scholarly journals Deciphering the functional role of EGR1 in Prostaglandin F2 alpha induced luteal regression applying CRISPR in corpus luteum of buffalo

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Meeti Punetha ◽  
Sai Kumar ◽  
Avishek Paul ◽  
Bosco Jose ◽  
Jaya Bharati ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Corpus Luteum ◽  
Caspase 3 ◽  
Cellular Proliferation ◽  
Luteal Cell ◽  
Wild Type ◽  
Luteal Regression ◽  
Luteal Cells ◽  
Prostaglandin F2 Alpha

Abstract Background PGF2α is essential for the induction of the corpus luteum regression which in turn reduces progesterone production. Early growth response (EGR) proteins are Cys2-His2-type zinc-finger transcription factor that are strongly linked to cellular proliferation, survival and apoptosis. Rapid elevation of EGR1 was observed after luteolytic dose of PGF2α. EGR1 is involved in the transactivation of many genes, including TGFβ1, which plays an important role during luteal regression. Methods The current study was conducted in buffalo luteal cells with the aim to better understand the role of EGR1 in transactivation of TGFβ1 during PGF2α induced luteal regression. Luteal cells from mid stage corpus luteum of buffalo were cultured and treated with different doses of PGF2α for different time durations. Relative expression of mRNAs encoding for enzymes within the progesterone biosynthetic pathway (3βHSD, CYP11A1 and StAR); Caspase 3; AKT were analyzed to confirm the occurrence of luteolytic event. To determine if EGR1 is involved in the PGF2α induced luteal regression via induction of TGFβ1 expression, we knocked out the EGR1 gene by using CRISPR/Cas9. Result The present experiment determined whether EGR1 protein expression in luteal cells was responsive to PGF2α treatment. Quantification of EGR1 and TGFβ1 mRNA showed significant up regulation in luteal cells of buffalo at 12 h post PGF2α induction. In order to validate the role of PGF2α on stimulating the expression of TGFβ1 by an EGR1 dependent mechanism we knocked out EGR1. The EGR1 ablated luteal cells were stimulated with PGF2α and it was observed that EGR1 KO did not modulate the PGF2α induced expression of TGFβ1. In PGF2α treated EGR1 KO luteal cell, the mRNA expression of Caspase 3 was significantly increased compared to PGF2α treated wild type luteal cells maintained for 12 h. We also studied the influence of EGR1 on steroidogenesis. The EGR1 KO luteal cells with PGF2α treatment showed no substantial difference either in the progesterone concentration or in StAR mRNA expression with PGF2α-treated wild type luteal cells. Conclusion These results suggest that EGR1 signaling is not the only factor which plays a role in the regulation of PGF2α induced TGFβ1 signaling for luteolysis.

scholarly journals HIF-1α Activation Promotes Luteolysis by Enhancing ROS Levels in the Corpus Luteum of Pseudopregnant Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Zonghao Tang ◽  
Jiajie Chen ◽  
Zhenghong Zhang ◽  
Jingjing Bi ◽  
Renfeng Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Corpus Luteum ◽  
Cell Apoptosis ◽  
In Vitro Study ◽  
Luteal Cell ◽  
Independent Manner ◽  
Luteal Regression ◽  
Luteal Cells

The increase of oxidative stress is one of the important characteristics of mammalian luteal regression. Previous investigations have revealed the essential role of reactive oxygen species (ROS) in luteal cell death during luteolysis, while it is unknown how ROS is regulated in this process. Considering the decrease of blood flow and increase of PGF2α during luteolysis, we hypothesized that the HIF-1α pathway may be involved in the regulation of ROS in the luteal cell of the late corpus luteum (CL). Here, by using a pseudopregnant rat model, we showed that the level of both HIF-1α and its downstream BNIP3 was increased during luteal regression. Consistently, we observed the increase of autophagy level during luteolysis, which is regulated in a Beclin1-independent manner. Comparing with early (Day 7 of pseudopregnancy) and middle CL (Day 14), the level of ROS was significantly increased in late CL, indicating the contribution of oxidative stress in luteolysis. Inhibition of HIF-1α by echinomycin (Ech), a potent HIF-1α inhibitor, ameliorated the upregulation of BNIP3 and NIX, as well as the induction of autophagy and the accumulation of ROS in luteal cells on Day 21 of pseudopregnancy. Morphologically, Ech treatment delayed the atrophy of the luteal structure at the late-luteal stage. An in vitro study indicated that inhibition of HIF-1α can also attenuate PGF2α-induced ROS and luteal cell apoptosis. Furthermore, the decrease of cell apoptosis can also be observed by ROS inhibition under PGF2α treatment. Taken together, our results indicated that HIF-1α signaling is involved in the regression of CL by modulating ROS production via orchestrating autophagy. Inhibition of HIF-1α could obviously hamper the apoptosis of luteal cells and the process of luteal regression.

