| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
RECEPTORS AND SIGNAL TRANSDUCTION
Centers for 1Perinatal Research and 2Gene Therapy, Columbus Children's Research Institute, Department of Pediatrics, The Ohio State University, Columbus, Ohio; and 3Department of Pediatrics, Children's Foundation Research Center at Le Bonheur Children's Medical Center, University of Tennessee Health Sciences Center at Memphis, Memphis, Tennessee
Submitted 26 March 2006 ; accepted in final form 17 April 2007
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
lung injury; macrophage; ornithine; mitogen-activated protein kinases
, IFN-
, 8-bromo-cGMP, and hyperoxia (10, 26, 27, 28). The L-ornithine produced by arginase is a precursor for polyamine and L-proline synthesis, which are vital to tissue repair processes following injury (35). Thus it has been postulated that, in inflammatory diseases, NO production from L-arg is involved in the initial host response, whereas L-ornithine production from L-arg is involved in healing (17, 23).
It has been found in macrophages that T-cell helper (Th) 1 cytokines, such as TNF- and IFN-, result in iNOS expression and Th2 cytokines, such as IL-13, result in arginase expression (16). The idea that NOS and arginase may have important yet divergent roles in the immune response led us to postulate that switching mechanisms may exist that allow macrophages to redirect L-arg metabolism from NOS to arginase. Previously, it has been reported that the mitogen-activated protein kinases (MAPK) contribute to iNOS induction in LPS-stimulated RAW264.7 cells (4, 7). We have recently shown that the MAPK phosphatase-1 (MKP-1) plays a crucial role in the downregulation of MAPK signaling in LPS-stimulated macrophages (9, 32). For example, we have recently shown that macrophages overexpressing MKP-1 have decreased total expression and a shorter duration of p38 and JNK activation following LPS stimulation (32, 36). Thus we hypothesize that MKP-1 attenuates LPS-induced iNOS expression, thus acting as a switch to change L-arg metabolism from the production of NO and L-citrulline to the production of urea and L-ornithine. To test this hypothesis, we utilized RAW264.7 cell lines stably transfected with an MKP-1 expression vector, as well as thioglycollate-elicited peritoneal macrophages from Mkp-1–/– mice. The role of MAPK in LPS-induced NO and urea production was confirmed using pharmacological inhibitors of p38, extracellular signal-regulated kinase kinases (MEK1/2), and c-Jun NH2-terminal kinase (JNK) in RAW264.7 macrophages. In general, we found that overexpression of MKP-1 resulted in decreased iNOS induction and NO production but greater urea production in LPS-stimulated macrophages, whereas deficiency of MKP-1 resulted in greater LPS-induced iNOS expression and NO production but less urea production. Studies were also carried out in vivo using LPS-treated Mkp-1–/– and wild-type mice. Our results strongly suggest that MKP-1 represents a novel switching mechanism in shifting L-arg metabolism from production of NO to production of urea and L-ornithine during host inflammatory responses.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-FLAG-MKP-1) together with pcDNA3 (Invitrogen) or pcDNA3 alone using FuGENE6 transfection reagent (Roche, Indianapolis, IN) according to the manufacturer's specifications and as previously described (32). Cells were selected in medium containing G418, and resistant clones were isolated. One clone expressing exogenous MKP-1 was designated PC53, whereas a clone harboring pcDNA3 was designated D3. LPS (E. coli, O55:B5) was purchased from Sigma Chemicals (St. Louis, MO) dissolved in serum-free medium and added to the medium. Mice. The generation of MKP-1 knockout mice was described previously (14). Cryopreserved embryos of Mkp-1 knockout mouse (–/+ and –/–) on a C57BL6/129 mixed background were kindly provided by Bristol-Myers Squibb Pharmaceutical Research Institute (Lawrenceville, NJ) and were regenerated into mice in The Jackson Laboratory (Bar Habor, ME). These mice were bred in house to yield both wild-type and Mkp-1–/– mice. All mice were maintained at 24°C with a relative humidity between 30 and 70% on a 12-h day-night cycle. Mice were fed Harlan Tecklad irradiated diet (Harlan Sprague-Dawley) ad libitum. All animals received humane care in accordance with the guidelines of the National Institutes of Health under a protocol approved by the Institutional Animal Care and Use Committee of the Columbus Children's Research Institute.
