Induction of Polyamine Oxidase 1 by Helicobacter pylori Causes Macrophage Apoptosis by Hydrogen Peroxide Release and Mitochondrial Membrane Depolarization

Abstract

Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H2O2, which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N1-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme (polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N1-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H2O2 generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H2O2 was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H2O2 release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection. Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H2O2, which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N1-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme (polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N1-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H2O2 generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H2O2 was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H2O2 release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection. Helicobacter pylori is a Gram-negative, microaerophilic bacterium that selectively colonizes the mammalian stomach and causes gastritis, peptic ulcers, and gastric cancer. Intriguingly the human host mounts a vigorous innate and adaptive immune response, yet this results only in lifelong gastritis without eradication of the organism. H. pylori has evolved several strategies to enhance its own survival in the face of this immune response. For example, we have shown that while the host produces NO derived from inducible nitric-oxide synthase in response to soluble products of H. pylori (1Wilson K.T. Ramanujam K.S. Mobley H.L. Musselman R.F. James S.P. Meltzer S.J. Gastroenterology. 1996; 111: 1524-1533Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 2Gobert A.P. Mersey B.D. Cheng Y. Blumberg D.R. Newton J.C. Wilson K.T. J. Immunol. 2002; 168: 6002-6006Crossref PubMed Scopus (120) Google Scholar), an arginase enzyme expressed by the bacterium can competitively inhibit host NO production and prevent NO-mediated killing (3Gobert A.P. McGee D.J. Akhtar M. Mendz G.L. Newton J.C. Cheng Y. Mobley H.L. Wilson K.T. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 13844-13849Crossref PubMed Scopus (318) Google Scholar). Additionally H. pylori has been shown to induce apoptosis of T cells (4Wang J. Brooks E.G. Bamford K.B. Denning T.L. Pappo J. Ernst P.B. J. Immunol. 2001; 167: 926-934Crossref PubMed Scopus (92) Google Scholar) and macrophages (5Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr., R.A. Newton J.C. Wilson K.T. J. Immunol. 2002; 168: 4692-4700Crossref PubMed Scopus Google Scholar), which is to significantly to the of the by in immune the macrophage studies (5Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr., R.A. Newton J.C. Wilson K.T. J. Immunol. 2002; 168: 4692-4700Crossref PubMed Scopus Google Scholar) we have that H. pylori expression and activity of the enzyme arginase which produces from and activity of ornithine ornithine spermidine/spermine polyamine H. pylori of mitochondrial membrane small which produces from that is to the polyamines spermidine and H. pylori-induced macrophage apoptosis is but is by inhibition of arginase or and by of spermidine or spermine (5Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr., R.A. Newton J.C. Wilson K.T. J. Immunol. 2002; 168: 4692-4700Crossref PubMed Scopus Google Scholar). These studies the as to the mechanism of macrophage apoptosis. is the enzyme for polyamine are several of polyamine that are to in and spermidine can be by an oxidative that results in the release of this can occur in the back-conversion pathway, spermine or spermidine is by the enzyme spermidine/spermine N1-acetyltransferase to or Jr., R.A. J. PubMed Scopus Google Scholar, Casero Jr., R.A. PubMed Scopus Google Scholar, Jr., R.A. S.J. J. Full Text PDF PubMed Google Scholar), which are by polyamine oxidase to spermidine or Jr., R.A. J. PubMed Scopus Google this enzyme has recently been S. J. PubMed Scopus Google Scholar). this enzyme has been to Jr., R.A. Wang Y. A. PubMed Google Scholar). an was in human cells Y. A. Casero Jr., R.A. 2001; Google Scholar, Wang Y. Casero Jr., R.A. J. 2002; PubMed Google Scholar), and the enzyme was spermine oxidase S. J. 2002; PubMed Scopus Google Scholar) and spermine to spermidine without the acetylation the we the mouse which we induced by polyamine has been to oxidation of polyamines and of H2O2 in cell that small cell Casero Jr., R.