doi: 10.1161/hy1201.097201
(Hypertension. 2002;39:161.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Inflammatory Cytokines Stimulate Adrenomedullin Expression Through Nitric Oxide–Dependent and –Independent Pathways
From the Institut für Physiologie der Universität Regensburg (K.-H.H., A.K., P.S.), Regensburg, Germany; and Klinik für Kinder und Jugendliche (E.S.), Erlangen, Germany.
Correspondence to Armin Kurtz, MD, Institut für Physiologie I, Universität Regensburg, D-93040 Regensburg, Germany. E-mail armin.kurtz{at}vkl.uni-regensburg.de
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Abstract |
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A body of evidence indicates that the production of adrenomedullin (ADM) in vivo is activated in states of inflammation. Our aim was to characterize the intracellular signaling pathways along which inflammation leads to a stimulation of ADM expression. For this purpose, we characterized the effects of inflammatory cytokines, tumor necrosis factor-
(100 µg/L), interleukin-1ß (20 µg/L), and interferon-
(0.5 U/L) on ADM gene expression in rat aortic vascular smooth muscle cells (AVSMCs). We found that inflammatory cytokines induced a time-dependent 12-fold upregulation of ADM mRNA in AVSMCs that was paralleled by a substantial increase in inducible NO synthase mRNA expression. The stimulatory effect of cytokines on ADM gene expression was attenuated by NO deprivation induced by N
-nitro-L-arginine methyl ester (1 mmol/L) and was in part mimicked by the NO donor S-nitroso-N-acetylpenicillamine (100 µmol/L). The cGMP analog 8-bromo-cGMP (100 µmol/L) had no effect on ADM gene expression, and inhibition of cGMP production by 1H-oxodiazolo-quinoxalin-1 (ODQ, 200 µmol/L) was not able to abrogate the increase of ADM mRNA induced by NO donation using S-nitroso-N-acetylpenicillamine (100 µmol/L). The significant induction of ADM gene expression by inflammatory cytokines and NO donation was also observed in mesangial cells, endothelial cells, and hepatocytes. These findings suggest that NO is a direct activator of ADM gene expression in a variety of cell types and that inflammatory cytokines stimulate ADM expression via both NO-dependent and -independent mechanisms. The stimulatory effect of NO appears to not be related to the classic guanylate cyclase–cGMP pathway.
Key Words: nitric oxide • adrenomedullin • cytokines • muscle, smooth, vascular
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Introduction |
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Adrenomedullin (ADM) is a 52-amino-acid peptide that was originally discovered as hypotensive factor produced by human adrenal pheochromocytoma cells.1 Meanwhile, a number of biological effects of ADM have been described, including vasodilatation, natriuresis, diuresis,2,3 inhibition of aldosterone production,4 or enhancement of tumor cell growth.5,6 Although the physiological regulation of ADM formation is not well understood, there is good evidence that ADM production in vivo is increased in several pathophysiological states. Thus, ADM production in vivo is increased during cardiac,7,8 hepatic, respiratory, and renal failure9; during malignant tumor growth10,11; during tissue hypoxygenation12; and in states of inflammation.13,14 The mechanisms regulating ADM production at the cellular level are only poorly understood. There is agreement that ADM is not stored in cells and that ADM release is therefore controlled on the transcription level.15,16 Recent evidence suggests that hypoxia stimulates ADM gene expression at the cellular level through the formation of hypoxia-inducible factor-1 (HIF-1).11,17 How inflammatory processes could stimulate ADM expression at the cellular and molecular levels has not yet been elucidated. Although it is well established that lipopolysaccharide stimulates ADM in vivo as well as in vitro,18–22 there are only preliminary reports that inflammatory cytokines, such as tumor necrosis factor (TNF)-
and interleukin (IL)-1ß could upregulate ADM mRNA,15,20,23,24 suggesting that cytokines might trigger ADM gene expression during inflammation. We were therefore interested to characterize the effects of inflammatory cytokines on ADM gene expression with regard to the intracellular signaling pathways involved. We found that inflammatory cytokines induced ADM gene expression in rat aortic vascular smooth muscle cells (AVSMCs) via NO-dependent and -independent pathways that do not involve the classic cGMP cascade.
