Adenosine is an endogenous signaling molecule that is highly up-regulated in inflammatory states. Adenosine acts through the A2b receptor, a G protein-coupled receptor that couples positively to Gαs and activates adenylate cyclase. This leads to cAMP-mediated electrogenic chloride secretion in intestinal epithelia. To better understand the regulation of the A2b receptor in intestinal epithelia, we studied the effects of interferon-γ (IFN-γ), a potent immunomodulatory cytokine, in the T84 cell line. Pretreatment of cells with 500 units/ml IFN-γ for 12 h inhibited an adenosine-induced short circuit current (Isc) without affecting the transepithelial resistance. Under these conditions, IFN-γ did not inhibit the protein expression or membrane recruitment of the A2b receptor, shown to be essential for its function. Interestingly, IFN-γ inhibited cAMP levels as well as its downstream signaling pathway as shown by the inhibition of adenosine-induced phosphorylation of cAMP response element-binding protein and protein kinase A activity. Similar studies with forskolin, a direct activator of adenylate cyclase, also demonstrated inhibition of cAMP and its downstream response by IFN-γ. However, IFN-γ did not affect secretory responses to the calcium-dependent secretagogue carbachol or cAMP analog 8-bromo-cAMP, indicating that normal secretory responses to adequate second messengers in IFN-γ-treated cells are achievable. Moreover, IFN-γ inhibited the expression of adenylate cyclase isoforms 5 and 7. In conclusion, we demonstrate that IFN-γ down-regulates adenosine-mediated signaling possibly through the direct inhibition of adenylate cyclase expression. We propose that IFN-γ may acutely affect global cAMP-mediated responses in the intestinal epithelia, thereby decreasing secretory responses, which may consequently aggravate inflammatory processes. Adenosine is an endogenous signaling molecule that is highly up-regulated in inflammatory states. Adenosine acts through the A2b receptor, a G protein-coupled receptor that couples positively to Gαs and activates adenylate cyclase. This leads to cAMP-mediated electrogenic chloride secretion in intestinal epithelia. To better understand the regulation of the A2b receptor in intestinal epithelia, we studied the effects of interferon-γ (IFN-γ), a potent immunomodulatory cytokine, in the T84 cell line. Pretreatment of cells with 500 units/ml IFN-γ for 12 h inhibited an adenosine-induced short circuit current (Isc) without affecting the transepithelial resistance. Under these conditions, IFN-γ did not inhibit the protein expression or membrane recruitment of the A2b receptor, shown to be essential for its function. Interestingly, IFN-γ inhibited cAMP levels as well as its downstream signaling pathway as shown by the inhibition of adenosine-induced phosphorylation of cAMP response element-binding protein and protein kinase A activity. Similar studies with forskolin, a direct activator of adenylate cyclase, also demonstrated inhibition of cAMP and its downstream response by IFN-γ. However, IFN-γ did not affect secretory responses to the calcium-dependent secretagogue carbachol or cAMP analog 8-bromo-cAMP, indicating that normal secretory responses to adequate second messengers in IFN-γ-treated cells are achievable. Moreover, IFN-γ inhibited the expression of adenylate cyclase isoforms 5 and 7. In conclusion, we demonstrate that IFN-γ down-regulates adenosine-mediated signaling possibly through the direct inhibition of adenylate cyclase expression. We propose that IFN-γ may acutely affect global cAMP-mediated responses in the intestinal epithelia, thereby decreasing secretory responses, which may consequently aggravate inflammatory processes. Adenosine is an important modulator of physiological as well as inflammatory responses in humans. Adenosine is generated during active inflammation, and levels increase both in the intestinal lumen and in tissue during inflammation to as high as 500–600 nm (1Cronstein B.N. J. Appl. Physiol. 