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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA
Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan (F.K., H.S.B., N.H., K.O.); and Yasuda Women's University, Hiroshima, Japan (K.O.)
Received October 27, 2006; accepted January 17, 2007.
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B-
were not inhibited by these drugs. In an air pouch-type LPS-induced inflammation model in mice 30 mg/kg amiloride and 10 mg/kg EIPA as well as the COX inhibitor indomethacin (10 mg/kg), significantly reduced the level of PGE2 in the pouch fluid at 8 h and the vascular permeability from 4 to 8 h. The accumulation of pouch fluid and leukocytes in the pouch fluid at 8 h was significantly inhibited by amiloride and EIPA but not by indomethacin. These findings suggested that the NHE inhibitors suppress the production of PGE2 through inhibiting the release of arachidonic acid and the increase in COX-2 protein levels and thus induce anti-inflammatory activity.
). The pathway for biosynthesis of PG consists of three steps (Murakami and Kudo, 2004): release of arachidonic acid from the membrane phospholipids by cytosolic phospholipase A2 (PLA2); conversion from arachidonic acid to PGG2 and PGH2 by cyclooxygenase (COX); and finally, conversion from PGH2 to each PG by specific PG synthase. The two isoforms of COX, COX-1 and COX-2, have been identified (O'Banion et al., 1992; His et al., 1994). COX-1 is constitutively expressed in most tissues, whereas the expression of COX-2 is induced by inflammatory stimuli, including lipopolysaccharide (LPS) (O'Sullivan et al., 1992), phorbol ester (DuBois et al., 1994), and cytokines such as interleukin (IL)-1
, and tumor necrosis factor (TNF)- (Mitchell et al., 1994). Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the production of PGE2 by suppressing the activity of COXs. Therefore NSAIDs reduce fever, relieve pain, and have anti-inflammatory actions. However, NSAIDs might cause gastrointestinal dysfunction by inhibiting the activity of COX-1. Thus, selective COX-2 inhibitors have been developed, but they, too, have side effects, causing myocardial infarction and cerebral infarction by suppressing the production of prostacyclin (Andersohn et al., 2006; Hermann and Ruschitzka, 2006). Thus, the direct inhibition of COX-1 and COX-2 sometimes leads to a disruption of the biological balance regulated by PGs.
Na+/H+ exchangers (NHEs) are transmembrane proteins that exchange one intracellular H+ for an extracellular Na+. So far, nine mammalian isoforms of NHE have been identified (NHE1–9), which differ in their distribution, regulatory properties, and physiological functions (Masereel et al., 2003; Nakamura et al., 2005). NHE-1 is ubiquitously expressed in the plasma membrane of nonpolarized cells and the basolateral membrane of epithelial cells, where it mediates basic functions such as the regulation of cell volume and intracellular pH (Wakabayashi et al., 1997; Lang et al., 1998) and growth and adhesion (Grinstein et al., 1989; Tominaga and Barber, 1998). Furthermore, NHE-1 regulates functions of macrophages. NHE-1 in macrophages is activated by various stimuli, including LPS, TNF- (Vairo et al., 1992), and interferon-
(Prpic et al., 1989). The increased activity of NHE-1 contributes to the production of cytokines (Rolfe et al., 1992), up-regulation of Ia expression (Prpic et al., 1989), expression of the Fc receptor (Cassatella et al., 1990), and colony stimulating factor-1-induced proliferation (Vairo et al., 1990) in macrophages. However, little is known about the involvement of NHE in the production of PGs by macrophages.
In this study, we examined the effects of NHE inhibitors on the LPS-induced production of PGE2 in the murine macrophage cell line RAW 264. In addition, we compared the anti-inflammatory effects of the NHE inhibitor with those of indomethacin, a COX inhibitor, using the LPS-induced inflammation model in mice.
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Cell Culture. RAW 264, a mouse macrophage cell line, was obtained from Riken Gene Bank (Tsukuba, Japan) and cultured at 37°C under 5% CO2, 95% air in Eagle's minimal essential medium (Nissui Pharmaceutical, Tokyo, Japan) containing 10% (v/v) fetal bovine serum (Sigma-Aldrich), 15 µg/ml penicillin G potassium, and 50 µg/ml streptomycin sulfate (Meiji Seika, Tokyo, Japan). RAW 264 cells were suspended at 2.5 x 105 cells/ml in the same medium, and 0.1, 0.5, or 1.0 ml of the cell suspension was seeded in each well of a 96-, 24-, and 12-cluster dish (Greiner BioOne GmbH, Frickenhausen, Germany), respectively.