Peritoneal macrophage isolation and culture. Peritoneal macrophages were obtained from Mkp-1–/– mice and their wild-type littermates as previously described (32). Briefly, mice were injected with 2 ml of 3% brewer thioglycollate medium (BD Diagnostics, Sparks, MD) intraperitoneally. Four days later, cells were harvested by lavage with cold RPMI 1640 medium (Invitrogen) containing 5% FBS and plated into tissue culture plates. Cells were allowed to adhere for 2 h, washed free of nonadherent cells, and maintained in RPMI 1640 medium containing 5% FBS.
Protein isolation. Protein was isolated from the RAW264.7 cells and peritoneal macrophages as previously described (32, 36). Briefly, cells were washed with HBSS, and 750 µl of lysis buffer [0.2 M NaOH, 0.2% SDS with the following added to each milliliter 30 min before use (in µg): 2 aprotinin, 5 leupeptin, 0.7 pepstatin A, and 174 phenylmethylsulfonyl fluoride]. The lysis buffer was sterile filtered in a syringe and added to each plate of cells. The cells were scraped and centrifuged at 12,000 g for 10 min. Total protein concentration was determined by the Bradford method using a commercially available assay kit (Bio-Rad, Hercules, CA).
RNA isolation. RNA was isolated as previously described (32, 36). Briefly, 1 ml of Trizol (Invitrogen) was added to each plate containing the cells and incubated for 5 min at room temperature. Chloroform (0.2 ml) was added and the tubes shaken for 15 s and then incubated at room temperature for 3 min. The mixture was centrifuged at 12,000 g for 15 min at 4°C. The supernatant was transferred to a fresh 1.5-ml tube. Isopropyl alcohol (0.5 ml) was added and the mixture incubated at room temperature for 10 min, then centrifuged at 12,000 g for 15 min at 4°C. The supernatant was discarded, and the pellet was washed with 75% ethanol and centrifuged at 7,500 g for 5 min at 4°C. The supernatant was discarded, and the pellet was partially dried, dissolved in RNAse free water, and stored at –70°C.
Nitrite assay. The medium samples were assayed in duplicate for nitrite using a chemiluminescence NO analyzer (model 280, Sievers Instruments, Boulder, CO) as previously described (10, 27, 28). Briefly, 100 µl of sample was placed in a reaction chamber containing a mixture of NaI in glacial acetic acid to reduce nitrite to NO. The NO gas was carried into the NO analyzer using a constant flow of He gas. The analyzer was calibrated using a NaNO2 standard curve.
Urea assay. The medium samples were assayed in duplicate for urea colorimeterically as previously described (10, 27, 28). Briefly, 100 µl of sample was added to 3 ml of chromogenic reagent [5 mg of thiosemicarbazide, 250 mg of diacetyl monoxime, 37.5 mg of FeCl3 in 150 ml 25% (vol/vol) H2SO4, 20% (vol/vol) H3PO4] or the same reagents with 0.5 U urease added. After 1 h at 37°C, the mixtures were vortexed and then boiled at 100°C for 5 min. The mixtures were cooled to room temperature, and the difference in absorbance (530 nm) with and without urease was determined and compared with a urea standard curve.
Western blotting.
The protein lysate from the cells was assayed for MKP-1, FLAG, iNOS, arginase I, and/or arginase II proteins by Western blot analysis, as previously described (27, 32, 36). Aliquots of cell lysate containing equal amounts of protein were diluted 1:1 with SDS sample buffer, heated to 80°C for 15 min, and then centrifuged at 10,000 g at room temperature for 2 min. Aliquots of the supernatant were used for SDS-polyacrylamide gel electrophoresis. The proteins were transferred to polyvinylidene difluoride membranes and blocked overnight in PBS with 0.1% Tween containing 5% nonfat dried milk and 3% albumin. The membranes were then incubated with the primary antibody MKP-1 (1:500; Santa Cruz Biotechnologies, Santa Cruz, CA), FLAG (1:4,000; Berkeley Antibody, Richmond, CA), iNOS (1:5,000; BD Transduction Laboratories, San Diego, CA), arginase I (1:1,000, Abcam, Cambridge, MA), or arginase II (1:200, Santa Cruz Biotechnology) for 4 h and then washed three times with PBS-Tween with 1% nonfat dried milk. The membranes were then incubated with the biotinylated IgG secondary antibody (1:5,000; Vector Laboratories; Burlingame, CA) for 1 h, washed, and then incubated with streptaviden-horseradish peroxidase conjugate (1:1,500; Bio-Rad) for 30 min. The protein bands were visualized using chemiluminescence (ECL reagent; Amersham Pharmacia Biotech, Piscataway, NJ) and quantified using densitometry (Sigma Gel, Jandel Scientific, San Rafael, CA). To control for protein loading, the blots were then stripped using a stripping buffer (62.5 mM Tris·HCl pH 6.8, 2% SDS, and 100 mM 2-
-mercaptoethanol), and the blots were reprobed for -actin or IgG (1:10,000; Abcam), as described above.