scholarly journals Expression and regulation of secreted phosphoprotein 1 in the bovine corpus luteum and effects on T lymphocyte chemotaxis

Reproduction ◽  
2013 ◽  
Vol 146 (6) ◽  
pp. 527-537 ◽  
Author(s):  
Daniel H Poole ◽  
Kalidou Ndiaye ◽  
Joy L Pate
Keyword(s):  
Corpus Luteum ◽  
Estrous Cycle ◽  
Cell Function ◽  
Luteal Cell ◽  
Cellular Interactions ◽  
Western Blots ◽  
Luteal Regression ◽  
Luteal Cells ◽  
Bovine Corpus Luteum ◽  
Secreted Phosphoprotein 1

Secreted phosphoprotein 1 (SPP1) in the bovine corpus luteum (CL) regulates cell function during the transitional periods of luteinization and luteal regression. The objectives were to i) characterize SPP1 expression in the CL throughout the estrous cycle, ii) determine factors that regulate SPP1 expression in luteal cells, and iii) examine the role of SPP1 in lymphocyte chemotaxis, proliferation, and function.SPP1mRNA was greater in fully functional (d10) CL and late cycle (d18) CL compared with developing (d4) CL. Additionally,SPP1mRNA increased within 1 h and remained elevated 4 and 8 h following induction of luteolysis with prostaglandin (PG)F2α. Expression of the SPP1 receptor, β3integrin, was not different throughout the estrous cycle but decreased following induction of luteolysis. Expression ofCD44increased during the estrous cycle but did not change during luteal regression. In cultured luteal cells,SPP1mRNA was upregulated by PGF2αand/or tumor necrosis factor α. Western blots revealed the presence of both full-length SPP1 and multiple cleavage products in cultured luteal cells and luteal tissue. Depletion of endogenous SPP1 did not hinder luteal cell-induced lymphocyte proliferation or lymphocyte phenotype but did inhibit lymphocyte migration toward luteal cells. Based on these data, it is concluded that SPP1 is initially activated to establish and maintain cellular interactions between steroidogenic and nonsteroidogenic cells during the development of the CL. Upon induction of luteolysis, SPP1 serves as a signaling molecule to recruit or activate immune cells to facilitate luteal regression and tissue degradation.

scholarly journals Interaction of Mouse Placental Lactogens and Androgens in Regulating Progesterone Release in Cultured Mouse Luteal Cells

Endocrinology ◽  
1997 ◽  
Vol 138 (8) ◽  
pp. 3236-3241 ◽  
Author(s):  
G. Thordarson ◽  
S. Galosy ◽  
G. O. Gudmundsson ◽  
B. Newcomer ◽  
R. Sridaran ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Corpus Luteum ◽  
De Novo ◽  
Pituitary Hormones ◽  
Pregnant Mouse ◽  
Placental Lactogen ◽  
Luteal Cell ◽  
Corpora Lutea ◽  
Luteal Cells

Abstract Pituitary hormones are essential for the maintenance of the corpus luteum in the pregnant mouse during the first half of gestation. Thereafter, hormones from the placenta take over the luteotropic role of the pituitary hormones. Mouse placental lactogen-I (mPL-I) and mPL-II, two PRL-like hormones produced in the placenta, are probably necessary for the maintenance of the corpus luteum in the latter half of pregnancy. A culture system of luteal cells from pregnant mice was developed to investigate the role of hormones from the placenta that may be important for the function of the corpus luteum. Mice were killed on days 10, 14, and 18 of pregnancy, and the corpora lutea were excised from the ovaries and digested in 0.1% collagenase, 0.002% DNase for 1 h. The resulting luteal cell suspension was plated onto 96-well plates coated with fibronectin (1 × 105 cells/well) and cultured for 1–3 days. Medium was changed daily. The cells were treated with various concentrations and combinations of mPL-I, mPL-II, mouse PRL, androstenedione, dihydrotestosterone, 17β-estradiol (E2), testosterone, hydroxyflutamide, cycloheximide, actinomycin D, and fadrozole to study the effects of these different treatments on progesterone (P4) production. The three lactogens (mPL-I, mPL-II, and mouse PRL) all stimulated the release of P4 from the luteal cells. The potency of the lactogens was similar and did not depend on the stage of pregnancy at which the luteal tissue was obtained. However, the responsiveness of the cells to all hormone-stimulated P4 release was gradually reduced the later in pregnancy the tissue was collected. Androgens also stimulated the release of P4 from the luteal cells, and when administered together, the lactogens and the androgens acted synergistically to stimulate P4 release. The androgens acted directly but not through conversion to E2, as determined by the findings that 1) the effects of the androgens could not be reproduced by E2 administration, 2) nonaromatizable androgen dihydrotestosterone was as effective as aromatizable androgens, and 3) aromatase inhibitor did not prevent the action of the androgens to stimulate the P4 release. The effect of the androgens on the P4 release was rapid, occurring within 15 min of hormone administration. It was not prevented by inhibitors of protein and RNA synthesis, and the intracellular androgen receptor antagonist hydroxyflutamide did not affect the androgen action. Therefore, the androgen effects were not mediated through the intracellular androgen receptor and de novo protein synthesis was not needed for androgen-stimulated P4 release.