Measurement of PGE2 Concentrations. RAW 264 cells (1.25 x 105) were incubated for 20 h at 37°C in 0.5 ml of the medium. The cells were then washed three times with warmed phosphate-buffered saline (PBS) and further incubated for 8 h at 37°C in 0.5 ml of the medium containing 1 µg/ml LPS and various concentrations of drugs. After the incubation, the conditioned medium was collected and centrifuged at 1500g for 5 min at 4°C. The PGE2 concentration in the supernatant was determined by radioimmunoassay as described previously (Ohuchi et al., 1985). PGE2 antiserum was purchased from Assay Designs (Ann Arbor, MI).
Measurement of Cell Viability. RAW 264 cells (2.5 x 104) were incubated for 20 h at 37°C in 0.1 ml of medium. The cells were then incubated for 4 h at 37°C in 0.1 ml of medium containing 1 µg/ml LPS and various concentrations of drugs. Ten microliters of PBS containing 5 mg/ml 3'-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was added into each well, and the cells were further incubated for 4 h at 37°C. After the removal of the medium, 0.1 ml of dimethyl sulfoxide was added into each well, and the absorbance at 570 nm was determined.
Measurement of Radioactivity Released from [3H]Arachidonic Acid-Labeled RAW 264 Cells. RAW 264 cells (1.25 x 105) were incubated for 20 h at 37°C in 0.5 ml of medium containing 3.7 kBq of [3H]arachidonic acid (2438.3 GBq/mmol; PerkinElmer Life and Analytical Sciences, Boston, MA). The cells were then washed three times with PBS to remove free [3H]arachidonic acid, and then they were incubated for 4 h at 37°C in 0.5 ml of medium containing 1 µg/ml LPS and various concentrations of drugs. After the incubation, the level of radioactivity in the conditioned medium was determined.
Western Blot Analysis. RAW 264 cells (2.5 x 105) were incubated for 20 h at 37°C in 1 ml of medium. The cells were then washed three times with PBS and further incubated for 20 min or 6 h at 37°C in 1 ml of medium containing 1 µg/ml LPS and various concentrations of drugs. The cells were washed three times with PBS and lysed in 90 µl of ice-cold lysis buffer [20 mM HEPES, pH 7.4, 1% (v/v) Triton X-100, 10% (v/v) glycerol, 50 mM sodium fluoride, 2.5 mM p-nitrophenyl phosphate, 10 µg/ml phenylmethylsulfonyl fluoride, 1 mM Na3VO4, 10 µg/ml leupeptin, and 1 mM EDTA]. The proteins in the cell lysates were separated by SDS-polyacrylamide gel electrophoresis and transferred electrophoretically onto a nitrocellulose membrane (Whatman Schleicher and Schuell BioScience GmbH, Dassel, Germany). COX-2, inhibitor of B(IB)-, and actin were detected by immunoblotting using polyclonal antibodies for COX-2, IB-, and actin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), respectively. The phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK) was detected using polyclonal antibodies for phospho-p44/42 MAPK (Thr202/Tyr204), phospho-p38 MAPK (Thr180/Tyr182) (Cell Signaling Technology Inc., Danvers, MA), and phospho-JNK (Thr183/Tyr185) (Santa Cruz Biotechnology, Inc.), respectively. The proteins were detected by using a chemiluminescence detection system (enhanced chemiluminescence system; PerkinElmer Life and Analytical Sciences). The protein levels of actin and COX-2 were quantified by scanning densitometry and subjected to statistical analysis.