Reverse-transcription PCR. Reverse-transcription PCR was performed as previously described (10, 27, 28). Briefly, 2 µg of total RNA were reversed transcribed in a 40-µl reaction containing 2.5 µM dT16 (Applied Biosystems), 20 U AMV-RT, 1 mM dNTP, 1x buffer (Promega), and RNase-free water. The samples were incubated in a PCR-iCycler (Bio-Rad) at 42°C for 60 min, followed by 95°C for 5 min. PCR reactions were carried out in 50-µl reactions containing 5 µl of reverse-transcription product, 1 mM MgCl2, 1.25 U AmpliTaqGold (Applied Biosystems), 0.2 mM dNTP (Promega), and 15 µM forward and 15 µM reverse primers. iNOS was amplified using forward primer (5'-TCCAGAAGCAGAATGTGACC-3') and reverse primer (5'-GGACCAGCCAAATCCAGT-3'). Arginase I was amplified using forward primer (5'-AGAATGGAAGAGTCAGTGTGGTGC-3') and reverse primer (5'-GTTGAGTTCCGAAACAAGCGAAGG-3'). Arginase II was amplified using forward primer (5'-ACAGGGTTGCTGTCAGCTCT-3') and reverse primer (5'-TGATCCAGACAGCCATTTCA-3'). The mixed samples were heated to 94°C for 4 min, and followed by 94°C for 1 min, 53°C for 1 min, and 72°C for 2 min for 35 cycles for iNOS, 40 cycles for arginase I, and 37 cycles for arginase II. The PCR products were sized by electrophoresis in 2.0% agarose gel and poststaining with Syber Gold (Molecular Probes, Eugene, OR) for 30 min. The gels were scanned and densitized using a MultiGenius Bio Imaging System (Syngene, Frederick, MD), and band density analysis was performed on a personal computer with SigmaGel (Jandel Scientific) software.
Statistical analysis. Values are means ± SE. One-way ANOVA was used to compare the data between the groups. Significant differences were identified using a Neuman-Keuls post hoc test. Differences were considered significant when P < 0.05.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
35% by the p38 inhibitor SB20358 (Fig. 1). Moreover, the LPS-induced increase in NO production was attenuated by 60% by the JNK inhibitor SP600125 (Fig. 1). In contrast, the MEK1/2 inhibitor U0126 had no discernible effect on the LPS-induced increase in NO production (Fig. 1). These results demonstrate that p38 and JNK activation are involved in the LPS-induced NO production in macrophages.
|
|
38% lower (Fig. 2C), indicating that enhanced MKP-1 expression inhibits the induction of iNOS mRNA by LPS. In the absence of LPS stimulation, both D3 and PC53 cells had trace amounts of iNOS protein (Fig. 2D). LPS treatment resulted in substantially greater iNOS protein levels in both D3 and PC53 cells. However, compared with iNOS protein levels in LPS-stimulated D3 cells, iNOS protein levels in LPS-stimulated PC53 cells were 40% lower (Fig. 2E), further confirming the observation that MKP-1 attenuates the expression of iNOS.
MKP-1 overexpression had little effect on arginase expression.