1994; 76: 5-13Crossref PubMed Scopus (575) Google Scholar). The intestinal adenosine 2b receptor (A2bR), 1The abbreviations used are: A2bR, adenosine 2b receptor; AA, apical adenosine; AC-1 through AC-9, adenylate cyclase isoforms 1–9; BA, basolateral adenosine; Bs, basolateral; 8-Br-cAMP, 8-bromo-cAMP; CFTR, cystic fibrosis conductance regulator; CREB, cAMP-responsive element-binding protein; FSK, forskolin; Isc, short circuit current; IFN-γ, interferon-γ; PKA, protein kinase A; RT, reverse transcription; TER, transepithelial resistance; VIP, vasoactive intestinal peptide.1The abbreviations used are: A2bR, adenosine 2b receptor; AA, apical adenosine; AC-1 through AC-9, adenylate cyclase isoforms 1–9; BA, basolateral adenosine; Bs, basolateral; 8-Br-cAMP, 8-bromo-cAMP; CFTR, cystic fibrosis conductance regulator; CREB, cAMP-responsive element-binding protein; FSK, forskolin; Isc, short circuit current; IFN-γ, interferon-γ; PKA, protein kinase A; RT, reverse transcription; TER, transepithelial resistance; VIP, vasoactive intestinal peptide. one of the four adenosine receptor subtypes (A1, A2a, A2b, and A3), mediates the biological effects of adenosine (2Bucheimer R.E. Linden J. J. Physiol. (Lond.). 2004; 555: 311-321Crossref Scopus (110) Google Scholar, 3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Interestingly, the A2bR is the predominant adenosine receptor expressed in the caecum and colon in both the model colonic cell line T84 and in intact human colonic mucosa (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 4Rivkees S.A. Reppert S.M. Mol. Endocrinol. 1992; 6: 1598-1604PubMed Google Scholar). Indeed, in the model colonic epithelia T84 cells, the A2bR is the only adenosine receptor expressed (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 5Christofi F.L. Zhang H. Yu J.G. Guzman J. Xue J. Kim M. Wang Y.Z. Cooke H.J. J. Comp. Neurol. 2001; 439: 46-64Crossref PubMed Scopus (109) Google Scholar). Depending on the organ, the A2bR activates pro- or anti-inflammatory pathways. For example, in the joints and cardiovascular system, the A2bR is anti-inflammatory, whereas in the lung the A2bR is a potent proinflammatory mediator, and the A2bR antagonists are evolving as potential drugs for reactive airway disease (2Bucheimer R.E. Linden J. J. Physiol. (Lond.). 2004; 555: 311-321Crossref Scopus (110) Google Scholar). In the intestine, apical or basolateral stimulation of the A2bR results in cAMP-dependent electrogenic chloride secretion through the activation of chloride channels (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 6Barrett K.E. Cohn J.A. Huott P.A. Wasserman S.I. Dharmsathaphorn K. Am. J. Physiol. 1990; 258: C902-C912Crossref PubMed Google Scholar). Active chloride secretion by intestinal crypt enterocytes is known to be the central pathophysiological disturbance in acute and chronic diarrheal illnesses (7Baird A.W. Ir. J. Med. Sci. 1994; 163: 277-281Crossref PubMed Scopus (3) Google Scholar). In addition to chloride secretion, adenosine also induces apically directed interleukin-6 secretion and fibronectin secretion (8Sitaraman S.V. Merlin D. Wang L. Wong M. Gewirtz A.T. Si-Tahar M. Madara J.L. J. Clin. Invest. 2001; 107: 861-869Crossref PubMed Scopus (154) Google Scholar, 9Walia B. Castaneda F.E. Wang L. Kolachala V.L. Bajaj R. Roman J. Merlin D. Gewirtz A.T. Sitaraman S.V. Biochem. J. 2004; 382: 589-596Crossref PubMed Scopus (40) Google Scholar). Thus adenosine, acting through the A2bR, modulates intestinal secretion and inflammatory response in a cAMP-dependent manner. In the intestinal epithelial cells, the A2bR couples positively to Gαs and activates adenylate cyclase. Apical or basolateral stimulation of the A2bR induces an increase in intracellular cAMP and downstream cAMP signaling including phosphorylation and activation of the transcription factor, CREB and the activation of PKA (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 10Sitaraman S.V. Si-Tahar M. Merlin D. Strohmeier G.R. Madara J.L. Am. J. Physiol. 