酒精对大鼠结肠内iNOS表达的上调作用及其机制研究
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摘要
我们最近的研究发现,酒精抑制大鼠结肠运动,该作用是由NO介导的,但其机制不清。已有报道,酒精可引起肝实质细胞和枯否细胞中iNOS mRNA表达增高,Blanco等研究者也发现,在人工培养的星形胶质细胞中酒精刺激可通过NF-κB途径使iNOS的基因表达上调。
核因子κB(nuclear factor-κB,NF-κB)作为转录因子,广泛参与肿瘤、炎症及免疫性疾病的发病过程,参与机体防御反应、组织损伤和应激、细胞分化和细胞凋亡以及肿瘤生长抑制等过程的信息转导。NF-κB包括NF-κB_1、NF-κB_2和某些癌基因蛋白(如RelA)等,通常与其抑制蛋白IκB结合,以二聚体的形式存在于胞浆中,当细胞受到外界刺激时,如病毒或细菌感染、紫外线照射、氧化应激等,IκB被迅速磷酸化,释放NF-κB使之转入胞核内,结合于特定的κB序列,启动和调节众多与免疫、炎症反应有关的基因转录。
我们推测,酒精可能通过激活NF-κB、提高iNOS表达而引起了NO释放。本课题主要是对该假设进行验证。
材料与方法
实验选用健康雄性Wistar大鼠,实验前禁食18h。快速牺牲大鼠,制备近端结肠纵形肌肌条,在灌流肌槽中孵育并记录肌条自发收缩活动。以平滑肌肌条张力变化为指标,分别观察经PDTC(NF-κB的阻断剂)和SMT(iNOS的阻断剂)预处理后,酒精对结肠纵形肌肌条运动的影响,用Western blot技术测定胞浆中iNOS和IκB表达量,以及NF-κB在胞核中的表达量,免疫组织化学的方法定位结肠内表达iNOS的细胞,NO试剂盒测定结肠组织NO释放量。
所有数据均采用均数±标准误表示,采用单因素方差分析进行统计学处理,以P＜0.05为显著性差异界值。
实验结果:
1.酒精(8.7×10~(-4)M)明显抑制离体结肠纵型肌肌条的自发收缩活动。加入酒精后,记录2～4分钟,7～9分钟,12～14分钟和17～19分钟,肌条张力的R值从1降低到0.90±0.02,0.87±0.02,0.89±0.03 and 0.87±0.01。
2.灌流液中分别加入PDTC(10~(-2)M)(NF-κB的阻断剂)或SMT(10~(-3)M)(选择性iNOS拮抗剂)后,再加入同样剂量的酒精,酒精对结肠肌条运动的抑制作用明显减弱。
3.酒精(0.17×10~(-3)M- 1.30×10~(-3)M)上调iNOS的表达,其中以8.7×10~(-4)M的酒精作用最明显。PDTC(10~(-2)M)明显抑制酒精(8.7×10~(-4)M)对iNOS的表达的上调作用。
4.酒精(8.7×10~(-4)M)增加胞核中NF-κB的表达量,但减少胞浆中IκB的表达量。PDTC逆转酒精的这种作用。
5.免疫组化发现iNOS在结肠肌间神经丛中表达。
6.正常大鼠结肠中NO含量为1.112±0.128μmol/g,加入酒精后20分钟,NO含量增加为7.194±0.497μmol/g(P＜0.05,n=6),PDTC预处理后再加入酒精,结肠中NO含量降为3.267±0.314μmol/g(P＜0.05,n=6)
结论:
酒精抑制结肠运动的作用是通过激活NF-κB,上调iNOS表达,从而增加NO释放量引起的。
Inducible nitric oxide synthase(iNOS) is an inducible member of the three nitric oxide synthase isoforms including endothelial nitric oxide synthase(eNOS), neural nitric oxide synthase(nNOS) and iNOS.They catalyze the oxidation-reduction reaction of L-arginine in the presence of oxygen to form nitric oxide(NO) and 1-citrulline.The expression of iNOS has been located in keratinocytes,dendritic cells (DC),and Langerhans cells.Our recent study indicated that ethanol inhibited the motility of longitudinal muscle strips of proximal colon via iNOS and NO,but the mechanisms are not completely understood.