Arginase I mRNA bands were only readily detectable in cells treated with LPS, regardless of whether the cells expressed exogenous MKP-1 (Fig. 3). On LPS treatment, arginase I mRNA levels were increased by 16-fold. There was no significant differences in arginase I mRNA levels between the LPS-treated D3 and PC53 cells (Fig. 3B). Arginase II mRNA, was present in both control and LPS-stimulated D3 and PC53 cells. The relative induction of arginase II by LPS treatment was much less than for arginase I in these cells (only about twofold in both D3 and PC53 cells; Fig. 3D). These data indicate that LPS-treatment induced arginase I and II expression and that MKP-1 overexpression had little effect on the LPS-induced arginase I or II expression.
|
50% that of D3 cells (Fig. 4A), indicating that MKP-1 overexpression attenuated LPS-induced NO production. LPS treatment resulted in a substantial increase in urea production in both D3 and PC53 cells (Fig. 4B). Interestingly, despite no significant differences in either arginase I or II mRNA expression between LPS-treated PC53 and D3 cells, LPS-treated PC53 cells had 50% more urea production than did LPS-treated D3 cells (Fig. 4B).
|
|
6 h after challenge (Fig. 5D). The LPS-induced NO production was greater in peritoneal macrophages from Mkp-1–/– mice than in peritoneal macrophages from wild-type mice at 6, 8, 14, and 24 h post-LPS treatment (Fig. 5D). Treatment with LPS resulted in greater urea production in macrophages harvested from both wild-type and Mkp-1–/– mice beginning 4–6 h after LPS treatment (Fig. 5E). Contrary to what was observed for NO production, the LPS-induced urea production was greater in the wild-type macrophages than in Mkp-1–/– macrophages (Fig. 5E). Thus, in the absence of MKP-1, NO production was enhanced, whereas urea production was attenuated following LPS stimulation. Given that iNOS protein levels were substantially greater and that levels of arginase I and II were not less following LPS-challenge in the Mkp-1–/– macrophages, these results suggest that the greater NO production resulted in decreased L-arg bioavailability to arginase in the LPS-stimulated Mkp-1–/– macrophages. Mkp-1 knockout mice exhibit increased iNOS expression and NO production following LPS challenge. The plasma concentrations of nitrates were greater in Mkp-1–/– mice than in their wild-type littermates, whereas the plasma concentrations of urea were lower in Mkp-1–/– mice than in their wild-type littermates 24 h after LPS challenge (Fig. 6A). Western blot analysis of tissue homogenates revealed a remarkable increase in iNOS protein levels in the lungs and livers from Mkp-1–/– mice but not in tissues from their wild-type littermates (Fig. 6B). However, the levels of arginase I protein were not different in the lungs and livers between LPS-treated Mkp-1–/– mice and their wild-type littermates (Fig. 6C). In the lungs, there was no difference in arginase II protein levels between Mkp-1–/– and wild-type mice (Fig. 6D). We were unable to reliably detect arginase II protein in the livers from either LPS-treated Mkp-1–/– mice or LPS-treated wild-type mice.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
The greater production of urea in the PC53 cells after LPS challenge may be due to increased bioavailability of L-arg to arginase, given that there was little change in arginase protein expression. It has been suggested that the co-induction of iNOS and arginase is a mechanism to limit NO production in macrophages to avoid NO overproduction (6). Although the concept that NOS and arginase compete for a common pool of L-arg is somewhat curious given that the L-arg Km for NOS is 10 µM and for arginase is 1 mM, these Km values would suggest that there should be adequate L-arg concentrations in the cell medium and plasma to maintain adequate L-arg bioavailability to both enzymes. However, in cultured cell studies where either NOS (33) or arginase (23) were overexpressed, the activities of the other enzyme, whose expression was unaltered by the treatment, were decreased. In studies in cytokine-stimulated pulmonary arterial endothelial cells and macrophages, NO production was significantly enhanced by inhibition of arginase (5, 6, 10). Therefore, taken together, these studies are consistent with the concept that arginase and NOS compete for a common pool of intracellular L-arg.