2000; 278: C1230-C1236Crossref PubMed Google Scholar). The former is involved in interleukin-6 secretion in the intestine in response to adenosine (11Sitaraman S.V. Wang L. Wong M. Bruewer M. Hobert M. Yun C.H. Merlin D. Madara J.L. J. Biol. Chem. 2002; 277: 33188-33195Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), and PKA is involved in the chloride secretory pathway activated by adenosine (11Sitaraman S.V. Wang L. Wong M. Bruewer M. Hobert M. Yun C.H. Merlin D. Madara J.L. J. Biol. Chem. 2002; 277: 33188-33195Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 12Singh A.K. Tasken K. Walker W. Frizzell R.A. Watkins S.C. Bridges R.J. Bradbury N.A. Am. J. Physiol. 1998; 275: C562-C570Crossref PubMed Google Scholar). Unlike mast cells, where the A2bR also couples to Gq and increases intracellular calcium (13Feoktistov I. Goldstein A.E. Biaggioni I. Mol. Pharmacol. 1999; 55: 726-734PubMed Google Scholar), cAMP is the only signaling pathway mediated by the A2bR in the intestinal epithelial cells (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Studies in our laboratory have demonstrated that the A2bR is recruited to the membrane upon agonist stimulation and exists as a multiprotein complex at the membrane with the PDZ domain-containing protein, NHERF-2, cytoskeletal anchoring protein, ezrin, and PKA (11Sitaraman S.V. Wang L. Wong M. Bruewer M. Hobert M. Yun C.H. Merlin D. Madara J.L. J. Biol. Chem. 2002; 277: 33188-33195Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Although the expression and biological effect of adenosine in the intestine have been characterized, the regulation of the A2b is not known. The major goal of this study is to characterize the regulation of the A2bR by interferon-γ (IFN-γ). IFN-γ is an immunoregulatory cytokine produced by T helper 1 cells. It is highly up-regulated during chronic inflammatory diseases such as inflammatory bowel disease as well as during acute viral or bacterial enteritis and is thought to play a central role in the pathogenesis of inflammation and diarrhea associated with these diseases (14Vancott J.L. McNeal M.M. Choi A.H. Ward R.L. J. Interferon Cytokine Res. 2003; 23: 163-170Crossref PubMed Scopus (55) Google Scholar, 15Stockmann M. Schmitz H. Fromm M. Schmidt W. Pauli G. Scholz P. Riecken E.O. Schulzke J.D. Ann. N. Y. Acad. Sci. 2000; 915: 293-303Crossref PubMed Scopus (37) Google Scholar, 16Schroder K. Hertzog P.J. Ravasi T. Hume D.A. J. Leukocyte Biol. 2004; 75: 163-189Crossref PubMed Scopus (2790) Google Scholar). During inflammation, IFN-γ directly affects the enterocytes, including the Cl–-secreting crypt cells, and regulates enterocyte functions including barrier regulation and ion secretion (17Fish S.M. Proujansky R. Reenstra W.W. Gut. 1999; 45: 191-198Crossref PubMed Scopus (137) Google Scholar, 18Breese E. Braegger C.P. Corrigan C.J. Walker-Smith J.A. MacDonald T.T. Immunology. 1993; 78: 127-131PubMed Google Scholar, 19Niessner M. Volk B.A. Clin. Exp. Immunol. 1995; 101: 428-435Crossref PubMed Scopus (377) Google Scholar). The effect of chronic exposure to IFN-γ (>24 h) on enterocyte function has been studied extensively. Prior studies vasoactive intestinal and carbachol demonstrated in transepithelial and chloride secretion with IFN-γ h) without the of cells. This inhibition in secretory response has been to of cystic fibrosis conductance G. I. D. Am. J. Physiol. 1994; PubMed Google Scholar), for secretion K. M. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Although the chronic effects of IFN-γ have been well characterized, the acute effect of this cytokine on secretory response in intestinal epithelia is not known. In this study we the effect of acute IFN-γ exposure on the and secretory function of the for and at and CREB at IFN-γ cyclase at for and for used at at A cAMP and the PKA and The cells and in as D. L. Strohmeier G.R. Lencer W.I. Madara J.L. Am. J. Physiol. 