scholarly journals Role of gap junctions in regulation of progesterone secretion by ovine luteal cells in vitro

Reproduction ◽  
2007 ◽  
Vol 133 (3) ◽  
pp. 641-651 ◽  
Author(s):  
Ewa Borowczyk ◽  
Mary Lynn Johnson ◽  
Jerzy J Bilski ◽  
Magda A Bilska ◽  
Dale A Redmer ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Mrna Expression ◽  
Estrous Cycle ◽  
Luteal Cell ◽  
Gap Junctional Intercellular Communication ◽  
Luteal Cells ◽  
Progesterone Secretion ◽  
Cx43 Mrna

To evaluate the role of gap junctions in the regulation of progesterone secretion, two experiments were conducted. In Experiment 1, luteal cells obtained on days 5, 10, and 15 were cultured overnight at densities of 50×103, 100×103, 300×103, and 600×103cells/dish in medium containing: (1) no treatment (control), (2) LH, or (3) dbcAMP. In Experiment 2, luteal cells from days 5 and 10 of the estrous cycle were transfected with siRNA, which targeted the connexin (Cx) 43 gene. In Experiment 1, progesterone secretion, Cx43 mRNA expression, and the rates of gap junctional intercellular communication (GJIC), were affected by the day of the estrous cycle, cell density, and treatments (LH or dbcAMP). The changes in progesterone secretion were positively correlated with the changes in Cx43 mRNA expression and the rates of GJIC. Cx43 was detected on the luteal cell borders in every culture, and luteal cells expressed 3β-hydroxysteroid dehydrogenase. In Experiment 2, twoCx43gene-targeted sequences decreased Cx43 mRNA expression and progesterone production by luteal cells. The changes in Cx43 mRNA expression were positively correlated with changes in progesterone concentration in media. Thus, our data demonstrate a relationship between gap junctions and progesterone secretion that was supported by (1) the positive correlations between progesterone secretion and Cx43 mRNA expression and GJIC of luteal cells and (2) the inhibition of Cx43 mRNA expression by siRNA that resulted in decreased production of progesterone by luteal cells. This suggests that gap junctions may be involved in the regulation of steroidogenesis in the ovine corpus luteum.

scholarly journals Control of Steroidogenesis in Small and Large Bovine Luteal. Cells

1987 ◽  
Vol 40 (3) ◽  
pp. 331 ◽  
Author(s):  
William Hansel ◽  
Hector W Alila ◽  
Joseph P Dowd ◽  
Xiangzhong Yang
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Corpus Luteum ◽  
Luteal Cell ◽  
Lipoxygenase Pathway ◽  
Luteal Cells ◽  
Kinase C ◽  
Bovine Corpus Luteum ◽  
Progesterone Synthesis

Evidence was cited to show that: (1) prostacyclin (PGI2) plays a luteotrophic role in the bovine corpus luteum and that products of the lipoxygenase pathway of arachidonic acid metabolism, especially 5-hydroxyeicosatetraenoic acid play luteolytic roles; (2) oxytocin of luteal cell origin plays a role in development, and possibly in regression, of the bovine corpus luteum; and (3) luteal cells arise from two sources; the characteristic small luteal cells at all stages of the o~strous cycle and pregnancy are of theca cell origin; the large cells are of granulosa cell origin early in the cycle, but a population of theca-derived large cells appears later in the cycle. Results of in vitro studies with total dispersed cells and essentially pure preparations of large and small luteal cells indicate that : (1) the recently described Ca2+ -polyphosphoinositol-protein kinase C second messenger system is involved in progesterone synthesis in the bovine corpus luteum; (2) activation of protein kinase C is stimulatory to progesterone synthesis in the small luteal cells; (3) activation of protein kinase C has no effect on progesterone synthesis in the large luteal cells; and (4) protein kinase C exerts its luteotrophic effect in total cell preparations, in part at least, by stimulating the production of prostacyclin. The protein kinase C system may cause down regulation of LH receptors in the large cells.

scholarly journals Is the canine corpus luteum an insulin-sensitive tissue?