Reverse Transcription-Polymerase Chain Reaction for COX-2 mRNA. RAW 264 cells (2.5 x 105) were incubated for 20 h at 37°C in 1 ml of medium and then further incubated for 3 h at 37°C in 1 ml of medium containing 1 µg/ml LPS and various concentrations of drugs. After the incubation, the cells were washed three times with PBS and total RNA was extracted using a GenElute Mammalian Total RNA kit (Sigma-Aldrich) according to the manufacturer's instructions. The extracted RNA (1 µg) was reverse transcribed at 37°C for 1 h in 20 µl of a solution containing 5 µM random hexamer oligonucleotides (Invitrogen, Carlsbad, CA), 200 units of reverse transcriptase (Takara Bio Inc., Shiga, Japan), 0.5 mM deoxyribonucleotide triphosphates (Takara Bio Inc.), and 10 mM dithiothreitol (Takara Bio Inc.). The PCR primers for mouse COX-2 were 5'-TTG AAG ACC AGG AGT ACA GC-3' (forward) and 5'-GGT ACA GTT CCA TGA CAT CG-3' (reverse). PCR was performed for 25 cycles; 0.5 min of denaturation at 94°C, 0.5 min of annealing at 52°C, and 0.5 min of extension at 72°C by using a DNA thermal cycler (Takara Bio Inc.). The PCR primers for mouse glyceraldehyde 3-phosphate dehydrogenase were 5'-TGA TGA CAT CAA GAA GGT GGT GGA-3' (forward) and 5'-TCC TTG GAG GCC ATG TAG GCC AT-3' (reverse). PCR was performed for 24 cycles; 0.5 min of denaturation at 94°C, 1 min of annealing at 57°C, and 2 min of extension at 72°C. After PCR, 10 µl of the reaction mixture was subjected to electrophoresis on a 1.5% agarose gel, and the PCR products were visualized by ethidium bromide staining.
LPS-Induced Air Pouch-Type Inflammation in Mice. Male ddY mice (30–40 g; specific pathogen-free; SLC, Shizuoka, Japan) were treated in accordance with procedures approved by the Animal Ethics Committee of the Graduate School of Pharmaceutical Sciences (Tohoku University, Sendai, Japan).
Mice were injected subcutaneously with 4 ml of air on the dorsum to make an oval-shaped air pouch. Six days later, 2 ml of air was again injected into the pouch. Twenty-four hours later, the indicated amount of LPS dissolved in 2 ml of a sterile solution of 2% (w/v) sodium carboxymethylcellulose (Cellogen F3H; Daiichi Kogyo, Niigata, Japan) in saline supplemented with antibiotics (0.1 mg/ml penicillin G potassium and 0.1 mg/ml streptomycin sulfate) was injected into the preformed air pouch to provoke inflammation.
Measurement of Pouch Fluid Volume, Vascular Permeability, Leukocyte Infiltration, and PGE2 Concentration in the Pouch Fluid. Four hours after the injection of LPS, the mice were injected intravenously with 0.2 ml of 0.5% (w/v) Evans blue (Wako Pure Chemicals) in saline. An additional 4 h later, the mice were sacrificed by cutting the carotid artery under diethyl ether anesthesia, and all the pouch fluid was collected and weighed. The pouch fluid was diluted 2- or 10-fold with saline, and the number of cells in the diluted fluid was counted using a hemocytometer. To determine the amount of Evans blue that leaked into the pouch fluid, the diluted pouch fluid was centrifuged at 7430g for 10 min at 4°C, and the absorbance at 595 nm of 100 µl of the supernatant fraction was measured. PGE2 was extracted from the supernatant of pouch fluid as described previously (Ohuchi et al., 1982), and then a radioimmunoassay was performed as described above.
Drug Treatment. Amiloride, DMA, EIPA, and indomethacin were suspended in a 0.5% (w/v) sodium carboxymethylcellulose solution. The mice were orally administered 30 mg/kg amiloride, 10 mg/kg DMA, 10 mg/kg EIPA, or 10 mg/kg indomethacin 1 h before the injection of LPS.
Statistical Analysis. Values in the figures are expressed as means from three or four samples with the S.E.M. shown by vertical bars. The statistical significance of the results was analyzed using Dunnett's test for multiple comparisons.
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More selective NHE inhibitors, DMA (3 and 10 µM) and EIPA (1 and 3 µM), also had an inhibitory effect (Fig. 1B). These inhibitors at the concentrations used did not decrease the cell viability as determined by 3'-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (Fig. 1, C and 1D). However, because DMA at 30 µM and EIPA at 10 µM decreased the cell viability to about 90%, the effects of higher concentrations of these inhibitors on the LPS-induced production of PGE2 were not examined. These findings suggest that NHE inhibitors commonly suppress the LPS-induced production of PGE2. The inhibitory effect of amiloride at 100 µM was almost same as that of the COX inhibitor indomethacin at 0.01 µM (Fig. 1E).
