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Cutting Edge: Physiologic Attenuation of Proinflammatory Transcription by the G_s Protein-Coupled A2A Adenosine Receptor In Vivo

Dmitriy Lukashev^*, Akio Ohta^*, Sergey Apasov^*, Jiang-Fan Chen and Michail Sitkovsky^1,*

^* Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Neurology, Boston University School of Medicine, Boston, MA 02118

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The A2A adenosine receptor plays a critical role in the physiologic immunosuppressive pathway that protects normal tissues from excessive collateral damage by overactive immune cells and their proinflammatory cytokines. In this study, we examine and clarify the mechanism of tissue protection by extracellular adenosine using A2AR-deficient mice and show that the A2AR inhibits TLR-induced transcription of proinflammatory cytokines in vivo. The observed increase in proinflammatory cytokines mRNA in A2AR-deficient mice was associated with enhanced activity of the NF-B transcription factor. These observations provide the genetic in vivo evidence for attenuation of proinflammatory transcriptional activity of NF-B by a "metabokine" adenosine and point to the need to re-evaluate the regulation of other transcription factors in hypoxic and adenosine-rich microenvironments of inflamed normal tissues and solid tumors.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Local tissue hypoxia-associated accumulation of extracellular adenosine and subsequent signaling through the A2A adenosine receptor (A2AR)² are critical in inhibiting overactive immune cells and protecting normal tissues from excessive collateral damage in vivo (1). The A2AR-mediated mechanism of tissue protection from overactive immune cells in inflamed areas is triggered by excessive inflammatory damage to endothelial cells and the microcirculation with ensuing interruption of normal blood and oxygen supply (2), which results in local tissue hypoxia. The hypoxia is associated with 1) a decrease in intracellular ATP; 2) an increase in intracellular AMP; 3) an inhibition of adenosine kinase (3) an activation of 5'-nucleotidase (4); 4) an accumulation of intracellular adenosine (3); and 5) subsequent transport or diffusion of adenosine from cells into the extracellular space. High levels of extracellular adenosine trigger the signaling by cAMP-elevating A2A and/or A2B (A2BR) adenosine receptors on the surface of surrounding immune cells. This chain of events culminates in a delayed inhibition of overactive immune cells in a negative feedback manner due to the well-established immunosuppression by the A2AR (reviewed in Ref. 2).

The identification of this mechanism offers new opportunities for rational management of inflammatory processes by pharmacologically inhibiting the A2AR pathway to increase inflammation (e.g., to improve cancer immunotherapy or vaccination) or by using drugs that activate the A2AR pathway to decrease inflammatory tissue damage in, for example, sepsis (reviewed in Ref. 2). The use of selective agonists of A2AR has provided pharmacologic evidence directly implicating A2AR in protection from ischemia-reperfusion injury (5, 6). A2AR activation was shown to down-regulate the cytokine and chemokine transcripts in tissues following ischemia-reperfusion injury (5, 6).

The further development of A2AR-based strategy of immunomodulation requires the knowledge of the exact molecular mechanism of A2AR-mediated inhibition of proinflammatory processes, including effects on secretion of cytokines by activated immune cells. It is important to discriminate whether activation of the A2AR inhibits production of proinflammatory cytokines at the level of 1) transcription, 2) mRNA stabilization; 3) translation; 4) secretion; 5) number of cytokine receptors; or all of the above. In this study, we focus on the question whether the A2AR is capable of negatively regulating proinflammatory transcription in vivo. The experiments required to answer this question are methodologically demanding because they should be performed in vivo since it is challenging to recreate in vitro the hypoxic and adenosine-rich microenvironment of inflamed tissues. This is due to uncertainties in their three-dimensional organization, levels of oxygen tension, and exact concentrations of locally produced extracellular adenosine.

In this study, we report in vivo evidence for transcriptional regulation of immune cells by the A2AR. These data represent an example of a G_s protein-coupled cAMP-elevating receptor and of cAMP playing a critical and nonredundant role in regulation of proinflammatory transcription in vivo. cAMP has been known to be pharmacologically capable of attenuating immune cells (7, 8, 9) and of inhibiting the proinflammatory transcriptional activities of NF-B in vitro (10, 11). The genetic evidence provided here that the cAMP-elevating A2AR strongly affects NF-B in vivo suggests that this pathway plays an important role in the physiologic regulation of innate immunity.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Animals

A2AR-deficient (A2AR^–/–) mice have been backcrossed 11 times to C57BL/6 mice and were described previously (12). The A2AR genotypes of mice were determined by Southern blot analysis. Littermates or age-matched wild-type (WT) and homozygous A2AR^–/– mice were used for better reproducibility of results. Mice were maintained and treated according to regulations approved by the National Institutes of Health Animal Care Committee.