1998; 275: PubMed Google in a of and with and by on cells for on of or well in as This apical and basolateral to be with apical and basolateral a to that for The T84 cells a high on T84 cells and cells on well of 1 and to The and in an and with at and with and The on of the 5 of and of by and to a to and by The current the are to the apical and at whereas the to The with in to be used for the The 1 in the in the with potential that the with cell The apical and the the current by a the cell with or without IFN-γ with and 1 to a cells with apical or basolateral adenosine and The increase in of membrane T84 cells in as G. M. G. R. W. M. G. J. Sci. 2002; PubMed Scopus Google Scholar). in with a and with a in The cell at for at The at for at G. M. G. R. W. M. G. J. Sci. 2002; PubMed Scopus Google Scholar). The in membrane in the and with and and to the to and with with and with exposure to high For with the of of a cAMP cells with or without basolateral IFN-γ and cells with apical and basolateral adenosine and cAMP in cell a cAMP with PKA the of PKA in IFN-γ-treated cells, T84 cells with or without basolateral IFN-γ for and with basolateral adenosine or PKA a protein kinase of cell to the PKA cAMP PKA and and and with and the a for protein the protein PKA as of of protein, and the increase in PKA in to the of T84 cells by the The used to of the of by the The on the of the in the A by for with the A reverse transcription at for activation at for by of for for for 1 and at for are as the or of with IFN-γ in T84 the effect of IFN-γ on adenosine-induced Isc, of epithelial cells, on well with 500 units/ml IFN-γ for 12 The in a shown in IFN-γ did not affect and with cell cells and and cells with IFN-γ and results demonstrate that the barrier function as by not by IFN-γ To the effect of IFN-γ on the regulation of adenosine-induced Isc, with apical or basolateral adenosine or basolateral carbachol a shown in IFN-γ both apical and basolateral adenosine IFN-γ 1 with adenosine the IFN-γ effect on IFN-γ carbachol 5 We the response of inhibition of adenosine-mediated T84 cells on well with IFN-γ and 500 for 12 on an with adenosine for 5 and The inhibition of adenosine-induced at and at 500 with an at of IFN-γ. IFN-γ A2bR or to IFN-γ inhibited the we studied its effect on the receptor protein expression. T84 cells on a with 500 units/ml IFN-γ for 12 h and with apical or basolateral adenosine for 5 shown in the of cell in cells second and cells with IFN-γ IFN-γ IFN-γ studies in our laboratory have demonstrated that the A2bR is recruited to the membrane upon agonist stimulation (11Sitaraman S.V. Wang L. Wong M. Bruewer M. Hobert M. Yun C.H. Merlin D. Madara J.L. J. Biol. Chem. 2002; 277: 33188-33195Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, L. Kolachala B. R.A. Merlin D. Sitaraman S.V. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). To the effect of IFN-γ on the recruitment of the receptor to the we of the A2bR on membrane The cells with apical or basolateral adenosine with or without IFN-γ for 12 membrane as and shown in adenosine stimulation in recruitment of the receptor to the membrane 5 and IFN-γ did not the adenosine-induced recruitment of the receptor to the membrane The of A2bR recruitment to the as and as membrane are IFN-γ A2b A2bR couples positively to Gαs and activates adenylate cyclase. We have shown that apical or basolateral stimulation of the A2bR induces an increase in intracellular cAMP (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). We studied the effect of IFN-γ on adenosine-induced T84 cells with or without 500 units/ml IFN-γ for 12 and cAMP levels by apical adenosine and basolateral adenosine a as and both apical and basolateral adenosine cAMP which at 5 stimulation shown in of cells with IFN-γ in the inhibition of both apical and basolateral cAMP levels by and IFN-γ cells, IFN-γ did not affect cAMP with cells and cells, IFN-γ cAMP-mediated of CREB and PKA of the A2bR leads to downstream cAMP signaling including phosphorylation and activation of the transcription CREB and the activation of To the effect of IFN-γ on downstream cAMP to its effect on phosphorylation of T84 with or without 500 units/ml IFN-γ for 12 h and with cell to shown in the of adenosine phosphorylation of CREB at and at and IFN-γ inhibited adenosine-induced CREB activation at and and The at the of of CREB which demonstrated in in cells with cells. To study the effect of IFN-γ on PKA T84 with 500 units/ml IFN-γ for 12 h the addition of apical or basolateral adenosine for 5 and The PKA as and the apical and basolateral adenosine PKA which at 5 and to line at