Tetrahydrobiopterin Synthesis in Rat Cardiac Myocytes; An Event Required for Cytokine-induced NO Generation

Pteridines ◽  
1998 ◽  
Vol 9 (1) ◽  
pp. 8-12
Author(s):  
Yoshiyuki Hattori ◽  
Nobuo Nakanishi ◽  
Steven S. Gross ◽  
Kikuo Kasai
Keyword(s):  
Cardiac Myocytes ◽  
Limit Of Detection ◽  
High Capacity ◽  
Interferon Γ ◽  
Significant Rise ◽  
Inos Mrna ◽  
No Production ◽  
No Formation ◽  
Absolute Requirement ◽  
Rat Cardiac Myocytes

SummaryCardiac myocytes are known to express the high-capacity inducible isoform of nitric oxide (NO) synthase (iNOS). Since tetrahydrobiopterin (BH4) is an essential cofactor for NO formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultutred rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with inter-leukin-1α. and interferon-γ (IL-1/IFN) caused a significant rise in biopterin levels and induced NO synthesis. iNOS mRNA and GTP cyclohydrolase I (GTPCH) mRNA were induced by IL-1/IFN in parallel. 2,4-Diamino-6-hydroxypyridine (DAHP), a selective inhibitor of GTPCH, inhibited both the increase in cellular levels of BH4 as well as the concomitant formation of NO caused by IL-1/IFN. This inhibition by DAHP was reversed by coaddition of sepiapterin which is a substrate for BH4 synthesis. Thus BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation

1997 ◽  
Vol 273 (2) ◽  
pp. H665-H672 ◽  
Author(s):  
K. Kasai ◽  
Y. Hattori ◽  
N. Banba ◽  
S. Hattori ◽  
S. Motohashi ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
De Novo ◽  
Limit Of Detection ◽  
Interleukin 1 ◽  
Significant Rise ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Ifn Gamma ◽  
Rat Cardiac Myocytes

Because tetra-hydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultured rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with interleukin-1 alpha (IL-1 alpha) + interferon-gamma (IFN-gamma) caused a significant rise in biopterin levels and induced NO synthesis. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I (the rate-limiting enzyme for de novo BH4 synthesis), completely abolished the elevation in biopterin levels induced by IL-1 alpha + IFN-gamma. DAHP also caused a concentration-dependent inhibition of (IL-1 alpha + IFN-gamma)-induced NO synthesis. Similarly, N-acetylserotonin, an inhibitor of the BH4 synthetic enzyme sepiapterin reductase, blocked increases in biopterin levels as well as NO synthesis induced by IL-1 alpha + IFN-gamma. Sepiapterin, substrate for BH4 synthesis via the pterin salvage pathway, prevented this inhibition by DAHP or N-acetylserotonin, and this effect was blocked by methotrexate. Sepiapterin and, to a lesser extent, BH4 dose dependently enhanced (IL-1 alpha + IFN-gamma)-induced NO synthesis, suggesting that the concentration of BH4 limits the rate of NO production. Inducible NO synthase mRNA and GTP cyclohydrolase I mRNA were induced by IL-1 alpha + IFN-gamma in parallel. We thus demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

scholarly journals Acquired interferon γ responsiveness during Caco-2 cell differentiation: effects on iNOS gene expression

Gut ◽  
1999 ◽  
Vol 44 (5) ◽  
pp. 659-665 ◽  
Author(s):  
A M Chavez ◽  
M J Morin ◽  
N Unno ◽  
M P Fink ◽  
R A Hodin
Keyword(s):  
Nitric Oxide ◽  
Cell Differentiation ◽  
Interferon Γ ◽  
Intestinal Barrier Function ◽  
Inos Mrna ◽  
Pyrrolidine Dithiocarbamate ◽  
No Production ◽  
Mrna Induction ◽  
Ifn Γ ◽  
Inos Induction