NF-κB consists of multi-subunit proteins of Rel family(p50,p52,p65(RelA), c-Rel and RelB).The p65/p50 dimer is the predominant form in most cell types. Under normal conditions or in resting cells,NF-κB is localized in the cytoplasm and bound with inhibitory proteins,generically called inhibitory factor B(I-κB.When the cell is activated,I-κB protein is phosphorylated and dissociated from NF-κB rapidly.NF-κB then undergoes rapid nuclear translocation and participates in the induction of numerous cellular genes.NF-κB is activated following a wide range of stimuli such as cytokines,oxidative stress and some pharmaceutical drugs and chemicals.After activation,NF-κB triggers the transcriptional induction of cytokines and inflammatory mediators,such as iNOS and COX-2.In cultured astrocytes,ethanol induced iNOS expression via activation of NF-κB.Therefore,we hypothesized that the similar mechanism existed in colon.NF-κB might mediate the upregulation of iNOS expression following ethanol administration in colon.In order to test this hypothesis,we investigated the effect of Pyrrolidine dithiocarbamate (PDTC),the specific NF-κB inhibitor,on the inhibitory effect of ethanol on the contraction of LP strips of colon.The expression of iNOS,cytoplamic I-κB and nuclear P65 was detected by Western blot analysis.The expression of iNOS in colon was located by immunohistochemistry.
MATERIALS AND METHODS
Animal and muscle strips preparation
Male Wistar rats,they were fasted overnight with free access to water before experiments.The method has been described elsewhere with some modification. Immediately after animal was sacrificed,a segment of proximal colon(1cm from caecum) was removed.The segment was opened along the mesenteric border and the resulting rectangular sheet was pinned flat(mucosa up) in a silgard lined Petri dish filled with oxygenated Krebs solution.Muscle strips(8×3mm) were then cut parallel to the longitudinal muscle fibres,these were designated LP.Finally,the mucosa layer on each strip was carefully scraped away.The muscle strips were suspended in tissue chambers containing 5ml Krebs solution(37℃) and bubbled continuously with 95% O_2 and 5%CO_2.Isometric contraction of the strips was monitored.
Western blot
The segments of proximal colon were removed and the mucosa layer on each strip was carefully scraped away.The tissue was treated with ethanol for 20min before it was prepared for Western blot.The body homogenates were electrophoresed and transferred to nitrocellulose membranes.Membranes were blocked for 1hr at room temperature in blocking buffer(5%nonfat dry milk,TTBS),washed in TTBS(0.1% Tween 20,50mM Tris,and 150mM NaCl),and incubated overnight with rabbit anti-iNOS antibody(1:500,sc 651;Santa Cruz) or rabbit anti-NF-κB antibody(1:500, sc 8008;Santa Cruz) or rabbit anti-IκB antibody(1:800,sc 371;Santa Cruz).After washing three times,membranes were incubated for 1hr at room temperature with horseradish peroxidase(HRP)-conjugated secondary antibodies(1:20000).Finally, immunoreactive proteins were detected by ECL plus(Millipore,USA).
Immunohistochemistry
The segments of proximal colon were removed and treated with ethanol for 20min. Immunohistochemistry for nitric oxide synthase(iNOS) was performed on 4-μm-thick paraffin-embedded sections from LP of rats,utilizing the labeled streptavidin-biotin method using a Two-Step IHC Detection Reagent(ZSGB-BIO,Beijing,China).The paraffin-embedded sections were heated for 2h at 120℃,deparaffinized in xylene, and rehydrated through graded ethanol at room temperature.After three rinses in PBS, microwave accentuation was used for 10minutes.Then after two rinses in PBS, sections were put in a humid chamber for 15minutes.Next,sections were treated for 40min at room temperature with 2%bovine serum albumin,and incubated overnight at 4℃with primary antibodies,anti-iNOS mouse monoclonal antibody(diluted 1:200 in PBS,sc 651;Santa Cruz).After the sections were washed,they were incubated with biotinylated goat anti-rabbit serum(ZSGB-BIO,Beijing,China) for 30min at room temperature.The sections were next washed and then treated with HRP-labeled streptavidin-complex(ZSGB-BIO) for 30min at room temperature.After several rinses,peroxidase was revealed by a 3,3'-diaminobenzidine tetrahydrochloride substrate kit(ZSGB-BIO).In negative controls,the sections were incubated with PBS instead of primary antibody.
Measurement of tissue NO levels
The segments of proximal colon were removed and the mucosa layer was carefully scraped away.The tissue was treated with ethanol for 20min before it was prepared for the measurement of NO.The samples were thawed,weighed and homogenized in 1:9 w:v in 0.9%saline.The homogenates were then centrifuged at 1 000 r/min for 5 min at 4℃,the supernatant was taken for NO assay and total protein determination. NO was assayed spectrophotometrically by measuring total nitrate plus nitrite(NO_3~-plus NO_2~-) and the stable end products of NO metabolism.The procedure that nitrate was enzymatically converted into nitrite by the enzyme nitrate reductase was followed by quantization of nitrite using Griess reagent at the absorbance of 550nm.The level of NO was expressed asμmol/g protein.
The value are presented as mean±SEM.Differences between groups were evaluated by One way ANOVA and Students' t test,P<0.05 was considered to be significantly different.
The western blot results were quantified using Scion Image software, background band was subtracted and the band were expressed as relative protein amounts compared toβ-actin(cytoplamic protein) or c-jun(nuclear protein). Statistical comparisons were made using ANOVA,P<0.05 was considered to be significant.