2016 ◽  
Vol 231 (3) ◽  
pp. 223-233 ◽  
Author(s):  
Liza Margareth Medeiros de Carvalho Sousa ◽  
Renata dos Santos Silva ◽  
Vanessa Uemura da Fonseca ◽  
Rafael Magdanelo Leandro ◽  
Thiago Senna Di Vincenzo ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Corpus Luteum ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Glucose Disposal ◽  
Luteal Cell ◽  
Luteal Function ◽  
Luteal Cells ◽  
Glut4 Expression

This study aimed to determine in the canine corpus luteum throughout the dioestrus (1) the influence of insulin on glucose uptake; (2) the regulation of genes potentially involved; and (3) the influence of hypoxia on glucose transporter expression and steroidogenesis, after treatment with cobalt chloride (CoCl2). Glucose uptake by luteal cells increased 2.7 folds (P < 0.05) in response to insulin; a phenomenon related to increased expression of glucose transporter (GLUT) 4 and phosphorylation of protein kinase B (AKT). The gene expression of insulin receptor and SLC2A4 (codifier of GLUT4) genes after insulin stimulation increased on day 20 post ovulation (p.o.) and declined on day 40 p.o. (P < 0.05). Regarding potentially involved molecular mechanisms, the nuclear factor kappa B gene RELA was upregulated on days 30/40 p.o., when SLC2A4 mRNA was low, and the interleukin 6 (IL6) gene was upregulated in the first half of dioestrus, when SLC2A4 mRNA was high. CoCl2 in luteal cell cultures increased the hypoxia-inducible factor HIF1A/HIF1A and the SLC2A4/GLUT4 expression, and decreased progesterone (P4) production and hydroxyl-delta-5-steroid dehydrogenase 3 beta (HSD3B) mRNA expression (P < 0.05). This study shows that the canine luteal cells are responsive to insulin, which stimulates glucose uptake in AKT/GLUT4-mediated pathway; that may be related to local activity of RELA and IL6. Besides, the study reveals that luteal cells under hypoxia activate HIF1A-modulating luteal function and insulin-stimulated glucose uptake. These data indicate that insulin regulates luteal cells’ glucose disposal, participating in the maintenance and functionality of the corpus luteum.

CHANGES IN THE DENSITY AND PROGESTERONE CONTENT OF LUTEAL TISSUE IN THE EGYPTIAN BUFFALO DURING THE OESTROUS CYCLE

1967 ◽  
Vol 39 (2) ◽  
pp. 163-171 ◽  
Author(s):  
A. S. EL-SHEIKH ◽  
FRANÇOIS B. SAKLA ◽  
SAFAA O. AMIN
Keyword(s):  
Corpus Luteum ◽  
Cell Volume ◽  
Distribution System ◽  
Oestrous Cycle ◽  
Luteal Cell ◽  
Corpora Lutea ◽  
Luteal Cells ◽  
Functional Changes ◽  
Parallel Increase ◽  
Luteal Tissue

SUMMARY The histological and functional changes of 31 corpora lutea of Egyptian buffaloes during the various phases of the oestrous cycle were studied. The volumes of the corpora lutea were calculated, the volume per cell, the cell volume and the volume of the intercellular spaces were estimated from transverse serial sections stained with haematoxylin and eosin, Mallory's triple stain or van Gieson's stain. The nuclear volumes were also determined and the cytoplasmic volume was calculated. The progesterone content was estimated using column absorption chromatography and a counter-current distribution system. It was concluded that the luteal cells increase both in volume and in number due to mitosis. The luteal cells decrease in volume after the 15th day after ovulation, the cells lose their distinct outlines in the regressive stage and disappear completely in the corpus albicans. There was a parallel increase in luteal cell volume and progesterone content until the 15th post-ovulatory day followed by a decrease in the regressive phase and disappearance of the hormone in the corpus albicans. A highly significant correlation (r = +0·875) was found between the progesterone content and the cytoplasmic volume. Progesterone concentration/g. luteal tissue increased from the corpus haemorrhagicum to the mature corpus luteum, decreased in the regressive corpus luteum and completely disappeared in the corpus albicans.