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Methods |
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Cell Cultures
Rat AVSMCs (A7r5 from BDXI rats, American Type Culture Collection CRL 1444) were cultured in 75-cm2 flasks (Sarstedt) with 15 mL DMEM containing 10% FCS and penicillin/streptomycin ([P/S] 10 000 U/10 000 µg/mL; Biochrom) kept in room air with 10% CO2 at 37°C. The medium was changed every second day, and cells were confluent on days 7 to 10 after splitting, which was achieved with trypsin-EDTA for 5 minutes at 37°C.
Primary cultures of rat mesangial cells were prepared from kidneys of male Sprague-Dawley rats (100 g) as described previously25 and were grown in 15 mL RPMI 1640 medium (Biochrom), 10% FCS, 660 U/mL insulin (Sigma), and P/S (10 000 U/10 000 µg/mL) in 75-cm2 flasks kept in room air with 5% CO2 at 37°C. The medium was changed every third day, and confluency was observed after 4 to 5 weeks.
Rat glomerular endothelial cells from Sprague-Dawley rats were purchased from DSMZ (reference ACC 262). Culture conditions and the medium were identical to those for the mesangial cell culture. The medium was changed the second day after cell splitting, and confluency was observed on the third day.
Primary cultures of rat hepatocytes were isolated from the liver of a 50- to 70-g male Sprague-Dawley rat as previously described26 and were suspended in MEM (Biochrom), 10% FCS, 660 U/mL insulin 0.2% hydrocortisone (Sigma), and P/S (10 000 U/10 000 µg/mL). The hepatocytes were sawed confluently into 75-cm2 flasks and incubated with room air and 5% CO2 overnight.
Incubation Experiments
For the results shown in Figures 1, 2, 5, 6, 7, and 8, we conducted 10 independent series of incubation experiments. Each experiment value is the mean measurement of 2 culture flasks per incubation condition per time point per experiment. For the results shown in Figures 3, 4, and 9 and the Table, we conducted 6 independent series of incubation experiments. Each experiment value is the mean measurement of 2 culture flasks per incubation condition per time point per experiment.
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Incubation With Inflammatory Cytokines
Confluent AVSMCs were grown in 75-cm2 flasks and treated with a combination of inflammatory cytokines, containing 20 µg/L medium IL-1ß (Sigma), 100 µg/L TNF- (Sigma), and 0.5 U/L IFN- (GIBCO) (this is termed cytokine mix here) for 0.5, 1.5, 3, 4.5, and 12 hours (Figure 1). Controls were incubated without cytokines.
Incubation With Inflammatory Cytokines and N-Nitro-L-Arginine Methyl Ester
AVSMCs were treated (1) with the cytokine mix as described earlier, (2) with the cytokine mix in combination with 1 mmol/L N-nitro-L-arginine methyl ester (L-NAME) (Figure 2), and (3) with each individual cytokine, IL-1ß (20 µg/L), TNF- (100 µg/L), and IFN- (0.5 U/L), in the absence and the presence of L-NAME (1 mmol/L), all for 1.5, 3, 4.5, and 12 hours (Figures 5, 6, and 7). In addition, AVSMCs were treated with double combinations of cytokines, TNF-+IL-1ß, INF-+IL-1ß, and TNF-+INF-, for 12 hours (Figure 8). Controls were grown without any treatment (Figure 8).
Incubation With S-Nitroso-N-Acetylpenicillamine, 8-bromo-cGMP, and ODQ
AVSMCs were treated for 1.5, 4.5, and 12 hours with 100 or 500 µmol/L S-nitroso-N-acetylpenicillamine ([SNAP] BIOMOL) (Figure 3), and endothelial cells, mesangial cells, and hepatocytes were treated for 12 hours with 100 µmol/L SNAP (Figure 9). Controls were grown without any treatment.
AVSMCs were treated for 1.5, 4.5, and 12 hours with 100 or 500 µmol/L 8-bromo-cGMP (BIOMOL); controls were grown without any treatment (Figure 3). AVSMCs were treated for 12 hours with SNAP (100 µmol/L) and with the cytokine mix in the presence of 200 µmol/L 1H-oxodiazolo-quinoxalin-1 (ODQ, BIOMOL). Controls were grown without any treatment (Figure 4).