Reagents

Phosphorothioate-stabilized CpG oligodeoxynucleotide (CpG DNA) (TCC ATG ACG TTC CTG ATG CT) was purchased from Operon Qiagen (Chatsworth, CA). CGS21680 and LPS were purchased from Sigma-Aldrich (St. Louis, MO) and ZM241385 from Tocris Cookson (Ballwin, MO).

Activation of peritoneal macrophages

To recruit macrophages, 2 ml of 3% thioglycolate medium (Sigma-Aldrich) was injected i.p. into each mouse. After 2 days, the mice received i.p. injections of 3 nmol of CpG DNA. Mice were sacrificed and the peritoneal exudate cells were collected immediately by washing the peritoneal cavity with 6 ml of ice-cold RPMI 1640 medium. Levels of IL-12p40 in peritoneal exudate lavage were measured by ELISA (R&D Systems, Minneapolis, MN).

Purification of macrophages from spleen cells

After lysing erythrocytes using ACK lysing buffer (BioSource International, Camarillo, CA), spleen cells were labeled with FITC-conjugated anti-CD11b Ab (BD PharMingen, San Diego, CA), followed by anti-FITC microbeads (Miltenyi Biotec, Auburn, CA). CD11b⁺ cells were then separated from spleen cells by AutoMACS (Miltenyi Biotec). Unseparated spleen cells and macrophages (CD11b⁺ fraction) were examined by RNase protection assay (RPA) for expression of cytokine mRNA.

LPS-Induced shock

LPS was dissolved in sterile saline and injected i.p. at 3 mg/kg to male WT (n = 10) and A2AR^–/– mice (n = 11). Survival of mice was monitored for at least 7 days.

Induction of cytokines by CpG oligonucleotide in vivo

CpG DNA (3–20 nmol/mouse) was injected i.p; expression of cytokine mRNA in the spleen was examined after 1 h by RPA. Some mice were pretreated with CGS21680 (2 mg/kg i.p.) or with ZM241385 (10 mg/kg i.p.) 1 h before CpG DNA.

RNA preparation and RPA

Spleen was homogenized in 1 ml of RNA STAT-60 (Tel-Test, Friendswood, TX) using a syringe with a 22-gauge needle. RNA was extracted according to the manufacturer’s instructions. Total RNA was dissolved in water and 1–5 µg of RNA was analyzed in RPA using the multiprobe RPA system (BD PharMingen) according to the manufacturer’s protocol. Multiprobe template sets mck2b and mck3b (BD PharMingen) were used. Data are representative of several experiments.

EMSA

Nuclear extracts and cytoplasmic fractions from peritoneal macrophages were prepared according to previously described methods (11). EMSA was performed using a gel shift assay system (Promega, Madison, WI) according to the manual. Samples were analyzed using Novex 6% DNA retardation gel (Invitrogen, San Diego, CA). Data are representative of several experiments.

Western blot

Western blot was performed according to procedures described elsewhere (11). Abs against IB (Santa Cruz Biotechnology, Santa Cruz, CA) at a 1/500 dilution or -actin (Sigma-Aldrich) at a 1/5000 dilution were used with HRP-conjugated goat anti-mouse Ab (Santa Cruz Biotechnology) at a 1/5000 dilution before detection using SuperSignal Substrate (Pierce, Rockford, IL).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Deletion of the A2AR results in enhanced transcription of proinflammatory cytokines

Our study was performed with immune cells activated in vivo and then analyzed for expression of proinflammatory cytokine mRNA and transcriptional activities of NF-B ex vivo. The parallel use of matched group WT mice vs A2AR^–/– mice and of pharmacologic agents with proven selectivity for A2AR (13, 14), demonstrated an increase of proinflammatory transcription in the absence of the A2AR and thereby revealed its anti-inflammatory role in vivo (Figs. 1 and 2). Acute inflammation was triggered by treatment of mice with TLR-activating agents, such as the bacterial endotoxin LPS (15) or oligodeoxyribonucleotides, which contain nonmethylated CpG dinucleotides (CpG DNA) (16, 17). The use of CpG DNA in these experiments was also motivated by possible clinical implications because of the potential use of these ligands as adjuvants in vaccine development (18, 19).