RESULTS
Effect of PDTC and SMT on ethanol-induced inhibition on LP contraction
Ethanol(8.7×10~(-4) M) inhibited the spontaneous contraction of LP from rats.The contraction of LP decreased immediately after the ethanol administration.At 5,10,15 and 20min after ethanol administration,R of LP decreased from 1(baseline) to 0.90±0.02,0.87±0.02,0.89±0.03 and 0.87±0.01 respectively. Both PDTC(10~(-2) M),a specific inhibitor of NF-κB,and SMT(10~(-3) M),a specific inhibitor of iNOS,partially reversed the inhibitory effect of ethanol on the contraction of LP.
Expression of iNOS,I-κB and NF-κB following ethanol treatment with and without the pretreatment of PDTC
Ethanol(0.35-1.3×10~(-3) M) increased the expression of iNOS in colon(Fig 3A). Pretreatment of PDTC(10~(-2) M) significantly attenuated the increase of iNOS expression following ethanol.
Ethanol(8.7×10~(-4) M) significantly decreased the amount of cytoplasmic I-κB and increased nuclear P65 in colon.Pretreatment of PDTC(10~(-2) M) partly reversed these change.
Immunohistochemistry
Inducible NOS immunoreactivity was expressed in myenteric plexus.No labeling was detected in control experiments where tissues were treated with PBS instead of primary antibody.
The NO content in colon
The NO content in colon following ethanol administration increased from 1.112±0.128μmol/g(control) to 7.194±0.497μmol/g(P<0.05,n=6).With the pretreatment of PDTC,the increase of NO content following ethanol administration was significantly attenuated(P<0.05,n=6).
CONCLUSION
These results suggested that:acute exposure of ethanol inhibited the LP contraction of LP in rat colon through activation of NF-κBand the subsequent expression of iNOS and release of NO from myenteric plexus.
核因子κB(nuclear factor-κB,NF-κB)作为转录因子,广泛参与肿瘤、炎症及免疫性疾病的发病过程,参与机体防御反应、组织损伤和应激、细胞分化和细胞凋亡以及肿瘤生长抑制等过程的信息转导。NF-κB包括NF-κB_1、NF-κB_2和某些癌基因蛋白(如RelA)等,通常与其抑制蛋白IκB结合,以二聚体的形式存在于胞浆中,当细胞受到外界刺激时,如病毒或细菌感染、紫外线照射、氧化应激等,IκB被迅速磷酸化,释放NF-κB使之转入胞核内,结合于特定的κB序列,启动和调节众多与免疫、炎症反应有关的基因转录。
我们推测,酒精可能通过激活NF-κB、提高iNOS表达而引起了NO释放。本课题主要是对该假设进行验证。
材料与方法
实验选用健康雄性Wistar大鼠,实验前禁食18h。快速牺牲大鼠,制备近端结肠纵形肌肌条,在灌流肌槽中孵育并记录肌条自发收缩活动。以平滑肌肌条张力变化为指标,分别观察经PDTC(NF-κB的阻断剂)和SMT(iNOS的阻断剂)预处理后,酒精对结肠纵形肌肌条运动的影响,用Western blot技术测定胞浆中iNOS和IκB表达量,以及NF-κB在胞核中的表达量,免疫组织化学的方法定位结肠内表达iNOS的细胞,NO试剂盒测定结肠组织NO释放量。
所有数据均采用均数±标准误表示,采用单因素方差分析进行统计学处理,以P＜0.05为显著性差异界值。
实验结果:
1.酒精(8.7×10~(-4)M)明显抑制离体结肠纵型肌肌条的自发收缩活动。加入酒精后,记录2～4分钟,7～9分钟,12～14分钟和17～19分钟,肌条张力的R值从1降低到0.90±0.02,0.87±0.02,0.89±0.03 and 0.87±0.01。
2.灌流液中分别加入PDTC(10~(-2)M)(NF-κB的阻断剂)或SMT(10~(-3)M)(选择性iNOS拮抗剂)后,再加入同样剂量的酒精,酒精对结肠肌条运动的抑制作用明显减弱。
3.酒精(0.17×10~(-3)M- 1.30×10~(-3)M)上调iNOS的表达,其中以8.7×10~(-4)M的酒精作用最明显。PDTC(10~(-2)M)明显抑制酒精(8.7×10~(-4)M)对iNOS的表达的上调作用。
4.酒精(8.7×10~(-4)M)增加胞核中NF-κB的表达量,但减少胞浆中IκB的表达量。PDTC逆转酒精的这种作用。
5.免疫组化发现iNOS在结肠肌间神经丛中表达。
6.正常大鼠结肠中NO含量为1.112±0.128μmol/g,加入酒精后20分钟,NO含量增加为7.194±0.497μmol/g(P＜0.05,n=6),PDTC预处理后再加入酒精,结肠中NO含量降为3.267±0.314μmol/g(P＜0.05,n=6)
结论:
酒精抑制结肠运动的作用是通过激活NF-κB,上调iNOS表达,从而增加NO释放量引起的。
Inducible nitric oxide synthase(iNOS) is an inducible member of the three nitric oxide synthase isoforms including endothelial nitric oxide synthase(eNOS), neural nitric oxide synthase(nNOS) and iNOS.They catalyze the oxidation-reduction reaction of L-arginine in the presence of oxygen to form nitric oxide(NO) and 1-citrulline.The expression of iNOS has been located in keratinocytes,dendritic cells (DC),and Langerhans cells.Our recent study indicated that ethanol inhibited the motility of longitudinal muscle strips of proximal colon via iNOS and NO,but the mechanisms are not completely understood.