scholarly journals Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

2014 ◽  
Vol 306 (6) ◽  
pp. L508-L520 ◽  
Author(s):  
David I. Kasahara ◽  
Hye Y. Kim ◽  
Joel A. Mathews ◽  
Norah G. Verbout ◽  
Alison S. Williams ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Γδ T Cells ◽  
Pivotal Role ◽  
Ozone Exposure ◽  
Granulocyte Colony Stimulating Factor ◽  
Wild Type ◽  
Neutrophilic Inflammation ◽  
Stimulating Factor ◽  
Deficient Mice

Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24–72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient ( Adipo−/−) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo−/−mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 ( Adipo−/−/IL-6−/−) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo−/−vs. wild-type mice, but reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice. IL-17A+F4/80+cells and IL-17A+γδ T cells were also reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice exposed to ozone. Only BAL neutrophils were reduced in IL-6−/−vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1+F4/80−CD11c−cells, whereas in Adipo−/−mice F4/80+CD11c+cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 ( Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo−/−vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo−/−vs. wild-type mice but reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo−/−mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF.

Does prostacyclin (PGI2) support porcine corpus luteum function? – data from in vitro study

2016 ◽  
Vol 62 (5) ◽  
pp. 49
Author(s):  
Magdalena Julia Szymańska ◽  
Agnieszka Blitek
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Corpus Luteum ◽  
Estrous Cycle ◽  
In Vitro Study ◽  
Luteal Cells ◽  
Enzymatic Isolation ◽  
Effective Doses ◽  
And Function

Background. Prostacyclin (PGI2) of luteal origin is involved in the control of corpus luteum (CL) development and function in cattle. PGI2 may regulate the process of angiogenesis and may stimulate progesterone (P4) secretion by luteal cells via its specific receptors, PTGIR. In contrast to cattle, the role of PGI2 in the pig CL has not yet been described.Aim. The present study aimed to investigate the effect of PGI2 on 1) P4 secretion by luteal cells, and 2) the expression of angiogenesis-related genes in endothelial cells of the porcine CL.Methods. CL collected from gilts on day 5-7 of the estrous cycle were used for enzymatic isolation of luteal (Experiment 1) and endothelial (Experiment 2) cells. In Exp. 1, cultured luteal cells were incubated with increasing (0, 0.01, 0.1, 1, 5 µM) doses of PGI2 analogues: iloprost (ILO) and carbaprostacyclin (cPGI2) for 8 h. To determine the effective doses of PGI2 analogues, P4 concentration in culture medium was examined by RIA. Thereafter, luteal cells were treated with ILO and cPGI2 at the concentration of 1 and 5 µM in the presence or absence of PTGIR antagonist (CAY10441). After 8 h of incubation the medium was collected for P4 determination. In Exp. 2, isolated endothelial cells were treated for 24 h with ILO and cPGI2 at doses of 1 and 5 µM. Then, cells were collected for analysis of Ang-1 and -2 mRNA expression using qPCR.Results. Both, ILO and cPGI2 affected P4 secretion by luteal cells. Elevated levels of P4 were observed in medium after treatment of luteal cells with 1 µM of ILO and 0.1, 1 and 5 µM of cPGI2 compared with control values (p<0.05). The addition of CAY10441 inhibited the stimulatory effect of ILO on P4 secretion, while did not change P4 production by luteal cells incubated with cPGI2. Moreover, PGI2 analogues differentially affected (p<0.05) the expression of proangiogenic factors. ILO stimulated Ang-2, whereas cPGI2 positively affected Ang-1 mRNA expression in endothelial cells at concentrations of 1 µM and 5 µM, respectively.Conclusion. PGI2 affects P4 secretion during luteal phase of the estrous cycle and may regulate the process of angiogenesis in the porcine CL.

Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice

2012 ◽  
Vol 302 (10) ◽  
pp. G1133-G1142 ◽  
Author(s):  
Masashi Yasuda ◽  
Shinichi Kato ◽  
Naoki Yamanaka ◽  
Maho Iimori ◽  
Daichi Utsumi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Caspase 3 ◽  
Potential Role ◽  
Chemotherapeutic Agent ◽  
Wild Type ◽  
Villus Height ◽  
Tnf Α ◽  
Nadph Oxidase 1 ◽  
Intestinal Mucositis

Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

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