View larger version (11K): [in this window] [in a new window]   FIGURE 1. A, Comparison of survival of WT vs A2AR–/– during LPS-induced septic shock. A2AR–/– mice (n = 11, solid line) and WT mice (n = 10, dashed line) were injected i.p. with 3 mg/kg LPS as described in Materials and Methods. Survival was monitored according to regulations approved by the National Institutes of Health Animal Care Committee. Differences between groups were evaluated using the log rank test, p < 0.005. B, Increased levels of proinflammatory cytokines in A2AR-deficient mice. WT (n = 5) and A2AR–/– (n = 5) mice were injected i.p. with 2 ml of 3% thioglycolate medium 2 days before i.p. injection of 5 nmol of CpG DNA. Mice were sacrificed at 1 h and levels of IL-12p40 in peritoneal exudate lavage were measured by ELISA. Differences between groups were evaluated using Student’s t test, p < 0.01.

View larger version (59K): [in this window] [in a new window]   FIGURE 2. A, Increased expression of proinflammatory cytokines mRNA in A2AR-deficient mice. Total spleen RNA from WT and A2AR–/– mice was subjected to RPA 1 h after i.p. injection with 20 nmol of CpG DNA. B, Increased expression of proinflammatory cytokines’ mRNA in macrophages from A2AR-deficient mice. Macrophages were isolated from spleen of WT and A2AR–/– mice 1 h after i.p. injection with 20 nmol of CpG DNA using immunomagnetic bead separation as described in Materials and Methods. Cytokine mRNA expression was analyzed by RPA. C, Increased expression of proinflammatory cytokines mRNA in splenocytes with pharmacologically inactivated in vivo A2AR. Total spleen RNA from WT mice was subjected to RPA 1 h after i.p. injection with 5 nmol of CpG DNA with or without 1 h pretreatment with 10 mg/kg ZM241385 (ZM). D, Decreased expression of proinflammatory cytokine mRNA in splenocytes of mice with pharmacologically activated in vivo A2AR. Total spleen RNA from WT mice was subjected to RPA 1 h after i.p. injection with 10 nmol of CpG DNA with or without 1 h pretreatment with 2 mg/kg of CGS21680 (CGS).

It is shown (Fig. 1A) that the A2AR plays a nonredundant role in tissue protection during LPS-induced septic shock as confirmed by the accelerated death of A2AR-deficient mice when compared with control sets of WT mice. In agreement with survival studies (Fig. 1A), the absence of the A2AR resulted in a rapid increase of IL-12p40 and TNF- levels in serum after i.p. injection of CpG DNA (Fig. 1B and data not shown).

The increase in protein levels of TNF- and other proinflammatory cytokines can be in large part accounted for by dramatic enhancement of the transcription of proinflammatory cytokines in immune cells from A2AR^–/– mice after i.p. injection of LPS (data not shown) and CpG DNA (Fig. 2, A and B). RPA revealed significantly higher levels of TNF-, IL-12 p40, and other proinflammatory cytokines mRNA in splenocytes of A2AR^–/– mice compared with WT (Fig. 2A). Since CpG DNA used in this study was specifically potent in activation of macrophages (17), the difference in levels of proinflammatory cytokine mRNA was even more dramatic in purified splenic macrophages from A2AR^–/– and WT mice (Fig. 2B).

The control of proinflammatory transcription by the A2AR was further confirmed in experiments with WT mice in which A2AR and A2BR were pharmacologically inactivated in vivo by i.p. injection of an antagonist ZM241385 (14). Fig. 2C shows that pharmacologic inactivation of the A2AR also results in the transcriptional up-regulation of the same set of proinflammatory cytokines observed in comparisons of WT vs A2AR^–/– mice.

The capability of cAMP-elevating A2AR to regulate transcription of proinflammatory cytokines in vivo was further confirmed by using agonists of the A2AR. In this opposite approach, we found that i.p. injection of the selective A2AR agonist CGS21680 (13) inhibits proinflammatory transcription (Fig. 2D).

In addition to in vivo experiments (Fig. 2), it was shown in control in vitro experiments that transcriptional inhibitor actinomycin D blocks TLR-induced accumulation of proinflammatory cytokines mRNA in both WT and A2AR^–/– splenocytes (data not shown). Thus, pharmacologic activation of the A2AR by selective ligands (Fig. 2D) and by endogenously formed adenosine (Fig. 2, A and B) is capable of inhibiting transcription of proinflammatory cytokines in vivo.