NF-κB consists of multi-subunit proteins of Rel family(p50,p52,p65(RelA), c-Rel and RelB).The p65/p50 dimer is the predominant form in most cell types. Under normal conditions or in resting cells,NF-κB is localized in the cytoplasm and bound with inhibitory proteins,generically called inhibitory factor B(I-κB.When the cell is activated,I-κB protein is phosphorylated and dissociated from NF-κB rapidly.NF-κB then undergoes rapid nuclear translocation and participates in the induction of numerous cellular genes.NF-κB is activated following a wide range of stimuli such as cytokines,oxidative stress and some pharmaceutical drugs and chemicals.After activation,NF-κB triggers the transcriptional induction of cytokines and inflammatory mediators,such as iNOS and COX-2.In cultured astrocytes,ethanol induced iNOS expression via activation of NF-κB.Therefore,we hypothesized that the similar mechanism existed in colon.NF-κB might mediate the upregulation of iNOS expression following ethanol administration in colon.In order to test this hypothesis,we investigated the effect of Pyrrolidine dithiocarbamate (PDTC),the specific NF-κB inhibitor,on the inhibitory effect of ethanol on the contraction of LP strips of colon.The expression of iNOS,cytoplamic I-κB and nuclear P65 was detected by Western blot analysis.The expression of iNOS in colon was located by immunohistochemistry.
MATERIALS AND METHODS
Animal and muscle strips preparation
Male Wistar rats,they were fasted overnight with free access to water before experiments.The method has been described elsewhere with some modification. Immediately after animal was sacrificed,a segment of proximal colon(1cm from caecum) was removed.The segment was opened along the mesenteric border and the resulting rectangular sheet was pinned flat(mucosa up) in a silgard lined Petri dish filled with oxygenated Krebs solution.Muscle strips(8×3mm) were then cut parallel to the longitudinal muscle fibres,these were designated LP.Finally,the mucosa layer on each strip was carefully scraped away.The muscle strips were suspended in tissue chambers containing 5ml Krebs solution(37℃) and bubbled continuously with 95% O_2 and 5%CO_2.Isometric contraction of the strips was monitored.
Western blot
The segments of proximal colon were removed and the mucosa layer on each strip was carefully scraped away.The tissue was treated with ethanol for 20min before it was prepared for Western blot.The body homogenates were electrophoresed and transferred to nitrocellulose membranes.Membranes were blocked for 1hr at room temperature in blocking buffer(5%nonfat dry milk,TTBS),washed in TTBS(0.1% Tween 20,50mM Tris,and 150mM NaCl),and incubated overnight with rabbit anti-iNOS antibody(1:500,sc 651;Santa Cruz) or rabbit anti-NF-κB antibody(1:500, sc 8008;Santa Cruz) or rabbit anti-IκB antibody(1:800,sc 371;Santa Cruz).After washing three times,membranes were incubated for 1hr at room temperature with horseradish peroxidase(HRP)-conjugated secondary antibodies(1:20000).Finally, immunoreactive proteins were detected by ECL plus(Millipore,USA).
Immunohistochemistry
The segments of proximal colon were removed and treated with ethanol for 20min. Immunohistochemistry for nitric oxide synthase(iNOS) was performed on 4-μm-thick paraffin-embedded sections from LP of rats,utilizing the labeled streptavidin-biotin method using a Two-Step IHC Detection Reagent(ZSGB-BIO,Beijing,China).The paraffin-embedded sections were heated for 2h at 120℃,deparaffinized in xylene, and rehydrated through graded ethanol at room temperature.After three rinses in PBS, microwave accentuation was used for 10minutes.Then after two rinses in PBS, sections were put in a humid chamber for 15minutes.Next,sections were treated for 40min at room temperature with 2%bovine serum albumin,and incubated overnight at 4℃with primary antibodies,anti-iNOS mouse monoclonal antibody(diluted 1:200 in PBS,sc 651;Santa Cruz).After the sections were washed,they were incubated with biotinylated goat anti-rabbit serum(ZSGB-BIO,Beijing,China) for 30min at room temperature.The sections were next washed and then treated with HRP-labeled streptavidin-complex(ZSGB-BIO) for 30min at room temperature.After several rinses,peroxidase was revealed by a 3,3'-diaminobenzidine tetrahydrochloride substrate kit(ZSGB-BIO).In negative controls,the sections were incubated with PBS instead of primary antibody.
