by the endometrial lumenal epithelium (LE) and superficial ductal glandular epithelium (sGE) in response to binding of pituitary and/or luteal oxytocin to oxytocin receptors (OTR) and liberation of arachidonic acid, the precursor of PGF. Cyclooxygenase-one (COX-1) and COX-2 are rate-limiting enzymes in PGF synthesis, and COX-2 is the major form expressed in ovine endometrium. During pregnancy recognition, interferon tau (IFNtau), produced by the conceptus trophectoderm, acts in a paracrine manner to suppress development of the endometrial epithelial luteolytic mechanism by inhibiting transcription of estrogen receptor alpha (ERalpha) (directly) and OTR (indirectly) genes. Conflicting studies indicate that IFNtau increases, decreases or has no effect on COX-2 expression in bovine and ovine endometrial cells. In Study One, COX-2 mRNA and protein were detected solely in endometrial LE and sGE of both cyclic and pregnant ewes. During the estrous cycle, COX-2 expression increased from Days 10 to 12 and then decreased to Day 16. During early pregnancy, COX-2 expression increased from Days 10 to 12 and remained higher than in cyclic ewes. In Study Two, intrauterine infusion of recombinant ovine IFNtau in cyclic ewes from Days 11 to 16 post-estrus did not affect COX-2 expression in the endometrial epithelium. These results clearly indicate that IFNtau has no effect on expression of the COX-2 gene in the ovine endometrium. Therefore, antiluteolytic effects of IFNtau are to inhibit ERalpha and OTR gene transcription, thereby preventing endometrial production of luteolytic pulses of PGF. Indeed, expression of COX-2 in the endometrial epithelia as well as conceptus is likely to have a beneficial regulatory role in implantation and development of the conceptus.
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