Deficiency in the A2AR results in enhanced NF-B DNA-binding activity

Since NF-B is the major transcriptional factor responsible for production of proinflammatory cytokines in immune cells activated through TLR (17), we expected that NF-B might be inhibited by action of the A2AR. Therefore, the higher transcriptional activity of NF-B would be expected in A2AR-deficient mice and this would explain the enhanced transcription of, for example, TNF- mRNA in peritoneal macrophages from A2AR^–/– mice injected with CpG DNA (Fig. 3A). Accordingly, stronger NF-B DNA binding was observed in nuclear extracts from A2AR^–/– macrophages activated by CpG DNA in vivo as compared with WT (Fig. 3B). These properties of the A2AR were confirmed by observations of direct inhibition of NF-B DNA-binding activity in vivo by injection of the selective A2AR agonist CGS21680 (data not shown).

View larger version (53K): [in this window] [in a new window]   FIGURE 3. A, Up-regulation of TNF- mRNA in macrophages from A2AR-deficient mice. WT and A2AR–/– mice were injected i.p. with 2 ml of 3% thioglycolate medium 2 days before stimulation with 3 nmol of CpG DNA for 1 h. Total RNA from peritoneal macrophages was subjected to RPA. B, Increased NF-B DNA-binding activity in nuclear extracts of A2AR–/– macrophages in vivo. WT and A2AR–/– mice were injected i.p. with 2 ml of 3% thioglycolate medium 2 days before stimulation with 3 nmol of CpG DNA. After 1 h of activation, nuclear extracts were collected and 5-µg aliquots were analyzed for binding ability to NF-B-specific radiolabeled oligonucleotide with or without 50-fold excess of the same unlabeled oligonucleotide. C, Increased degradation of IB in A2AR–/– peritoneal macrophages. WT and A2AR–/– mice were injected i.p. with 2 ml of 3% thioglycolate medium 2 days before stimulation with 3 nmol of CpG DNA. After 20 min of activation, cytoplasmic fractions were collected and 50 µg of protein were analyzed for the presence of IB and -actin by Western blot.

In agreement with the observed inhibitory effects of cAMP-elevating A2AR on NF-B functions in vivo are earlier observations that pharmacologic stimulation of the protein kinase A signaling pathway has inhibitory effects on nuclear translocation and DNA-binding activity of NF-B (10). Moreover, activation of cAMP-elevating receptors such as -adrenergic receptor (22) and vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide receptor (VPAC1) (11, 23) prevents nuclear translocation of NF-B. Different cAMP-elevating ligands to the G_s protein-coupled receptors, including, for example, catecholamines, PGs, dopamine, histamine, and extracellular adenosine, have been shown to have immunosuppressive pharmacologic properties and have been considered among many molecular candidates as potential anti-inflammatory stimuli in vivo (24, 25, 26). The genetic controls in Figs. 2 and 3 emphasize a critical and nonredundant role of locally formed extracellular adenosine and A2AR in regulation of proinflammatory transcription in vivo.

Conclusion

The data reported here support the model of physiologic negative feedback regulation of inflammation in which the accumulation of extracellular adenosine serves as an "immediate early signal" and A2AR as a "sensor" of excessive tissue damage. Since secretion of a majority of proinflammatory cytokines is mediated by constitutive exocytosis, the inhibition on the level of transcription factors (e.g., NF-B) and transcription may be the most advantageous in local tissue protection by providing the immediate termination of inflammatory response.

	Acknowledgments

 
We thank Drs. Hermann Wagner and Dr. William Paul for support, discussions, and encouragement and Shirley Starnes for the help in preparation of this manuscript.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Michail Sitkovsky, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room llN256, Bethesda, MD 20892-1892. E-mail address: mvsitkov{at}helix.nih.gov

² Abbreviations used in this paper: A2BR, A2B adenosine receptor; A2BR, A2B adenosine receptor; WT, wild type; RPA, RNase protection assay.