BACKGROUNDImpairment of intestinal barrier function occurs under a variety of inflammatory conditions and is mediated at least in part by interferon γ (IFN-γ) induced nitric oxide (NO) production. Previous in vivo studies have shown that systemic lipopolysaccharide treatment caused an induction of the rat inducible nitric oxide synthase (iNOS) mRNA primarily in villus cells, rather than in undifferentiated crypt cells.AIMSTo examine iNOS induction by IFN-γ in vitro as a function of enterocyte differentiation.METHODSPreconfluent and postconfluent Caco-2 cells were treated with IFN-γ in the presence or absence of various inhibitors. Northern analyses were performed to assess the magnitude of iNOS mRNA induction. IFN-γ receptor mRNA and protein levels were determined.RESULTSiNOS mRNA induction by IFN-γ occurred at two hours and was not blocked by cycloheximide, indicating that it is an immediate early response. iNOS induction and nitrite/nitrate increases were inhibited by dexamethasone and pyrrolidine dithiocarbamate, supporting an important role for the NF-κB transcription factor in this process. The stimulated iNOS induction was seen almost exclusively under conditions of cellular differentiation—that is, in postconfluent Caco-2 cells. This increased IFN-γ responsiveness seen in postconfluent Caco-2 cells correlated with an increased expression of IFN-γ receptor, whereas T84 and HT-29 cells did not show any significant alterations in either iNOS induction or IFN-γ receptor levels as a function of postconfluent growth.CONCLUSIONSWith regard to iNOS mRNA induction, IFN-γ responsiveness is acquired during Caco-2 cell differentiation, perhaps related to an increase in the numbers of IFN-γ receptors.

Use of thapsigargin to study Ca2+ homeostasis in cardiac cells

1995 ◽  
Vol 15 (5) ◽  
pp. 341-349 ◽  
Author(s):  
Terry B. Rogers ◽  
Giuseppe Inesi ◽  
Robert Wade ◽  
W. J. Lederer
Keyword(s):  
Cardiac Myocytes ◽  
Calcium Current ◽  
Potent Inhibitor ◽  
Cell Voltage ◽  
Cardiac Cells ◽  
Heart Cells ◽  
Absolute Requirement ◽  
Rat Heart Myocytes ◽  
Rat Cardiac Myocytes

Several reports have documented that thapsigargin is a potent inhibitor of the SR Ca2+ ATPase isolated from cardiac or skeletal muscle. We have characterized the specificity of this agent in intact rat cardiac myocytes using cells maintained in the whole cell voltage clamp configuration. We have shown that thapsigargin decreases the magnitude of the Ca2+ transient and the twitch by about 80% while it slows the decay rate for these responses. These changes were not accompanied by any alterations in sarcolemmal currents or in the trigger Ca2+ generated by the inward calcium current. Taken together these results reveal that the action of thapsigargin is restricted to the SR Ca2+ ATPase in intact cardiac myocytes. Furthermore, it is demonstrated unambiguously that SR intracellular Ca2+ stores are an absolute requirement for the development of contractile tension in rat heart myocytes. It is shown that thapsigargin is a valuable probe to examine the importance of SR pools of Ca2+ and the role of the Ca2+ ATPase in intact myocytes as well as in genetically altered heart cells.

scholarly journals CHICKEN ANAEMIA VIRUS IMPAIRS NITRIC OXIDE PRODUCTION IN HD11 CHICKEN MACROPHAGES

2020 ◽  
Vol 57 (4) ◽  
Author(s):  
Katja Ester ◽  
William Lauman Ragland
Keyword(s):  
Nitric Oxide ◽  
Severe Disease ◽  
Interferon Γ ◽  
Economic Losses ◽  
No Production ◽  
Subclinical Infection ◽  
Chicken Anaemia Virus ◽  
No Formation ◽  
Chicken Macrophage ◽  
Oxide Synthase