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), Wang Y. A. Casero R.A. PubMed Scopus Google Scholar), J. PubMed Scopus Google Scholar), and Sci. 2002; PubMed Scopus Google Scholar). of H2O2 has been to of mitochondrial membrane Y. S. 2001; Google Scholar, M. M. M. A. 2001; PubMed Scopus Google Scholar, S. A. 2002; PubMed Scopus (92) Google Scholar), which is with the of apoptosis by release of cytochrome c from to the M. M. M. A. 2001; PubMed Scopus Google Scholar, M. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar) and activation of S. A. 2002; PubMed Scopus (92) Google Scholar, S.D. U. M. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). We hypothesized that oxidation of polyamines by H. pylori was the in macrophage apoptosis. We to the of the the PAO1 pathway, the of H. pylori to induce and the to apoptosis. is the of polyamine oxidation induction of PAO1 expression and activity in macrophages. We that a of in which oxidation of spermine results in H2O2 release, mitochondrial membrane depolarization, cytochrome c release, caspase-3 and apoptosis. for cell RNA and from MDL a was a from from H. pylori a human A. J. Gastroenterology. Full Text PDF PubMed Scopus Google Scholar), was on and For H. pylori from and in H. pylori was with a in (1Wilson K.T. Ramanujam K.S. Mobley H.L. Musselman R.F. James S.P. Meltzer S.J. Gastroenterology. 1996; 111: 1524-1533Abstract Full Text PDF PubMed Scopus (164) Google Scholar). we that induced apoptosis to a to to a consistent as we have in studies (1Wilson K.T. Ramanujam K.S. Mobley H.L. Musselman R.F. James S.P. Meltzer S.J. 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Casero Jr., R.A. PubMed Scopus Google Scholar). was a with was as a in and to with prior to of and with an For the of PAO1 of cell was to of of and and for and the was to the was and the was The of H2O2, and the expressed as of of The was in the of of of the to be in the For cell in as of the cell was to of of and as was for and the was to the was and the was and expressed as for PAO1 with the activity was in cell by an that the of from in as Google Scholar). The and in a of The was by of 1 and for The and in a activity was expressed as of of Polyamine by as reported Jr., R.A. S.J. Google Scholar). by the of (1Wilson K.T. Ramanujam K.S. Mobley H.L. Musselman R.F. James S.P. Meltzer S.J. 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Immunol. 2002; 168: 4692-4700Crossref PubMed Scopus Google Scholar) an in apoptosis The of cells was of a of of cells was by a with the cell The which is to by mitochondrial and h and in the for the h of the The of cells was on the of which was that mouse PAO1 from the that has to was as the of the or was with of was to a of in of The was for and cells in 1 of for 18 was and cells for 6 h in with for 6 h RNA was and PAO1 expression was by that the as and and PAO1 enzyme activity h of with or without cells with of and of and was 6 h transfection to and cells with for cells with and for apoptosis and PAO1 activity as was by the activity in H2O2 we the the reduced is to the when by Casero Jr., R.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, R.A. J.L. J. 2001; PubMed Google Scholar, H. PubMed Scopus Google Scholar). is oxidized by H2O2, and products of H2O2, while is to oxidation by R.A. J.L. J. 2001; PubMed Google Scholar, H. 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A. 2001; 98: 13844-13849Crossref PubMed Scopus (318) Google Scholar). with of for 6 and expression was by shown in of and while was was confirmed by with of and for and with macrophages. by of enzyme was h with was a in activity of with a 6 h by a h and a 18 PAO1 activity was significantly 6 and h with and with activity 18 h was until 18 h and was induced of the the of the H. pylori-induced enzyme we the and spermine h activation was of to but was a 18 h that was significantly reduced from this was an in spermidine 6 and h and an in spermine h by a in polyamines that was to the in from These polyamine are consistent with the back-conversion of spermine to spermidine that is by the induction of PAO1 from The in is to the in activity and back-conversion of polyamines by for with of and PAO1 polyamine synthesis and oxidative have been in the apoptosis of cell we the of and PAO1 activation to that of apoptosis in H. macrophages. of we and late apoptosis. that apoptosis, cells in was significantly by 6 h and by h as with the apoptosis from to was a in late apoptosis that 18 an that apoptosis was of a The of apoptosis 6 h is consistent with the in activity 6 h and the in PAO1 activity this and an of the in the apoptosis activity until 18 h on Polyamine the of induction of expression and enzyme activity of PAO1 and polyamine back-conversion with apoptosis, we the of an of MDL 72527 (4Wang J. Brooks E.G. Bamford K.B. Denning T.L. Pappo J. Ernst P.B. J. Immunol. 