Effects of the NHE Inhibitors on the LPS-Induced Release of Radioactivity from [3H]Arachidonic Acid-Labeled RAW 264 Cells. To clarify the mechanism of the inhibitory effect of the NHE inhibitors on the LPS-induced production of PGE2, we analyzed the effect of the NHE inhibitors on the LPS-induced release of arachidonic acid. LPS (1 µg/ml) increased the release of radioactivity from [3H]arachidonic acid-labeled cells into the medium at 4 h. Amiloride (10, 30, and 100 µM) inhibited the LPS-induced release of radioactivity in a concentration-dependent manner (Fig. 2A) without affecting the basal level (data not shown). DMA (10 µM) and 3 µM EIPA also significantly inhibited it (Fig. 2B), whereas indomethacin did not affect it (data not shown). The order of the inhibitory effects among 100 µM amiloride, 10 µM DMA, and 3 µM EIPA on the LPS-induced release of arachidonic acid correlated well with that on the production of PGE2. However, there was only a small decrease in the percentage of the radioactivity released when the NHE inhibitors were used.
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B-. To obtain further information on the actions of the NHE inhibitors, the effects of these drugs on the LPS-induced signal transduction in RAW 264 cells were examined. Stimulation of the cells with 1 µg/ml LPS increased the phosphorylation of p44/42 MAPK, p38 MAPK, and JNK at 20 min. The degradation of IB-, an inhibitory protein of nuclear factor-B, was also induced by LPS. The NHE inhibitors failed to inhibit the LPS-induced phosphorylation of these kinases (Fig. 4A) and the degradation of IB- (Fig. 4B).
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). NHE inhibitors repress the production of cytokines and chemokines, such as TNF-, IL-1, and IL-8, in several types of cell, including macrophages (Rolfe et al., 1992; Németh et al., 2001, 2002a,b; Haddad and Land, 2002). In this study, we revealed that the NHE inhibitor amiloride suppresses the LPS-induced production of PGE2 in the mouse macrophage-like cell line RAW 264 (Fig. 1). Although amiloride inhibits, in addition to NHE, Na+ channels and the Na+/Ca2+ exchanger (Kleyman and Cragoe, 1988), the main mechanism by which amiloride inhibits the production of PGE2 might be the inhibition of NHE, because selective inhibitors of NHE, DMA, and EIPA (Masereel et al., 2003) also significantly reduced the LPS-induced production of PGE2 (Fig. 1). Our findings that the NHE inhibitors reduced the LPS-induced production of PGE2 did not conflict with the observation that amiloride inhibits phorbol ester- and zymosan-induced PGE2 production in Kupffer cells (Dieter et al., 1987). Amiloride (100 µM) inhibited PGE2 production more potently than 10 µM DMA and 3 µM EIPA, although the inhibitory effect on NHE among these drugs at the concentrations used was nearly the same (Masereel et al., 2003). Therefore, the possibility could not be excluded that NHE is not the only target of amiloride.
Next, we analyzed the mechanisms by which the NHE inhibitors reduced the LPS-induced production of PGE2. We found that the NHE inhibitors reduced the LPS-induced release of arachidonic acid (Fig. 2) and increase in the level of COX-2 protein (Fig. 3). The release of arachidonic acid is mediated by cytosolic PLA2, which is activated by MAPK-dependent phosphorylation and an increase in [Ca2+]i (Murakami and Kudo, 2004). However, the LPS-induced activation of MAPKs, which include p44/42 MAPK, p38 MAPK, and JNK, was not inhibited by the NHE inhibitors (Fig. 4A). Our findings were consistent with the report that the LPS-induced phosphorylation of none of these kinases was altered by amiloride in mouse peritoneal macrophages (Németh et al., 2001). The activation of NHE results in the accumulation of intracellular Na+, which, in turn, increases [Ca2+]i via the Na+/Ca2+ exchanger (Rosoff and Cantley, 1985). In addition, the increase in intracellular pH enhances the responsiveness of PLA2 to Ca2+ (Sweatt et al., 1986). It has been reported that the NHE-1 inhibitor suppressed the increase in [Ca2+]i and release of arachidonic acid in collagen-stimulated rabbit platelets (Lee et al., 2006). We found that the NHE inhibitors also repressed the release of arachidonic acid induced by the Ca2+ ionophore ionomycin (data not shown). These findings suggested that the NHE inhibitors reduced the LPS-induced release of arachidonic acid by inhibiting the LPS-induced increase in [Ca2+]i and/or intracellular pH.