Measurement of tissue NO levels
The segments of proximal colon were removed and the mucosa layer was carefully scraped away.The tissue was treated with ethanol for 20min before it was prepared for the measurement of NO.The samples were thawed,weighed and homogenized in 1:9 w:v in 0.9%saline.The homogenates were then centrifuged at 1 000 r/min for 5 min at 4℃,the supernatant was taken for NO assay and total protein determination. NO was assayed spectrophotometrically by measuring total nitrate plus nitrite(NO_3~-plus NO_2~-) and the stable end products of NO metabolism.The procedure that nitrate was enzymatically converted into nitrite by the enzyme nitrate reductase was followed by quantization of nitrite using Griess reagent at the absorbance of 550nm.The level of NO was expressed asμmol/g protein.
The value are presented as mean±SEM.Differences between groups were evaluated by One way ANOVA and Students' t test,P<0.05 was considered to be significantly different.
The western blot results were quantified using Scion Image software, background band was subtracted and the band were expressed as relative protein amounts compared toβ-actin(cytoplamic protein) or c-jun(nuclear protein). Statistical comparisons were made using ANOVA,P<0.05 was considered to be significant.
RESULTS
Effect of PDTC and SMT on ethanol-induced inhibition on LP contraction
Ethanol(8.7×10~(-4) M) inhibited the spontaneous contraction of LP from rats.The contraction of LP decreased immediately after the ethanol administration.At 5,10,15 and 20min after ethanol administration,R of LP decreased from 1(baseline) to 0.90±0.02,0.87±0.02,0.89±0.03 and 0.87±0.01 respectively. Both PDTC(10~(-2) M),a specific inhibitor of NF-κB,and SMT(10~(-3) M),a specific inhibitor of iNOS,partially reversed the inhibitory effect of ethanol on the contraction of LP.
Expression of iNOS,I-κB and NF-κB following ethanol treatment with and without the pretreatment of PDTC
Ethanol(0.35-1.3×10~(-3) M) increased the expression of iNOS in colon(Fig 3A). Pretreatment of PDTC(10~(-2) M) significantly attenuated the increase of iNOS expression following ethanol.
Ethanol(8.7×10~(-4) M) significantly decreased the amount of cytoplasmic I-κB and increased nuclear P65 in colon.Pretreatment of PDTC(10~(-2) M) partly reversed these change.
Immunohistochemistry
Inducible NOS immunoreactivity was expressed in myenteric plexus.No labeling was detected in control experiments where tissues were treated with PBS instead of primary antibody.
The NO content in colon
The NO content in colon following ethanol administration increased from 1.112±0.128μmol/g(control) to 7.194±0.497μmol/g(P<0.05,n=6).With the pretreatment of PDTC,the increase of NO content following ethanol administration was significantly attenuated(P<0.05,n=6).
CONCLUSION
These results suggested that:acute exposure of ethanol inhibited the LP contraction of LP in rat colon through activation of NF-κBand the subsequent expression of iNOS and release of NO from myenteric plexus.
引文
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24. Imose M, Nagaki M, Kimura K, Takai S, Imao M, Naiki T, Osawa Y, Asano T, Hayashi H, and Moriwaki H. Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor kappaB. Hepatology (Baltimore, Md 40: 1160-1169,2004.
25. Karin M and Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annual review of immunology 18: 621-663, 2000.
26. Karuri AR, Huang Y, Bodreddigari S, Sutter CH, Roebuck BD, Kensler TW, and Sutter TR. 3H-l,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats. The Journal of pharmacology and experimental therapeutics 317: 61-67, 2006.
27. Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, and Benkirane M. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. The Journal of biological chemistry 278: 2758-2766, 2003.
28. Lee FS, Peters RT, Dang LC, and Maniatis T. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proceedings of the National Academy of Sciences of the United States of America 95: 9319-9324, 1998.
29. Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, and Horwitz MS. Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 96: 1042-1047, 1999.
30. Ling L, Cao Z, and Goeddel DV. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proceedings of the National Academy of Sciences of the United States of America 95: 3792-3797, 1998.
31. Lu L, Bonham CA, Chambers FG, Watkins SC, Hoffman RA, Simmons RL, and Thomson AW. Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis. J Immunol 157: 3577-3586,1996.