2001; 167: 926-934Crossref PubMed Scopus (92) Google Scholar). the of apoptosis we the of cells by to the apoptosis in shown in and was a in apoptosis h and MDL 72527 this apoptosis by and by that the apoptosis with cell we cell and that reduced macrophage survival by and MDL 72527 cell in a we had that the in apoptosis in the in PAO1 activity in we this by the of MDL 72527 on the apoptosis 6 and h with shown in the in apoptosis h was significantly attenuated by MDL is induced until 18 the inhibition of the apoptosis by inhibition 6 and h be to inhibition of that the induction of macrophage apoptosis in response to H. pylori is to PAO1 We the H. pylori results in the cell in macrophages. shown in when mouse macrophages with was a in apoptosis that was by with MDL that the mechanism of apoptosis is in we to PAO1 is to H. pylori-induced macrophage apoptosis. We PAO1 by cells with PAO1 and results to a shown in PAO1 the PAO1 expression and the induction of PAO1 enzyme activity apoptosis was the PAO1 the apoptosis and the cell to that of PAO1 expression macrophage apoptosis. the inhibition of apoptosis was we have direct that is for the apoptosis. Overexpression of PAO1 in of the of PAO1 in macrophage apoptosis, we cells with a for with cells with was a in PAO1 activity in cells that was to the with of cells apoptosis was by in cells was a in apoptosis with PAO1 transfection that the in enzyme activity and was to the in apoptosis with of H. pylori-induced PAO1 in H2O2 in and we had that the of activation of PAO1 that of the onset of apoptosis, inhibition of PAO1 by a or by PAO1 attenuated apoptosis, and PAO1 apoptosis, we to H2O2 by PAO1 activation was for the apoptosis. we H2O2 in response to by in the of MDL 72527 or the enzyme catalase. We from h we had that was induction of PAO1 and apoptosis 6 and have release of H2O2 from apoptosis. shown in and was inhibition of H2O2 and 6 h by MDL Additionally was of H2O2 by 6 the also we the that H2O2 in shown in of H2O2 by by and this was by by MDL 72527 and by by catalase. The of H2O2 by in the with the in the of by we have and that was an inhibition of H2O2 in the that polyamine oxidation is a of oxidative stress and H2O2 in H. macrophages. the H2O2 in the apoptosis, we the of on apoptosis. the of H2O2 the late of apoptosis, we apoptosis with and in as in and an of shown in and apoptosis in a with and inhibition for and We also apoptosis in the of and that was a inhibition of apoptosis with inhibition These studies that H2O2 is a cause of apoptosis. PAO1 in c from to and of has been in apoptosis, we the of H. pylori to cause this shown in was a in h that 18 of was significantly by MDL 72527 the from to h activation of the mitochondrial apoptosis pathway, release of cytochrome c from to was by shown in with was a in mitochondrial cytochrome c and a in cytochrome of cytochrome c from to cells with MDL was inhibition of the in mitochondrial and the in of cytochrome the of the of cytochrome These confirmed by shown in cells a of of while activation in and for cytochrome c in the of MDL 72527 in an to the cells with a of of inhibition of cytochrome c release from to c from which a in activation of and apoptosis A. M. Y. M. 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H. pylori induced of cytochrome c from to that was by this in polyamine apoptosis. are to polyamines and that be of is that H. polyamines to the apoptosis we have we have and spermine from of H. pylori to in the studies for of macrophages and polyamine Additionally we have reported that H. pylori apoptosis in macrophages in the of (5Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr., R.A. Newton J.C. Wilson K.T. J. Immunol. 2002; 168: 4692-4700Crossref PubMed Scopus Google Scholar). that macrophage apoptosis is to oxidation of polyamines by the host cells and the are to the we have that H. pylori of cell in human that is by MDL 72527 Additionally be to H. pylori we have that the which causes in PubMed Google Scholar), apoptosis in cells and macrophages in that is attenuated by MDL 72527 The of H. pylori in the human stomach for the of the host and the gastritis and for gastric that from an immune and response in the studies new the apoptosis of macrophages that to the immune response. we have shown that polyamine oxidation by the induction of PAO1 the macrophage apoptosis. We have also that this mechanism of apoptosis in gastric cells Y. M. A. A. Jr., and in but in or T Y. H. M. and We that the activation of and PAO1 is of the innate immune response to H. of polyamines can have on the of immune response M. Wang H. M. A. J. PubMed Scopus Google Scholar), and in cells have in J. Wang J.Y. J. PubMed Google Scholar), but new that of polyamine oxidation is to have in mucosal host defense in the of to and of PAO1 activation. be to the of and PAO1 in and to that we have that the expression of is in H. pylori gastritis Y. M. A. A. Jr., and in with polyamine oxidation to be a in host immune