shown in IFN-γ inhibited both apical and basolateral adenosine-mediated PKA activation IFN-γ IFN-γ of of that IFN-γ may inhibit A2bR signaling by affecting the of adenylate cyclase or by the of cAMP the activation of To the of we studied the effect of and on the inhibition of adenosine-mediated Interestingly, and did not reverse inhibition of not to that IFN-γ directly inhibited adenylate cyclase its expression. IFN-γ of in a and the effect of IFN-γ on cAMP and T84 cells with of IFN-γ 500 the the The cells with FSK, and and A inhibition of with cells The inhibition of 5 at units/ml and at 500 units/ml We IFN-γ inhibited in a manner. in the the inhibition of by IFN-γ at h and at 12 h IFN-γ CREB, and PKA studied the effect of IFN-γ on downstream cAMP signaling by T84 cells with 500 units/ml IFN-γ for 12 and the cells with of for 5 The cells and cAMP by a as and IFN-γ inhibited cAMP at and and with IFN-γ FSK, and The inhibition of cAMP by IFN-γ at and by of phosphorylation of CREB by in IFN-γ cells. second and in PKA inhibited by with IFN-γ IFN-γ IFN-γ of of To that adenylate cyclase and not the cAMP-dependent involved in adenosine-induced by IFN-γ, we studied the effect of 8-Br-cAMP, a cAMP on the T84 cells with IFN-γ for 12 h and with in not inhibited by IFN-γ that the response to adequate cAMP not inhibited by IFN-γ. IFN-γ of IFN-γ inhibited the of adenylate cyclase, we studied the IFN-γ effect on expression of adenylate cyclase. exists in isoforms through of which and are We the expression of in T84 cells and of membrane with T84 cells and reverse transcription and as and with a of and AC-9, by expression of and and isoforms not be We the effect of IFN-γ on the expression of T84 cells with 500 units/ml IFN-γ for 12 and to IFN-γ inhibited the expression of not affecting or that IFN-γ the expression of and did not affect The that IFN-γ directly the expression and of and its downstream signaling In this we the regulation of the A2bR by IFN-γ, the inflammatory cytokine that is highly up-regulated in acute and chronic in human and is known to play an important role in chloride secretion and barrier function in the intestine E. Braegger C.P. Corrigan C.J. Walker-Smith J.A. MacDonald T.T. Immunology. 1993; 78: 127-131PubMed Google Scholar, 19Niessner M. Volk B.A. Clin. Exp. 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Physiol. 1992; PubMed Google Scholar, P. J. M. L. Am. J. Physiol. Google Scholar, Am. J. Physiol. Google Scholar). Apical or basolateral adenosine, or has been demonstrated to cAMP-dependent electrogenic chloride secretion through the activation of apical chloride channels (3Strohmeier G.R. Reppert S.M. Lencer W.I. Madara J.L. J. Biol. Chem. 1995; 270: 2387-2394Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 6Barrett K.E. Cohn J.A. Huott P.A. Wasserman S.I. Dharmsathaphorn K. Am. J. Physiol. 1990; 258: C902-C912Crossref PubMed Google Scholar). studies have the effect of IFN-γ on secretory response and in T84 cells (7Baird A.W. Ir. J. Med. Sci. 1994; 163: 277-281Crossref PubMed Scopus (3) Google Scholar, 15Stockmann M. Schmitz H. Fromm M. Schmidt W. Pauli G. Scholz P. Riecken E.O. Schulzke J.D. Ann. N. Y. Acad. Sci. 2000; 915: 293-303Crossref PubMed Scopus (37) Google Scholar, 18Breese E. Braegger C.P. Corrigan C.J. Walker-Smith J.A. MacDonald T.T. 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Physiol. 2002; PubMed Scopus Google Scholar), may in in chloride secretion epithelia, which in such as acute diarrheal cystic secretory and inflammatory bowel disease K.E. Physiol. 2000; PubMed Scopus Google Scholar). The of crypt epithelial cells to to with chloride and secretion is an important of epithelial barrier that the intestine by of bacterial and to Gut. 2004; PubMed Scopus Google Scholar, K. J.L. Am. J. Physiol. 2001; Google Scholar). is that the effect of IFN-γ on may aggravate the proinflammatory in acute or chronic may be to of diarrhea and may have for IFN-γ in the acute We are to of for adenylate cyclase expression and We for with cell We are to M. for
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Kolachala et al. (2004) studied this question.