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objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.\n\nINTRODUCTION\nThe production of TNF-α following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

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objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.\n\nINTRODUCTION\nThe production of TNF-α following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

{"project":"GO-BP","denotations":[{"id":"T826","span":{"begin":178,"end":195},"obj":"http://purl.obolibrary.org/obo/GO_0032680"},{"id":"T827","span":{"begin":278,"end":297},"obj":"http://purl.obolibrary.org/obo/GO_0032680"},{"id":"T828","span":{"begin":445,"end":461},"obj":"http://purl.obolibrary.org/obo/GO_0032680"},{"id":"T834","span":{"begin":178,"end":195},"obj":"http://purl.obolibrary.org/obo/GO_0032640"},{"id":"T835","span":{"begin":278,"end":297},"obj":"http://purl.obolibrary.org/obo/GO_0032640"},{"id":"T836","span":{"begin":278,"end":295},"obj":"http://purl.obolibrary.org/obo/GO_0032640"},{"id":"T838","span":{"begin":81,"end":98},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T839","span":{"begin":409,"end":426},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T840","span":{"begin":645,"end":662},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T841","span":{"begin":1527,"end":1544},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T842","span":{"begin":1780,"end":1797},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T843","span":{"begin":99,"end":133},"obj":"http://purl.obolibrary.org/obo/GO_1901484"},{"id":"T844","span":{"begin":99,"end":133},"obj":"http://purl.obolibrary.org/obo/GO_0043433"},{"id":"T845","span":{"begin":99,"end":133},"obj":"http://purl.obolibrary.org/obo/GO_0032792"},{"id":"T846","span":{"begin":113,"end":126},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T847","span":{"begin":1661,"end":1676},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T848","span":{"begin":113,"end":144},"obj":"http://purl.obolibrary.org/obo/GO_0051091"},{"id":"T849","span":{"begin":113,"end":144},"obj":"http://purl.obolibrary.org/obo/GO_0032793"},{"id":"T850","span":{"begin":1642,"end":1660},"obj":"http://purl.obolibrary.org/obo/GO_0032793"},{"id":"T851","span":{"begin":113,"end":144},"obj":"http://purl.obolibrary.org/obo/GO_1901485"},{"id":"T852","span":{"begin":155,"end":163},"obj":"http://purl.obolibrary.org/obo/GO_0001906"},{"id":"T853","span":{"begin":155,"end":163},"obj":"http://purl.obolibrary.org/obo/GO_0008219"},{"id":"T854","span":{"begin":155,"end":163},"obj":"http://purl.obolibrary.org/obo/GO_0019835"},{"id":"T855","span":{"begin":155,"end":163},"obj":"http://purl.obolibrary.org/obo/GO_0070265"},{"id":"T856","span":{"begin":372,"end":384},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T857","span":{"begin":1938,"end":1950},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T858","span":{"begin":645,"end":672},"obj":"http://purl.obolibrary.org/obo/GO_0051344"},{"id":"T859","span":{"begin":771,"end":784},"obj":"http://purl.obolibrary.org/obo/GO_0051591"},{"id":"T860","span":{"begin":1160,"end":1175},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T861","span":{"begin":1189,"end":1204},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T862","span":{"begin":1284,"end":1299},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T863","span":{"begin":1628,"end":1652},"obj":"http://purl.obolibrary.org/obo/GO_0051092"}],"text":"OBJECTIVE\nThe objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.\n\nINTRODUCTION\nThe production of TNF-α following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

{"project":"GO-MF","denotations":[{"id":"T865","span":{"begin":81,"end":98},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T866","span":{"begin":409,"end":426},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T867","span":{"begin":645,"end":662},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T868","span":{"begin":1527,"end":1544},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T869","span":{"begin":1780,"end":1797},"obj":"http://purl.obolibrary.org/obo/GO_0008081"},{"id":"T870","span":{"begin":793,"end":800},"obj":"http://purl.obolibrary.org/obo/GO_0005488"},{"id":"T871","span":{"begin":835,"end":842},"obj":"http://purl.obolibrary.org/obo/GO_0005488"},{"id":"T872","span":{"begin":1218,"end":1225},"obj":"http://purl.obolibrary.org/obo/GO_0005488"},{"id":"T873","span":{"begin":1308,"end":1315},"obj":"http://purl.obolibrary.org/obo/GO_0005488"},{"id":"T874","span":{"begin":1681,"end":1688},"obj":"http://purl.obolibrary.org/obo/GO_0005488"},{"id":"T875","span":{"begin":793,"end":808},"obj":"http://purl.obolibrary.org/obo/GO_0005515"},{"id":"T876","span":{"begin":831,"end":842},"obj":"http://purl.obolibrary.org/obo/GO_0003677"},{"id":"T877","span":{"begin":1214,"end":1225},"obj":"http://purl.obolibrary.org/obo/GO_0003677"},{"id":"T878","span":{"begin":1304,"end":1315},"obj":"http://purl.obolibrary.org/obo/GO_0003677"},{"id":"T879","span":{"begin":1677,"end":1688},"obj":"http://purl.obolibrary.org/obo/GO_0003677"},{"id":"T880","span":{"begin":835,"end":851},"obj":"http://purl.obolibrary.org/obo/GO_0051059"}],"text":"OBJECTIVE\nThe objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.\n\nINTRODUCTION\nThe production of TNF-α following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

{"project":"GO-CC","denotations":[{"id":"T881","span":{"begin":253,"end":258},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T882","span":{"begin":529,"end":534},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T883","span":{"begin":977,"end":982},"obj":"http://purl.obolibrary.org/obo/GO_0005623"}],"text":"OBJECTIVE\nThe objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.\n\nINTRODUCTION\nThe production of TNF-α following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

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The mechanism by which phosphodiesterase inhibition alters TNF-α production in the presence of LPS remains unclear.\n\nMETHODS\nHuman mononuclear cells were stimulated with LPS (1 μg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-κBα, nuclear factor-κB p65 (NF-κB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-κB and CREB was verified by electrophoretic mobility shift assay. TNF-α levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA).\n\nRESULTS\nPTX was demonstrated to significantly reduce cytoplasmic I-κBα phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-κB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-α in the presence and absence Protein kinase A inhibition.\n\nDISCUSSION\nThe increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-κB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent.\n\nCONCLUSION\nPTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation. "}

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