On the other hand, the decreased urea production following LPS in the Mkp-1–/– macrophages may be secondary to inhibition of arginase activity. It has been found that arginase can be inhibited by an intermediate in the L-arg-NO pathway, NG-hydroxy-L-arginine (NOHA), during high-output NO synthesis. For example, Buga et al. (3) demonstrated that when cytokine-induced NO production was increased by 20-fold in rat aortic endothelial cells, intracellular levels of NOHA increased and arginase activity was inhibited. Furthermore, inhibition of NOS decreased levels of NOHA and increased urea production. The IC50 for NOHA inhibition of arginase has been found to be 10–40 µM (3, 12). Waddington et al. (34), found that NOHA inhibited arginase activity in macrophages at NO concentrations of 20 and 200 µM but not at an NO concentration of 2 µM. In our in vitro studies in macrophages, the media concentration of nitrite reached 50 µM in some studies at 24 h, and therefore it is likely that the decrease in urea production in LPS-treated Mkp-1–/– macrophages may have been due at least in part to inhibition of arginase activity by NOHA.
MKP-1 has been shown to prefer JNK and p38 as substrates (9, 32, 36). We found in this study that LPS-induced NO production is mediated, at least in part, by JNK and p38 and that overexpression of MKP-1 attenuated LPS-induced iNOS mRNA expression. Given the substrate preference of MKP-1, it is likely that overexpressing MKP-1 resulted in lower levels of phosphorylated p38 and/or JNK due to accelerated dephosphorylation of these kinases, as we have recently demonstrated (9, 36). This accelerated dephosphorylation of p38 and JNK would ultimately result in lower levels of iNOS mRNA expression. Conversely, knockout of MKP-1 would result in delayed dephosphorylation of p38 and JNK, as we have recently demonstrated (37), which would have resulted in prolonged activation and greater levels of iNOS mRNA and protein. Thus alterations in p38 and JNK phosphorylation were likely involved in the alterations in iNOS mRNA levels we found. It has recently been reported that LPS stimulates iNOS expression via activation of NF-
B in RAW264.7 macrophages (12) and that p38 activation is involved in this signaling pathway (11). Thus alterations in NF-B signaling caused by prolonged p38 activation due to Mkp-1 knockout may have also contributed to changes in the production of iNOS mRNA we found in this study. Regardless of which mechanism(s) were responsible, alterations in iNOS mRNA expression were associated with similar alterations in iNOS protein expression and NO production. For example, in the MKP-1-overexpressing cells, both iNOS mRNA and iNOS protein levels were decreased (Fig. 2). Given the recently described relatively short half-life of iNOS protein (22), the observed decrease in iNOS protein levels are consistent with the decrease in iNOS transcription found in these cells.
In terms of the LPS effect on arginase, treatment of RAW264.7 macrophage cell lines with LPS led predominantly to the upregulation of arginase I mRNA expression, a finding that is consistent with recent studies (15, 21, 29). The induction of arginase I has been reported to be controlled by activation of an enhancer 3 kb downstream of the basal promoter (29). The net effect of arginase I and/or arginase II induction by LPS was a dramatic increase in urea production. The biological significance of enhanced arginase activities in LPS-treated macrophages remains unclear. We speculate that arginase could represent a molecular mechanism used by macrophages to attenuate NO production and thereby dampen inflammatory responses (6, 19). We have recently reported that exogenous iNOS and native arginase compete for a common pool of L-arg in endothelial cells (33). Since iNOS and arginase compete for their common substrate, L-arg, the bioavailability of L-arg to iNOS would be limited by upregulating arginase, thereby resulting in a reduction in NO production. Further support for this concept comes from the reported finding that pharmacological inhibition of arginase leads to enhanced NO production (5, 10). Augmenting arginase activities also favors the formation of polyamines and/or L-proline from L-ornithine, which are important in cellular proliferation and repair after injury (19, 23). Thus we propose that arginase induction following endotoxin represents a change in macrophage phenotype following LPS stimulation, from a state favoring an acute inflammatory response to a state favoring repair and healing (31). This concept is supported by studies reporting that Th2 cytokines are potent inducers of arginase, whereas Th1 cytokines are potent inducers of iNOS (6, 25, 26). Given the key role of arginase in polyamine and proline synthesis, the induction of arginase by Th2 cytokines may be vital to attenuate aggressive inflammatory responses and allow for cellular proliferation (23). Consistent with this concept is a recent study by Ignarro et al. (18) in which vascular smooth muscle cells transfected with arginase I exhibited enhanced cellular proliferation. Therefore, we propose that the upregulation of arginase following LPS stimulation serves two complimentary roles that allow for host defense without causing damage to the host: first, arginase serves as an important negative regulator of NO production to limit tissue damage; and second, arginase facilitates tissue repair through participating in polyamine and proline synthesis.