Received for publication March 5, 2004. Accepted for publication May 3, 2004.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Ohta, A., M. Sitkovsky. 2001. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916.[Medline]
2. Sitkovsky, M., D. Lukashev, S. Apasov, H. Kojima, M. Koshiba, C. Caldwell, A. Ohta, M. Thiel. 2004. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22:657.[Medline]
3. Decking, U. K., G. Schlieper, K. Kroll, J. Schrader. 1997. Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ. Res. 81:154.[Abstract/Free Full Text]
4. Ledoux, S., I. Runembert, K. Koumanov, J. B. Michel, G. Trugnan, G. Friedlander. 2003. Hypoxia enhances ecto-5'-nucleotidase activity and cell surface expression in endothelial cells. Circ. Res. 92:848.[Abstract/Free Full Text]
5. Day, Y. J., M. A. Marshall, L. Huang, M. J. McDuffie, M. D. Okusa, J. Linden. 2004. Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. Am. J. Physiol. 286:G285.
6. Day, Y. J., L. Huang, M. J. McDuffie, D. L. Rosin, H. Ye, J. F. Chen, M. A. Schwarzschild, J. S. Fink, J. Linden, M. D. Okusa. 2003. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J. Clin. Invest. 112:883.[Medline]
7. Bourne, H. R., L. M. Lichtenstein, K. L. Melmon, C. S. Henney, Y. Weinstein, G. M. Shearer. 1974. Modulation of inflammation and immunity by cyclic AMP. Science :184.
8. Kammer, G. M.. 1988. The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol. Today 9:222.[Medline]
9. Weissmann, G., P. Dukor, R. B. Zurier. 1971. Effect of cyclic AMP on release of lysosomal enzymes from phagocytes. Nat. New Biol. 231:131.[Medline]
10. Neumann, M., T. Grieshammer, S. Chuvpilo, B. Kneitz, M. Lohoff, A. Schimpl, B. R. Franza, E. Serfling. 1995. RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A. EMBO J. 14:1991.[Medline]
11. Delgado, M., D. Ganea. 1999. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor B and Ets activation. J. Biol. Chem. 274:31930.[Abstract/Free Full Text]
12. Chen, J.-F., Z. Huang, J. Ma, J. Zhu, R. Moratalla, D. Standaert, M. A. Moskowitz, J. S. Fink, M. A. Schwartzschild. 1999. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19:9192.[Abstract/Free Full Text]
13. Apasov, S. G., J.-F. Chen, P. T. Smith, M. A. Schwarzschild, J. S. Fink, M. V. Sitkovsky. 2000. Study of A2A adenosine receptor gene-deficient mice reveals that adenosine analogue CGS 21680 possesses no A2A receptor-unrelated lymphotoxicity. Br. J. Pharmacol. 131:43.[Medline]
14. Alexander, S. P., P. J. Millns. 2001. [³H]ZM241385: an antagonist radioligand for adenosine A2A receptors in rat brain. Eur. J. Pharmacol. 411:205.[Medline]
15. Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. V. Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, et al 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085.[Abstract/Free Full Text]
16. Wagner, H.. 1999. Bacterial CpG DNA activates immune cells to signal infectious danger. Adv. Immunol. 73:329.[Medline]
17. Hemmi, H., O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K. Hoshino, H. Wagner, K. Takeda, S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740.[Medline]
18. Melief, C. J., S. H. Van Der Burg, R. E. Toes, F. Ossendorp, R. Offringa. 2002. Effective therapeutic anticancer vaccines based on precision guiding of cytolytic T lymphocytes. Immunol. Rev. 188:177.[Medline]
19. Rhee, E. G., S. Mendez, J. A. Shah, C. Y. Wu, J. R. Kirman, T. N. Turon, D. F. Davey, H. Davis, D. M. Klinman, R. N. Coler, et al 2002. Vaccination with heat-killed leishmania antigen or recombinant leishmanial protein and CpG oligodeoxynucleotides induces long-term memory CD4⁺ and CD8⁺ T cell responses and protection against Leishmania major infection. J. Exp. Med. 195:1565.[Abstract/Free Full Text]
20. Lukashev, D. E., P. T. Smith, C. C. Caldwell, A. Ohta, S. G. Apasov, M. V. Sitkovsky. 2003. Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in expression of A2b, A1 and A3 adenosine receptors in lymphoid organs. Biochem. Pharmacol. 65:2081.[Medline]
21. Karin, M., Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-B activity. Annu. Rev. Immunol. 18:621.[Medline]
22. Farmer, P., and J. 2000. Pugin. -adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IB/NF-B pathway. Am. J. Physiol. 279:L675.
23. Delgado, M., D. Ganea. 2000. Inhibition of IFN--induced Janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. J. Immunol. 165:3051.[Abstract/Free Full Text]
24. Abbracchio, M. P., G. Burnstock. 1998. Purinergic signalling: pathophysiological roles. Jpn. J. Pharmacol. 78:113.[Medline]
25. Kohm, A. P., V. M. Sanders. 2001. Norepinephrine and b2-adrenergic receptor stimulation regulate CD4⁺ T and B lymphocyte function in vitro and in vivo. Pharmacol. Rev. 53:487.[Abstract/Free Full Text]
26. Levy, B. D., C. B. Clish, B. Schmidt, K. Gronert, C. N. Serhan. 2001. Lipid mediator class switching during acute inflammation: signals in resolution. Nat. Immunol. 2:612.[Medline]

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