Immunosuppressive viruses cause substantial economic losses to the poultry industry. Chicken anaemia virus (CAV) causes severe disease in young chickens, whereas subclinical infection in older birds causes immunosuppression. In this study, we addressed the ability of CAV to interfere with production of antimicrobial molecule nitric oxide (NO) by macrophages. NO production in chicken macrophage cell line HD11 was induced using both Toll-like receptor 4 agonist, bacterial lipopolysaccharide, and an immune modulator, interferon-γ. In addition, we treated macrophages with CAV propagated in chicken lymphoblastoid cells. The levels of NO were measured by the Griess reaction. Addition of CAV decreased both the interferon-γ and the lipopolysaccharide associated induction of NO. Observed effect was not caused by CAV-related cytotoxicity, as no decrease in number of viable cells was observed. Although CAV could not completely abrogate NO production, attenuation of NO induction was clearly present. We have previously shown that CAV interferes with the expression of interferons in chickens during subclinical infection. Since the signalling pathways of expression of interferons and type 2 nitric oxide synthase, enzyme involved in NO formation, overlap, we conclude that measured decrease in NO levels is a consequence of CAV interference with interferon and NO synthase signalling. Regardless of the fact whether the attenuation of NO serves as a viral primary defence, or is only a secondary effect, it could impair the immune response to other pathogens and contribute to the global immunosuppression in chicken houses.Key words: chicken; immunosuppression; chicken anaemia virus (CAV); macrophage; nitric oxide (NO) VIRUS PIŠČANČJE ANEMIJE VPLIVA NA PROIZVODNJO DUŠIKOVIH OKSIDOV V MAKROFAGIH PIŠČANEV HD11 Povzetek: Imunosupresivni virusi povzročajo velike gospodarske izgube v perutninski industriji. Virus piščančje anemije (CAV) pri mladih piščancih povzroča hudo bolezen, medtem ko subklinična okužba pri starejših pticah povzroča oslabljen imunski odziv. V tej raziskavi je bil spremljan vpliv CAV na proizvodnjo dušikovih oksidov (NO) v makrofagih. Proizvodnja NO v piščančjih makrofagih v celični liniji HD11 je bila sprožena z uporabo agonista Toll-u podobnega receptorja 4, bakterijskega lipopolisaharida in imunskega modulatorja interferona-γ, makrofagi pa so bili okuženi s CAV, razmnoženim v piščančjih limfoblastoidnih celicah. Ravni NO so izmerili po Griessovi reakciji. Prisotnost CAV je zmanjšala proizvodnjo NO, spodbujeno tako z interferonom-γ, kot z lipopolisaharidom. Opaženega učinka ni povzročila citotoksičnost, povezana s CAV, saj ni bilo opaziti zmanjšanja števila živih celic. Čeprav CAV ni popolnoma zavrla nastajanja NO, je bilo očitno prisotno zmanjšanje nastajanja NO. Pred tem so pokazali, da CAV moti izražanje interferonov pri piščancih med subklinično okužbo. Ker se poti znotrajceličnega prenosa urejanja izražanja interferonov in sintaze dušikovih oksidov tipa 2, encima, ki sodeluje pri tvorbi NO, prekrivajo, predvidevamo, da je izmerjeno znižanje ravni NO posledica motenj CAV pri znotrajceličnem prenosu sporočila interferona do sintaze dušikovih oksidov. Ne glede na to, ali zaviranje nastajanja NO služi kot primarna virusna obramba ali je le sekundarni učinek, lahko poslabša imunski odziv na druge patogene in prispeva k splošnemu zmanjšanju imunskega odziva v kurnikih ali na kokošjih farmah.Ključne besede: piščanci; zmanjšanje imunskega odziva; virus piščančje anemije (CAV); makrofagi; dušikov oksid (NO)

Protein kinase A activation is required for IL-1-induced nitric oxide production by cardiac myocytes

1996 ◽  
Vol 271 (1) ◽  
pp. C429-C434 ◽  
Author(s):  
C. V. Oddis ◽  
R. L. Simmons ◽  
B. G. Hattler ◽  
M. S. Finkel
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cardiac Myocytes ◽  
Interleukin 1 ◽  
Neonatal Rat ◽  
Inos Mrna ◽  
No Production ◽  
Neonatal Rat Cardiac Myocytes ◽  
Kinase A