32. Ma XL, Li YH, Gao JX, Li J, Guo L, and Wu CZ. Expression of inducible nitric oxide synthase in the liver is under the control of nuclear factor kappa B in concanavalin A-induced hepatitis. Journal of gastroenterology and hepatology 23: e231-235, 2008.
33. MacMicking J, Xie QW, and Nathan C. Nitric oxide and macrophage function. Annual review of immunology 15: 323-350, 1997.
34. Mandrekar P, Catalano D, White B, and Szabo G Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcoholism, clinical and experimental research 30: 135-139,2006.
35. McCann SM, Haens G, Mastronardi C, Walczewska A, Karanth S, Rettori V, and Yu WH. The role of nitric oxide (NO) in control of LHRH release that mediates gonadotropin release and sexual behavior. Current pharmaceutical design 9: 381-390,2003.
36. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, and Manning AM. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Molecular and cellular biology 19:1526-1538,1999.
37. Morbidelli L, Donnini S, and Ziche M. Role of nitric oxide in the modulation of angiogenesis. Current pharmaceutical design 9: 521-530, 2003.
38. Muia C, Mazzon E, Maiere D, Zito D, Di Paola R, Domenico S, Crisafulli C, Britti D, and Cuzzocrea S. Pyrrolidine dithiocarbamate reduced experimental periodontitis. European journal of pharmacology 539: 205-210, 2006.
39. Musikacharoen T, Matsuguchi T, Kikuchi T, and Yoshikai Y. NF-kappa B and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression. J Immunol 166: 4516-4524, 2001.
40. Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, Tahan SR, and Su GL. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology (Baltimore, Md 30: 934-943, 1999.
41. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18: 6853-6866, 1999.
42. Papa A, Tursi A, Cammarota G, Certo M, Cuoco L, Montalto M, Cianci R, Papa V, Fedeli P, Fedeli G, and Gasbarrini G. Effect of moderate and heavy alcohol consumption on intestinal transit time. Panminerva medica 40: 183-185, 1998.
43. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 16: 49-57, 1996.
44. Pham LV, Tamayo AT, Yoshimura LC, Lo P, and Ford RJ. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171: 88-95, 2003.
45. Polk WW, Ellis ME, Kushleika JV, Simmonds PL, and Woods JS. RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells. Am J Physiol Cell Physiol 293:C1160-1170,2007.
46. Rothwarf DM and Karin M. The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999: RE1, 1999.
47. Rothwarf DM, Zandi E, Natoli G, and Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395: 297-300, 1998.
48. Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K, and Pasparakis M. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Molecular cell 5: 981-992, 2000.
49. Sen R and Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46: 705-716, 1986.
50. Silverman N and Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes & development 15: 2321-2342,2001.
51. Sim SS, Choi JC, Min DS, Rhie DJ, Yoon SH, Hahn SJ, Kim CJ, Kim MS, and Jo YH. Effect of ethanol on spontaneous phasic contractions of cat gastric smooth muscle. Scandinavian journal of gastroenterology 37: 23-27, 2002.
52. Spink J and Evans T. Binding of the transcription factor interferon regulatory factor-1 to the inducible nitric-oxide synthase promoter. The Journal of biological chemistry 272: 24417-24425, 1997.
53. Szabo G, Mandrekar P, Oak S, and Mayerle J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 7: 115-123, 2007.
54. Tarpey MM, Wink DA, and Grisham MB. Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. American journal of physiology 286: R431-444, 2004.
55. Ueda M, Kokura S, Imamoto E, Naito Y, Handa O, Takagi T, Yoshida N, and Yoshikawa T. Blocking of NF-kappaB activation enhances the tumor necrosis factor alpha-induced apoptosis of a human gastric cancer cell line. Cancer letters 193: 177-182,2003.
56. Vannucchi MG, Corsani L, Bani D, and Faussone-Pellegrini MS. Myenteric neurons and interstitial cells of Cajal of mouse colon express several nitric oxide synthase isoforms. Neuroscience letters 326: 191-195, 2002.
57. Venkataranganna MV, Rafiq M, Gopumadhavan S, Peer G, Babu UV, and Mitra SK. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through down-regulation of NFkappa-B and iNOS. World J Gastroenterol 13: 1103-1107,2007.
58. Wang J, Huang Q, and Chen M. The role of NF-kappaB in hepatocellular carcinoma cell. Chinese medical journal 116: 747-752, 2003.
59. Wang SL, Xie DP, Liu KJ, Qin JF, Feng M, Kunze W, and Liu CY. Nitric oxide mediates the inhibitory effect of ethanol on the motility of isolated longitudinal muscle of proximal colon in rats. Neurogastroenterol Motil 19: 515-521, 2007.
60. Wang W, Luo HS, and Yu BP. Expression of NF-kappaB and human telomerase reverse transcriptase in gastric cancer and precancerous lesions. World J Gastroenterol 10: 177-181,2004.