|
GRANTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
. J Infect Dis 179: 939–944, 1999.[CrossRef][ISI][Medline]2. Bian K, Murad F. Nitric oxide (NO)-biogeneration, regulation, and relevance to human diseases. Front Biosci 8: 264–278, 2003.[CrossRef]
3. Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ. Arginase activity in endothelial cells: inhibition by NG-hydroxy-L-arginine during high-output NO production. Am J Physiol Heart Circ Physiol 271: H1988–H1998, 1996.
4. Chan ED, Riches DWH. IFN- + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38mapk in a mouse macrophage cell line. Am J Physiol Cell Physiol 280: C441–C450, 2001.
5. Chang C, Liao JC, Kuo L. Arginase modulates nitric oxide production in activated macrophages. Am J Physiol Heart Circ Physiol 274: H342–H348, 1998.
6. Chang C, Zoghi B, Liao JC, Kuo L. The involvement of tyrosine kinases, cyclic AMP/protein kinase A, and p38 mitogen-activated protein kinase in IL-13-mediated arginase I induction in macrophages: its implications in IL-13-inhibited nitric oxide production. J Immunol 165: 2134–2141, 2000.
7. Chen C, Chen YH, Lin WW. Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 97: 124–129, 1999.[CrossRef][ISI][Medline]
8. Chen CC, Wang JK. P38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol Pharmacol 55: 481–488, 1999.
9. Chen P, Li J, Barnes J, Kokkonen GC, Lee JC, Liu Y. Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J Immunol 169: 6408–6416, 2002.
10. Chicoine LG, Paffett ML, Young TL, Nelin LD. Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol 287: L60–L68, 2004.
11. Cho SY, Park SJ, Kwon MJ, Jeong TS, Bok SH, Choi WY, Jeong WI, Ryu SY, Do SH, Lee CS, Song JC, Jeong KS. Quercetin suppresses proinflammatory cytokines production through MAP kinases and NF-B pathway in lipopolysaccharide-stimulated macrophages. Mol Cell Biochem 243: 153–160, 2003.[CrossRef][ISI][Medline]
12. Daghigh F, Fukuto JM, Ash DE. Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun 202: 174–180, 1994.[CrossRef][ISI][Medline]
13. Deng WG, Wu KK. Regulation of inducible nitric oxide synthase expression by p300 and p50 acetylation. J Immunol 171: 6581–6588, 2003.
14. Dorfman K, Carrasco D, Gruda M, Ryan C, Lira SA, Bravo R. Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene 13: 925–931, 1996.[ISI][Medline]
15. Gotoh T, Mori M. Arginase II downregulates nitric oxide (NO) production and prevents NO-mediated apoptosis in murine macrophage-derived RAW 264.7 cells. J Cell Biol 144: 427–434, 1999.
16. Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, Cheever AW, Pearce EJ, Wynn TA. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol 167: 6533–6544, 2001.
17. Hoet PH, Nemery B. Polyamines in the lung: polyamine uptake and polyamine-linked pathological or toxicological conditions. Am J Physiol Lung Cell Mol Physiol 278: L417–L433, 2000.
18. Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P. Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA 98: 4202–4208, 2001.
19. Kepka-Lenhart D, Mistry SK, Wu G, Morris SM Jr. Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages? Am J Physiol Regul Integr Comp Physiol 279: R2237–R2242, 2000.
20. Kim YH, Lee SH, Lee JY, Choi SW, Park JW, Kwon TK. Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-B and c-Jun NH2-terminal kinase. Eur J Pharmacol 494: 1–9, 2004.[CrossRef][ISI][Medline]
21. Klausen S, Hammermann R, Fuhrmann M, Lindemann D, Beck KF, Pfeilshifter J, Racké K. Glucocorticoids inhibit lipopolysaccharide-induced up-regulation of arginase in rat alveolar macrophages. Br J Pharmacol 132: 1349–1357, 2001.[CrossRef][ISI][Medline]
22. Kolodziejski PJ, Koo JS, Eissa NT. Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors. Proc Natl Acad Sci USA 101: 18141–6, 2004.