We have previously reported that interleukin-1 beta (IL-1) alone induced the transcription of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production by isolated neonatal rat cardiac myocytes (CM). The present studies were undertaken to explore the signal transduction pathways involved in IL-1-induced NO production by CM. The addition of IL-1 to CM resulted in a peak rise in both adenosine 3',5'-cyclic monophosphate (cAMP) and protein kinase A (PKA) activities by 10 min followed by rapid declines and return to basal levels within 60 min. The PKA inhibitor KT-5720 completely blocked NO-2 production by IL-1-stimulated CM (P < 0.01; n = 12). The protein kinase C (PKC) inhibitor, calphostin C, had no effect on NO2- production by IL-1 stimulated CM [P = not significant (NS); n = 12]. The addition of PKA+cAMP to cytosols derived from IL-1-treated CM did not directly enhance iNOS enzyme activity (P = NS; n = 3). CM treated with IL-1 alone stained positively for iNOS protein by immunohistochemistry. iNOS staining was absent in CM treated with IL-1+KT-5720. KT-5720 resulted in an earlier disappearance of iNOS mRNA from IL-1-treated CM, as detected by semiquantitative reverse transcriptase-polymerase chain reaction. We report for the first time that PKA (but not PKC) activation is required for IL-1-induced NO production by CM.

cAMP enhances inducible nitric oxide synthase mRNA stability in cardiac myocytes

1995 ◽  
Vol 269 (6) ◽  
pp. H2044-H2050 ◽  
Author(s):  
C. V. Oddis ◽  
R. L. Simmons ◽  
B. G. Hattler ◽  
M. S. Finkel
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cardiac Myocytes ◽  
Inducible Nitric Oxide Synthase ◽  
Mrna Stability ◽  
Neonatal Rat ◽  
Inos Mrna ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The effects of adenosine 3',5'-cyclic monophosphate (cAMP) on cardiac myocyte nitric oxide (NO) production were studied. Maximal nitrite (NO2(-)) production by cultured neonatal rat cardiac myocytes was achieved with 500 U/ml interleukin-1 beta (IL-1 beta) for 48 h (4.6 +/- 0.3 nmol/1.25 x 10(5) cells; n = 12). Cardiac myocytes exposed to 500 U/ml IL-1 beta for 48 h stained positively for inducible nitric oxide synthase (iNOS) by immunohistochemistry. Forskolin (FSK; adenylate cyclase stimulator) or dibutyryl cAMP (DBcAMP; membrane-permeable cAMP analogue) administration alone had no effect on NO2(-) production. The addition of FSK or DBcAMP to IL-1 beta significantly increased NO2-) levels vs. IL-1 beta alone (9.7 +/- 0.6 and 10.9 +/- 0.8 vs. 4.6 +/- 0.3 nmol/1.25 x 10(5) cells per 48 h, respectively; P < 0.01; n = 12). Semiquantitative reverse transcriptase-polymerase chain reaction revealed increased iNOS mRNA in myocytes treated with FSK+IL-1 beta or DBcAMP+IL-1 beta vs. those treated with IL-1 beta alone. The addition of FSK or DBcAMP to IL-1 beta increased iNOS mRNA half-life over IL-1 beta treatment alone (10.6, 11.7 vs. 2.4 h, respectively). Cardiac myocytes do not express iNOS in response to cAMP alone. Rather, cAMP enhances iNOS mRNA stability following cytokine exposure.

NF-kappa B and GTP cyclohydrolase regulate cytokine-induced nitric oxide production by cardiac myocytes

1996 ◽  
Vol 270 (5) ◽  
pp. H1864-H1868 ◽  
Author(s):  
C. V. Oddis ◽  
M. S. Finkel
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Nuclear Translocation ◽  
Interleukin 1 ◽  
No Synthase ◽  
Neonatal Rat ◽  
Inos Mrna ◽  
No Production ◽  
Gtp Cyclohydrolase ◽  
Nf Kappa B