RNA Isolation
After incubation experiments, total RNA was isolated from cells according to the protocol of Chomczynski and Sacchi.27 In brief, after removal of the medium from the cell surface, cells were lysated in 800 µL solution D (guanidine thiocyanate [4 mol/L] containing 0.5 mmol/L N-laurylsarcosinate, 10 mmol/L EDTA, 25 mmol/L sodium citrate, 700 mmol/L ß-mercaptoethanol), and 100 µL sodium acetate (pH 4), 200 mmol/L, 800 µL phenol, and 200 µL chloroform were sequentially added to the cells. After centrifugation at 4°C (10 000g), the supernatant was precipitated with an equal volume of isopropanol at -20°C. The resulting pellet was washed with 1 mL of 70% ethanol, vacuum dried, and resolved in diethylpyrocarbonate-treated water. The yield of RNA was measured at 260 nm, and the RNA was stored at -80°C until further processing.
RNase Protection Assay of ADM, Inducible NO Synthase, and ß-Actin mRNA
ADM and inducible NO synthase (iNOS) as ß-actin mRNA levels were measured by RNase protection assay as previously described.28–30 In brief, radiolabeled antisense cRNA probes were synthesized through in vitro transcription of plasmid vectors that carried subcloned cDNA fragments for ADM, iNOS, and ß-actin with SP6 polymerase (Promega) in the presence of [-32P]GTP (Amersham). Labeled cRNA probes were hybridized with total RNA at 60°C for 16 hours and then digested with RNase A/T1 at room temperature for 30 minutes and proteinase K at 37°C for 30 minutes. After phenol-chloroform extraction and ethanol precipitation, the protected RNA hybrids were separated through electrophoresis on 8% polyacrylamide gels. After the gels were dried, the amount of radioactivity was assessed with an Instant Imager (Packard) in counts per minute (cpm), and autoradiography was performed at -80°C for 1 day. Autoradiographs are shown for ADM mRNA (Figures 1 and 3, top) and iNOS mRNA (Figure 1, bottom). Results are expressed in cpm, and because ß-actin mRNA levels did not significantly change during all experiments performed (not shown), ADM and iNOS mRNA levels were directly expressed as cpm per microgram of total RNA.
cGMP Measurements
AVSMCs were grown under culture conditions as described earlier in 25-cm2 flasks and incubated for 3 hours with the mix of inflammatory cytokines (100 µg/L TNF-+20 µg/L IL-1ß+0.5 U/L INF-) or SNAP (100 µmol/L), both in the presence of 3-isobutyl-1-methylxanthine ([IBMX] 10 µmol/L; BIOMOL). Controls underwent no treatment but were also incubated with IBMX (10 µmol/L). cGMP was semiquantified with the cGMP EIA kit (Assay Designs Inc) as described in the manufacturer’s protocol using the acetylated version of the kit and 1 mL lysis reagent (Table).
Statistical Analysis
Levels of significance were calculated using ANOVA for intergroup comparisons and Tukey’s and Scheffé’ tests for multiple comparisons. P<0.05 was considered significant.
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Results |
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Influence of Inflammatory Cytokines (TNF-
, IL-1ß, and IFN-) on ADM and iNOS mRNATo investigate the combined action of inflammatory cytokines on ADM gene expression, we incubated rat AVSMCs with a combination of TNF-
(100 µg/L), IL-1ß (20 µg/L), and INF- (0.5 U/L [cytokine mix]) for 0.5, 1.5, 3, 4.5, and 12 hours. Quantification of ADM mRNA by RNase protection assay showed a time-dependent upregulation of ADM mRNA, which was significant after 1.5 hours of stimulation (2-fold; P<0.05), reaching plateau levels (12-fold) after 4.5 hours (Figure 1, top). As shown in Figure 1 (bottom), ADM mRNA induction was paralleled by substantial induction of iNOS gene expression, which succeeded ADM mRNA induction and was significant after 3 hours (18-fold; P<0.05), reaching plateau levels after 4.5 hours of treatment. As an indicator for NO generation, we considered cellular cGMP accumulation, which is determined by soluble guanylate cyclase activity triggered by NO. We found that inflammatory cytokines as NO donors were able to increase cGMP levels 19- and 17-fold, respectively (P<0.05) (Table), after 3 hours.