The NHE inhibitors partially inhibited the LPS-induced increase in the level of COX-2 protein without affecting the increase in the level of COX-2 mRNA (Fig. 3). Although the transcription of COX-2 mRNA in macrophages is mainly regulated by MAPKs and by the activation of nuclear factor-B, the NHE inhibitors did not inhibit them (Fig. 4). These findings suggested that the NHE inhibitors prevent the increase in the amount of COX-2 protein at the post-transcriptional level and not at the transcriptional level. LPS/interferon--induced production of IL-12 p40 by mouse macrophages was also post-transcriptionally repressed by the NHE inhibitors (Németh et al., 2001). Therefore, the activation of NHE might affect the translational stage and/or the protein stability. The molecular mechanisms by which the activation of NHE affects the post-transcriptional steps remain to be elucidated. In conclusion, it was suggested that the NHE inhibitors reduced the LPS-induced production of PGE2 by inhibiting the release of arachidonic acid and reducing the level of COX-2 protein.
We confirmed that NHE inhibitors exhibited anti-inflammatory actions in vivo. Consistent with the analysis in vitro, amiloride significantly inhibited the LPS-induced production of PGE2 in vivo (Fig. 6D). The COX inhibitor indomethacin, which reduced the level of PGE2 in the pouch fluid to almost the same level in the amiloride-treated group, significantly reduced vascular permeability from 4 to 8 h. Therefore, the reduction in vascular permeability caused by amiloride is probably due to inhibition of the production of PGE2. Because the volume of pouch fluid was reduced by amiloride but not by indomethacin, the reduction did not result from the decrease in vascular permeability. Amiloride is used clinically as a diuretic agent. Therefore, one possible explanation is that the diuretic action of amiloride enhanced lymph circulation, namely, the absorption of the plasma exudate at the inflammatory site is enhanced by amiloride.
Amiloride significantly lowered the number of leukocytes infiltrating the pouch, whereas indomethacin did not (Fig. 6). It has been reported that PGE2 negatively regulates the production of chemokines by various cells, such as macrophages (Takayama et al., 2002) and dendritic cells (Jing et al., 2003; McIlroy et al., 2006), and that indomethacin increases it (Janabi et al., 1999). In contrast, NHE inhibitors suppressed the production of several chemokines by macrophages (Rolfe et al., 1992; Németh et al., 2001) and the migration of neutrophils (Rosengren et al., 1994; Ritter et al., 1998). Therefore, it is possible that amiloride inhibited the infiltration of neutrophils into the pouch fluid by inhibiting the production of chemokines and the movement of leukocytes. These findings suggest that NHE inhibitors would be more effective anti-inflammatory agents in vivo than indomethacin. The results that the more selective inhibitor of NHE, EIPA, was also effective in vivo supported the conclusion. The lesser activities of DMA in vivo might be due to its pharmacokinetics, such as the absorption and the stability in vivo.
Although NHE is distributed in most tissues (Masereel et al., 2003), it is virtually quiescent under resting conditions, and it is activated by several inflammatory stimuli. Therefore, it is conceivable that NHE inhibitors selectively suppress the production of PGE2 in the activated inflammatory cells without affecting the physiological production of PGs. Taken together, it is suggested that NHE inhibitors could be a new type of anti-inflammatory drug reducing the pathological production of PGs selectively.
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ABBREVIATIONS: PG, prostaglandin; PLA2, phospholipase A2; COX, cyclooxygenase; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; NSAID, nonsteroidal anti-inflammatory drug; NHE, Na+/H+ exchanger; DMA, 5-(N,N-dimethyl)-amiloride; EIPA, 5-(N-ethyl-N-isopropyl)-amiloride; PBS, phosphate-buffered saline; IB, inhibitor of B; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; PCR, polymerase chain reaction.
Address correspondence to: Dr. Noriyasu Hirasawa, Laboratory of Pathological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan. E-mail: hirasawa{at}mail.pharm.tohoku.ac.jp
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