61. Weinmann O, Gutzmer R, Zwirner J, Wittmann M, Langer K, Lisewski M, Mommert S, Kapp A, and Werfel T. Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2. Immunology 110: 458-465, 2003.
62. Whiteman M, Chua YL, Zhang D, Duan W, Liou YC, and Armstrong JS. Nitric oxide protects against mitochondrial permeabilization induced by glutathione depletion: role of S-nitrosylation? Biochemical and biophysical research communications 339: 255-262, 2006.
63. Wu D, Marko M, Claycombe K, Paulson KE, and Meydani SN. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. The Journal of biological chemistry 278: 10983-10992,2003.
64. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, and Israel A. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93: 1231-1240, 1998.
65. Yoshida Y, Liu JQ, Nakano Y, Ueno S, Ohmori S, Fueta Y, Ishidao T, Kunugita N, Yamashita U, and Hori H. 1-BP inhibits NF-kappaB activity and Bcl-xL expression in astrocytes in vitro and reduces Bcl-xL expression in the brains of rats in vivo. Neurotoxicology 28: 381-386,2007.
66. Yu LL, Yu HG, Yu JP, and Luo HS. Nuclear factor-kappa B regulates cyclooxygenase-2 expression and cell proliferation in human colorectal carcinoma tissue. Eksperimental'naia onkologiia 26: 40-47, 2004.
67. Zeldin G, Yang SQ, Yin M, Lin HZ, Rai R, and Diehl AM. Alcohol and cytokine-inducible transcription factors. Alcoholism, clinical and experimental research 20: 1639-1645, 1996.
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22. Guo AH, Gong XW, Kan WH, Qin QH, Deng P, Wang JZ, and Jiang Y. Regulation of inducible nitricoxide synthase gene transcription by p38 mitogen-activated protein kinase in human embryonic kidney 293 cells. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA 23: 206-209, 2003.
23. Heck DE, Laskin DL, Gardner CR, and Laskin JD. Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing. The Journal of biological chemistry 267: 21277-21280, 1992.
24. Imose M, Nagaki M, Kimura K, Takai S, Imao M, Naiki T, Osawa Y, Asano T, Hayashi H, and Moriwaki H. Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor kappaB. Hepatology (Baltimore, Md 40: 1160-1169,2004.
25. Karin M and Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annual review of immunology 18: 621-663, 2000.
26. Karuri AR, Huang Y, Bodreddigari S, Sutter CH, Roebuck BD, Kensler TW, and Sutter TR. 3H-l,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats. The Journal of pharmacology and experimental therapeutics 317: 61-67, 2006.
27. Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, and Benkirane M. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. The Journal of biological chemistry 278: 2758-2766, 2003.
28. Lee FS, Peters RT, Dang LC, and Maniatis T. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proceedings of the National Academy of Sciences of the United States of America 95: 9319-9324, 1998.
29. Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, and Horwitz MS. Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 96: 1042-1047, 1999.
30. Ling L, Cao Z, and Goeddel DV. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proceedings of the National Academy of Sciences of the United States of America 95: 3792-3797, 1998.
31. Lu L, Bonham CA, Chambers FG, Watkins SC, Hoffman RA, Simmons RL, and Thomson AW. Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis. J Immunol 157: 3577-3586,1996.
32. Ma XL, Li YH, Gao JX, Li J, Guo L, and Wu CZ. Expression of inducible nitric oxide synthase in the liver is under the control of nuclear factor kappa B in concanavalin A-induced hepatitis. Journal of gastroenterology and hepatology 23: e231-235, 2008.
33. MacMicking J, Xie QW, and Nathan C. Nitric oxide and macrophage function. Annual review of immunology 15: 323-350, 1997.
34. Mandrekar P, Catalano D, White B, and Szabo G Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcoholism, clinical and experimental research 30: 135-139,2006.
35. McCann SM, Haens G, Mastronardi C, Walczewska A, Karanth S, Rettori V, and Yu WH. The role of nitric oxide (NO) in control of LHRH release that mediates gonadotropin release and sexual behavior. Current pharmaceutical design 9: 381-390,2003.
36. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, and Manning AM. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Molecular and cellular biology 19:1526-1538,1999.
37. Morbidelli L, Donnini S, and Ziche M. Role of nitric oxide in the modulation of angiogenesis. Current pharmaceutical design 9: 521-530, 2003.
38. Muia C, Mazzon E, Maiere D, Zito D, Di Paola R, Domenico S, Crisafulli C, Britti D, and Cuzzocrea S. Pyrrolidine dithiocarbamate reduced experimental periodontitis. European journal of pharmacology 539: 205-210, 2006.
39. Musikacharoen T, Matsuguchi T, Kikuchi T, and Yoshikai Y. NF-kappa B and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression. J Immunol 166: 4516-4524, 2001.
40. Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, Tahan SR, and Su GL. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology (Baltimore, Md 30: 934-943, 1999.
41. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18: 6853-6866, 1999.
42. Papa A, Tursi A, Cammarota G, Certo M, Cuoco L, Montalto M, Cianci R, Papa V, Fedeli P, Fedeli G, and Gasbarrini G. Effect of moderate and heavy alcohol consumption on intestinal transit time. Panminerva medica 40: 183-185, 1998.
43. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 16: 49-57, 1996.
44. Pham LV, Tamayo AT, Yoshimura LC, Lo P, and Ford RJ. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171: 88-95, 2003.
45. Polk WW, Ellis ME, Kushleika JV, Simmonds PL, and Woods JS. RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells. Am J Physiol Cell Physiol 293:C1160-1170,2007.
46. Rothwarf DM and Karin M. The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999: RE1, 1999.
47. Rothwarf DM, Zandi E, Natoli G, and Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395: 297-300, 1998.
48. Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K, and Pasparakis M. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Molecular cell 5: 981-992, 2000.
49. Sen R and Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46: 705-716, 1986.
50. Silverman N and Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes & development 15: 2321-2342,2001.
51. Sim SS, Choi JC, Min DS, Rhie DJ, Yoon SH, Hahn SJ, Kim CJ, Kim MS, and Jo YH. Effect of ethanol on spontaneous phasic contractions of cat gastric smooth muscle. Scandinavian journal of gastroenterology 37: 23-27, 2002.
52. Spink J and Evans T. Binding of the transcription factor interferon regulatory factor-1 to the inducible nitric-oxide synthase promoter. The Journal of biological chemistry 272: 24417-24425, 1997.
53. Szabo G, Mandrekar P, Oak S, and Mayerle J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 7: 115-123, 2007.
54. Tarpey MM, Wink DA, and Grisham MB. Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. American journal of physiology 286: R431-444, 2004.
55. Ueda M, Kokura S, Imamoto E, Naito Y, Handa O, Takagi T, Yoshida N, and Yoshikawa T. Blocking of NF-kappaB activation enhances the tumor necrosis factor alpha-induced apoptosis of a human gastric cancer cell line. Cancer letters 193: 177-182,2003.
56. Vannucchi MG, Corsani L, Bani D, and Faussone-Pellegrini MS. Myenteric neurons and interstitial cells of Cajal of mouse colon express several nitric oxide synthase isoforms. Neuroscience letters 326: 191-195, 2002.
57. Venkataranganna MV, Rafiq M, Gopumadhavan S, Peer G, Babu UV, and Mitra SK. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through down-regulation of NFkappa-B and iNOS. World J Gastroenterol 13: 1103-1107,2007.
58. Wang J, Huang Q, and Chen M. The role of NF-kappaB in hepatocellular carcinoma cell. Chinese medical journal 116: 747-752, 2003.
59. Wang SL, Xie DP, Liu KJ, Qin JF, Feng M, Kunze W, and Liu CY. Nitric oxide mediates the inhibitory effect of ethanol on the motility of isolated longitudinal muscle of proximal colon in rats. Neurogastroenterol Motil 19: 515-521, 2007.
60. Wang W, Luo HS, and Yu BP. Expression of NF-kappaB and human telomerase reverse transcriptase in gastric cancer and precancerous lesions. World J Gastroenterol 10: 177-181,2004.
61. Weinmann O, Gutzmer R, Zwirner J, Wittmann M, Langer K, Lisewski M, Mommert S, Kapp A, and Werfel T. Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2. Immunology 110: 458-465, 2003.
62. Whiteman M, Chua YL, Zhang D, Duan W, Liou YC, and Armstrong JS. Nitric oxide protects against mitochondrial permeabilization induced by glutathione depletion: role of S-nitrosylation? Biochemical and biophysical research communications 339: 255-262, 2006.
63. Wu D, Marko M, Claycombe K, Paulson KE, and Meydani SN. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. The Journal of biological chemistry 278: 10983-10992,2003.
64. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, and Israel A. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93: 1231-1240, 1998.
65. Yoshida Y, Liu JQ, Nakano Y, Ueno S, Ohmori S, Fueta Y, Ishidao T, Kunugita N, Yamashita U, and Hori H. 1-BP inhibits NF-kappaB activity and Bcl-xL expression in astrocytes in vitro and reduces Bcl-xL expression in the brains of rats in vivo. Neurotoxicology 28: 381-386,2007.
66. Yu LL, Yu HG, Yu JP, and Luo HS. Nuclear factor-kappa B regulates cyclooxygenase-2 expression and cell proliferation in human colorectal carcinoma tissue. Eksperimental'naia onkologiia 26: 40-47, 2004.
67. Zeldin G, Yang SQ, Yin M, Lin HZ, Rai R, and Diehl AM. Alcohol and cytokine-inducible transcription factors. Alcoholism, clinical and experimental research 20: 1639-1645, 1996.
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