Role of NO in Stimulation of ADM Expression by Cytokines
To elucidate whether NO is involved in the response of ADM gene expression toward cytokines, AVSMCs were treated with L-NAME (1 mmol/L) in arginine-free medium to inhibit endogenous NO production. This maneuver produced no effect on basal ADM gene expression. Inhibition of NO formation, however, markedly attenuated (by 60%) the stimulation of ADM gene expression by the combination of cytokines (Figure 2). Conversely, incubation of AVSMCs with the NO donor SNAP (100 and 500 µmol/L) significantly increased basal ADM mRNA in a time-dependent manner (Figure 3, top). This induction was already maximal with 100 µmol/L SNAP. Maximum levels were reached after 4.5 hours (5-fold; P<0.5).
Role of cGMP in Stimulation of ADM Expression by Cytokines
Because a main signaling pathway of NO in VSMCs is the activation of soluble guanylate cyclase leading to enhanced cGMP production, we aimed to mimic the NO effect by incubating rat AVSMCs with the cGMP analog 8-bromo-cGMP. As shown in Figure 3 (bottom), 8-bromo-cGMP (100 and 500 µmol/L) did not change ADM mRNA abundance at any time investigated. Moreover, we incubated AVSMCs with the guanylate cyclase inhibitor ODQ (200 mmol/L) for 12 hours and found no altered ADM gene expression compared with the controls without ODQ treatment (Figure 4). However, despite ODQ incubation, treatments with both SNAP and inflammatory cytokines were able to induce ADM mRNA 
12- and 5-fold, respectively, which was not significantly different from AVSMCs treated with inflammatory cytokines and SNAP only (Figure 4). We therefore conclude that the NO induction of ADM gene expression is not mediated by the guanylate cyclase–cGMP signaling pathway.
Because the stimulation of ADM gene expression by the combination of cytokines was attenuated but not obliterated by NOS inhibition and because the NO donor stimulated ADM expression less than the combination of cytokines, we inferred that the action of cytokines on ADM expression comprised both direct effects of cytokines independent of NO pathways and effects mediated by activation of the NO system. Because these differential effects may result from different pathways of the individual cytokines, we further determined the effect of each cytokine separately.
Influence of IL-1ß, TNF-, and IFN- on ADM mRNA
Both IL-1ß (20 µg/L) and TNF- (100 µg/L) stimulated ADM mRNA (Figures 5 and 6) to a similar extent (4-fold; P<0.05), reaching a plateau after 4.5 hours. In contrast, IFN- did not significantly increase ADM mRNA (Figure 7). Inhibition of NO synthesis by L-NAME markedly reduced the induction of ADM mRNA. This effect was significant for IL-1ß after 4.5 hours (P<0.05) and for TNF- after 3 hours (P<0.05) (Figures 5 and 6), again suggesting a major mediator role of NO for the effects of these 2 cytokines. The increase of ADM mRNA induced by the combination of the 3 cytokines appeared to be greater than the sum of the effects of IL-1ß and TNF-, suggesting synergistic effects of the inflammatory cytokines on ADM expression. To more precisely address this point, we used cytokines mixes consisting of 2 inflammatory cytokines, termed "double combinations."
Influence of Double Combinations of Inflammatory Cytokines on ADM mRNA
We stimulated AVSMCs for 12 hours with 3 different double combinations of cytokine mixes: (1) TNF- and IL-1ß, (2) IL-1ß and INF-, and (3) TNF- and INF-. As shown in Figure 8, induction of ADM mRNA was most prominent with the combination of TNF- and IL-1ß (8-fold; P<0.05), which seemed to be additive compared with stimulation by IL-1ß and TNF- alone (Figures 5 and 6). Nevertheless, the triple-cytokine mix upregulated ADM mRNA more potently (12-fold; P<0.05) than the double combination of IL-1ß and TNF- (Figure 8), suggesting a synergistic role for INF-. In fact, the addition of INF- to IL-1ß or TNF- increased ADM mRNA 5- and 6-fold, respectively (Figure 8), which was moderately, but significantly (P<0.05), greater than the effect of IL-1ß and TNF- used alone, which stimulated ADM mRNA 4-fold (Figures 5 and 6).