23. Li H, Meinninger CJ, Kelly KA, Hawker JR, Morris SM, Wu G. Activities of arginase I., and I.I. are limiting for endothelial cell proliferation. Am J Physiol Regul Integr Comp Physiol 282: R64–R69, 2002.
24. Louis CA, Reichner JS, Henry WL, Mastrofrancesco B, Gotoh T, Mori M, Albina JE. Distinct arginase isoforms expressed in primary and transformed macrophages: regulation by oxygen tension. Am J Physiol Regul Integr Comp Physiol 274: R775–R782, 1998.
25. Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol 25: 1101–1104, 1995.[ISI][Medline]
26. Morris SM, Kepka-Lenhart D, Chen LC. Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells. Am J Physiol Endocrinol Metab 275: E740–E747, 1998.
27. Nelin LD, Chicoine LG, Reber KM, English BK, Young TL, Liu Y. Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. Am J Respir Cell Mol Biol 33: 394–401, 2005.
28. Nelin LD, Krenz GS, Chicoine LG, Dawson CA, Schapira RM. L-Arginine uptake and metabolism following in vivo silica exposure in rat lungs. Am J Respir Cell Mol Biol 26: 348–355, 2002.
29. Pauleau AL, Rutschman R, Lang R, Pernis A, Watowich SS, Murray PJ. Enhancer-mediated control of macrophage-specific arginase I expression. J Immunol 172: 7565–73, 2004.
30. Que LG, Kantrow SP, Jenkinson CP, Piantadosi CA, Huang YCT. Induction of arginase isoforms in the lung during hyperoxia. Am J Physiol Lung Cell Mol Physiol 275: L96–L102, 1998.
31. Rauh MJ, Sly LM, Kalesnikoff J, Hughs MR, Cao LP, Lam V, Krystal G. The role of SHIP1 in macrophage programming and activation. Biochem Soc Trans 32: 785–788, 2004.[CrossRef][ISI][Medline]
32. Shepherd EG, Zhao Q, Welty SE, Hansen TN, Smith CV, Liu Y. The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages. J Biol Chem 279: 54023–54031, 2004.
33. Stanley KP, Chicoine LG, Young TL, Reber KM, Lyons CR, Liu Y, Nelin LD. Gene transfer with inducible nitric oxide synthase decreases production of urea by arginase in pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol 290: L298–L306, 2006.
34. Waddington SN, Tam FNK, Cool HT, Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells. Am J Physiol Renal Physiol 274: F473–F480, 1998.
35. Witte MB, Barbul A. Arginine physiology and its implication for wound healing. Wound Repair Regen 11: 419–423, 2003.[CrossRef][ISI][Medline]
36. Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu Y. The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharides: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem 280: 8101–8108, 2005.
37. Zhao Q, Wang X, Nelin LD, Yao Y, Matta R, Manson ME, Baliga RS, Meng X, Smith CV, Bauer JA, Chang CH, Liu Y. MAP kinase phosphatase-1 controls innate immune responses and suppresses endotoxic shock. J Exp Med 203: 131–140, 2006.
This article has been cited by other articles:
|
|
 |
|
  R. Chang, L. G. Chicoine, H. Cui, N. L. Kanagy, B. R. Walker, Y. Liu, B. K. English, and L. D. Nelin Cytokine-induced arginase activity in pulmonary endothelial cells is dependent on Src family tyrosine kinase activity Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L688 - L697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Hughes, S. Srinivasan, K. R. Lynch, R. L. Proia, P. Ferdek, and C. C. Hedrick Sphingosine-1-Phosphate Induces an Antiinflammatory Phenotype in Macrophages Circ. Res., April 25, 2008; 102(8): 950 - 958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Calvert, L. G. Chicoine, Y. Liu, and L. D. Nelin Deficiency of mitogen-activated protein kinase phosphatase-1 results in iNOS-mediated hypotension in response to low-dose endotoxin Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1621 - H1629. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
Mkp-1–/– LPS treated different from wild-type LPS treated (P < 0.05). B: LPS treatment resulted in somewhat greater arginase I protein expression in Mkp-1–/– macrophages than in wild-type macrophages. The top blots are arginase I and 