We previously reported that interleukin-1 beta (IL-1) alone stimulated nitric oxide (NO) production by neonatal rat cardiac myocytes (CM) in culture. The present studies were undertaken to explore the signal transduction pathways involved in IL-1-induced NO production by CM. Translocation from the cytosol to the nucleus of nuclear factor-kappa B (NF-kappa B) and activation of guanosine 5'-triphosphate (GTP) cyclohydrolase [rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis] have been implicated in IL-1 signaling. Accordingly, the effects of the NF-kappa B inhibitor pyrolidine dithiocarbamate (PDTC) and the GTP cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) on IL-1-induced NO production by CM were studied. PDTC and DAHP inhibited IL-1-induced NO2-production by CM (6.7 +/- 0.6 vs. 0.9 +/- 0.3 and 0.3 +/- 0.1 nmol. 1.25 x 10(5) cells(-1).48 h-1, respectively, P < 0.01, n = 12 for each). Immunohistochemical staining revealed that PDTC blocked IL-1-stimulated nuclear translocation of NF-kappa B. The membrane-permeable analogue of the NO synthase cofactor BH4, methyl-BH4 (mBH4), only partially reversed DAHP inhibition of NO2- formation (6.7 +/- 0.6 vs. 2.4 +/- 0.3 nmol. 1.25 x 10(5) cells-1.48 h-1, P < 0.01, n = 12). Semiquantitative reverse transcription polymerase chain reaction revealed no inducible NO synthase (iNOS) mRNA production in cells treated with IL-1 + PDTC.CM treated with IL-1 + DAHP did express iNOS mRNA. We report for the first time that nuclear translocation of NF-kappa B is essential for II-1-induced iNOS mRNA expression and GTP cyclohydrolase activity is required in addition in addition to BH4 for optimal NO production by CM.

Pulmonary surfactant inhibits LPS-induced nitric oxide production by alveolar macrophages

1999 ◽  
Vol 276 (1) ◽  
pp. L186-L196 ◽  
Author(s):  
P. R. Miles ◽  
L. Bowman ◽  
K. M. K. Rao ◽  
J. E. Baatz ◽  
L. Huffman
Keyword(s):  
Nitric Oxide ◽  
Alveolar Macrophages ◽  
Pulmonary Surfactant ◽  
Radical Scavenger ◽  
Inos Mrna ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Inos Protein ◽  
No Formation

The objectives of this investigation were 1) to report that pulmonary surfactant inhibits lipopolysaccharide (LPS)-induced nitric oxide (⋅ NO) production by rat alveolar macrophages, 2) to study possible mechanisms for this effect, and 3) to determine which surfactant component(s) is responsible. ⋅ NO produced by the cells in response to LPS is due to an inducible ⋅ NO synthase (iNOS). Surfactant inhibits LPS-induced ⋅ NO formation in a concentration-dependent manner; ⋅ NO production is inhibited by ∼50 and ∼75% at surfactant levels of 100 and 200 μg phospholipid/ml, respectively. The inhibition is not due to surfactant interference with the interaction of LPS with the cells or to disruption of the formation of iNOS mRNA. Also, surfactant does not seem to reduce ⋅ NO formation by directly affecting iNOS activity or by acting as an antioxidant or radical scavenger. However, in the presence of surfactant, there is an ∼80% reduction in the amount of LPS-induced iNOS protein in the cells. LPS-induced ⋅ NO production is inhibited by Survanta, a surfactant preparation used in replacement therapy, as well as by natural surfactant. ⋅ NO formation is not affected by the major lipid components of surfactant or by two surfactant-associated proteins, surfactant protein (SP) A or SP-C. However, the hydrophobic SP-B inhibits ⋅ NO formation in a concentration-dependent manner; ⋅ NO production is inhibited by ∼50 and ∼90% at SP-B levels of 1–2 and 10 μg/ml, respectively. These results show that lung surfactant inhibits LPS-induced ⋅ NO production by alveolar macrophages, that the effect is due to a reduction in iNOS protein levels, and that the surfactant component responsible for the reduction is SP-B.

HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-κB activation

2000 ◽  
Vol 279 (6) ◽  
pp. H3138-H3143 ◽  
Author(s):  
Hong Kan ◽  
Zirong Xie ◽  
Mitchell S. Finkel
Keyword(s):  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Myocardial Dysfunction ◽  
Neonatal Rat ◽  
Inos Mrna ◽  
Protein Kinase Activity ◽  
No Production ◽  
Direct Effects ◽  
Hiv Gp120 ◽  
Hiv 1

Human immunodeficiency virus (HIV) infection is associated with a surprisingly high frequency of myocardial dysfunction. Potential mechanisms include direct effects of HIV, indirect effects mediated by cytokines, or a combination. We have previously reported that interleukin-1β (IL-1β) (500 U/ml) alone induced nitric oxide (NO) production by neonatal rat cardiac myocytes (CM). Effects of the HIV-1 envelope, glycoprotein120 (gp120), on inducible NO synthase (iNOS) in CM have not been previously reported. Unlike IL-1β, recombinant HIV-gp120 (1 μg/ml) alone failed to enhance NO production in CM (0.5 ± 0.4 vs. 0.4 ± 0.5 μmol/1.25 × 105 cells/48 h, gp120 vs. control, respectively; n = 12, P = not significant). However, the addition of gp120 to IL-1β significantly enhanced iNOS mRNA expression (70 ± 1.5 vs. 26 ± 2.4 optical units, IL-1β + gp120 vs. IL-1β, respectively; n = 3), iNOS protein synthesis (42 ± 1.4 vs. 18 ± 0.8 optical units, IL-1β + gp120 vs. IL-1β, respectively; n = 3), and NO production (NO2 −) (6.6 ± 0.6 vs. 4.1 ± 0.8 μmol/1.25 × 105 cells/48 h, IL-1β + gp120 vs. IL-1β, respectively; n = 12, P ≤ 0.5). HIV-gp120 enhancement of IL-1β-induced NO2 −production was blocked by 10 μM of SB-203580 (SB), a selective p38 protein kinase inhibitor (3.6 ± 0.2 vs. 6.6 ± 0.6 μmol/1.25 × 105 cells/48 h, IL-1β + gp120 + SB vs. IL-1β + gp120, respectively; n = 12, P ≤ 0.5). HIV-gp120-enhanced p38 protein kinase activity was associated with an increase in IL-1β-stimulated NF-κB activity (184 ± 12.7 vs. 92 ± 10.7 optical units, IL-1β + gp120 vs. IL-1β, respectively; n = 3). None of these effects was seen with another recombinant HIV-1 protein, Tat. Thus HIV-gp120 enhancement of IL-1β-induced NO production is associated with p38-mediated activation of NF-κB. Direct effects of HIV-gp120 on CM may provide a previously unrecognized mechanism contributing to HIV cardiomyopathy.

Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NO production by rat cardiac myocytes

1999 ◽  
Vol 276 (1) ◽  
pp. H47-H52 ◽  
Author(s):  
Hong Kan ◽  
Zirong Xie ◽  
Mitchell S. Finkel
Keyword(s):  
Map Kinase ◽  
Mrna Expression ◽  
Cardiac Myocytes ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Inos Mrna ◽  
No Production ◽  
Text Production ◽  
Mitogen Activated Protein ◽  
Adrenergic Blocker

The effect of norepinephrine (NE) on cytokine-stimulated nitric oxide (NO) production by cardiac myocytes has not been previously reported. NE alone caused no significant increase in [Formula: see text] levels over vehicle. Addition of NE to interleukin-1β (IL-1β) significantly increased inducible NO synthase (iNOS) mRNA expression, iNOS protein, and [Formula: see text] production vs. IL-1β alone. Addition of the α-adrenergic blocker prazosin or the β-adrenergic blocker propranolol partially reduced the NE-mediated increase in iNOS mRNA expression and[Formula: see text] production. Addition of prazosin and propranolol together completely abolished the NE-induced increase in iNOS mRNA expression and[Formula: see text] production. NE significantly enhanced mitogen-activated protein (MAP) kinase activity that was reduced by prazosin, propranolol, and PD-98059, a selective MAP kinase kinase inhibitor. Addition of PD-98059 reduced the NE-mediated increase in iNOS mRNA expression and [Formula: see text]production. We report for the first time that NE enhances IL-1β-stimulated NO production by activation of α- and β-adrenergic receptors through a novel MAP kinase mechanism.

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