Influence of Inflammatory Cytokines and NO on ADM mRNA in Endothelial Cells, Mesangial Cells, and Hepatocytes
Our previous experiments showed substantial influence of NO on ADM gene expression for AVSMCs only, so we wondered if NO is able to influence ADM mRNA in other cell types of different origin. We stimulated endothelial cells, mesangial cells, and hepatocytes with SNAP (100 µmol/L). In all cell types that we investigated, NO donation was able to substantially induce ADM mRNA: 2.5-fold in endothelial cells, 2-fold in mesangial cells, and 6-fold in hepatocytes (Figure 9). This suggests that NO-induced ADM gene expression is a more general phenomenon valid for different tissues and different cell types.
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Discussion |
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The present study was undertaken to determine the effects of inflammatory cytokines on ADM gene expression and to characterize the intracellular signaling pathways that mediate this effect. We found that inflammatory cytokines strongly stimulated ADM mRNA in AVSMCs in a time-dependent manner. This observation fits with previous reports that TNF-
and IL-1ß increase ADM mRNA in VSMCs,15,23 in retinal epithelial cells,31 and in endothelial cells.16 Furthermore, it was demonstrated that lipopolysaccharide treatment, which induces inflammatory cytokines, enhances ADM formation not only in vivo but also in endothelial cells, VSMCs, macrophages, and monocytes.18–20,22 The cellular signaling pathway for the activation of ADM gene expression, however, remained unclear. Because inflammatory cytokines are known to enhance iNOS gene expression and, consequently, the formation of NO, we examined whether NO is involved in the cytokine effect on ADM mRNA. We found that NOS inhibition markedly reduced the cytokine-induced stimulation of ADM mRNA (Figure 2). Conversely, NO donation directly stimulated ADM mRNA expression (Figure 3, top). These results suggest that NO is a direct activator of ADM gene expression and that cytokine stimulation of ADM gene expression is mainly mediated by NO. ADM thus belongs to the recently discovered group of gene products, such as IL-8 or macrophage inflammatory protein-1, that are directly activated both by NO and by cytokines.32–35 The pathways along which NO activates ADM gene expression remain to be elucidated. Our findings render an involvement of the classic cGMP signaling pathway rather unlikely, because a classic cGMP analog had no effect on ADM gene expression (Figure 3, bottom) and because guanylate cyclase inhibition by ODQ could not attenuate the induction of ADM mRNA by NO (Figure 4).
Because the NO donor could not completely mimic the effects of cytokines and because the effects of cytokines were not fully blunted by NOS inhibition, we infer that cytokines exert also an NO-independent stimulatory effect on ADM expression. In fact, the time course of cytokine induction of ADM compared with iNOS mRNA (Figure 1) showed an earlier upregulation of ADM mRNA, which fit with the assumption that cytokines also trigger ADM gene expression apart from NO. More is known about the mechanisms through which cytokines directly influence gene expression. IL-1ß and TNF- frequently act along rather similar pathways, namely through the activation of nuclear factor-
B,36 for which possible binding sites in the promoter region of the ADM gene were already suggested.37 These putative binding sites likely explain why IL-1ß and TNF- exerted rather similar effects on ADM gene expression, which were also additive, when combining these 2 cytokines (Figure 8). IFN-, which acts through the JAK/STAT pathway38,39 alone, did not change ADM gene expression. We assume, however, that in combination with IL-1ß and TNF-, IFN- enhanced their effects as previously described for insulin-producing cells,40 and therefore seems to play a more permissive role in ADM mRNA induction. In fact, our experiments showed that IL-1ß or TNF- combined with INF- activates ADM gene expression more effectively than a single cytokine (Figure 8), which confirmed a permissive role of IFN-.
Moreover, we could demonstrate that in addition to AVSMCs, NO was able to upregulate ADM mRNA in endothelial cells, mesangial cells, and hepatocytes, suggesting a more general signal transduction pathway working in different cell types and tissues, which might also help to elucidate mechanisms behind the NO-ADM axis in hepatic, respiratory, and renal failure.
Taken together, our findings suggest that ADM gene expression can be directly activated by NO. The enhanced formation of NO by inflammatory cytokines likely explains to a major extent the stimulation of ADM expression by cytokines, which also have an additional direct effect on ADM expression.
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Acknowledgments |
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This study was supported by grant Ku 859/5-3 from the Deutsche Forschungsgemeinschaft (DFG).
Received June 8, 2001; first decision July 2, 2001; accepted July 24, 2001.
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