Inhibition of nitric-oxide synthase-I (NOS-I)-dependent nitric oxide production by lipopolysaccharide plus interferon-gamma is mediated by arachidonic acid. Effects on NFkappaB activation and late inducible NOS expression. Export

@article{citeulike:271751, abstract = {Previous results have indicated that lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) inhibits nitric-oxide synthase (NOS)-I activity in glial cells. We report here that arachidonic acid (AA) plays a pivotal role in this response, which was consistently reproduced in different glial cell lines and in primary rat astrocytes. This notion was established using pharmacological inhibitors of phospholipase A2 (PLA2), cytosolic PLA2 (cPLA2) antisense oligonucleotides, and AA add-back experiments. This approach not only allowed the demonstration that AA promotes inhibition of NOS-I activity but also produced novel experimental evidence that LPS/IFNgamma itself is a potential stimulus for NOS-I. Indeed, LPS/IFNgamma fails to generate nitric oxide (NO) via NOS-I activation simply because it activates the AA-dependent signal that impedes NOS-I activity. Otherwise, LPS/IFNgamma promotes NO formation, sensitive to exogenous AA, in cells in which cPLA2 is pharmacologically inhibited or genetically depleted. Because NO suppresses the NFkappaB-dependent NOS-II expression, inactivation of NOS-I by the LPS/IFNgamma-induced AA pathway provides optimal conditions for NFkappaB activation and subsequent NOS-II expression. Inhibition of cPLA2 activity, while reducing the availability of AA, consistently inhibited NFkappaB activation and NOS-II mRNA induction and delayed NO formation. These responses were promptly reestablished by addition of exogenous AA. Finally, we have demonstrated that the LPS/IFNgamma-dependent tyrosine phosphorylation of NOS-I and inhibition of its activity are mediated by endogenous AA.}, address = {Istituto di Farmacologia e Farmacognosia, Universit\`{a} di Urbino Carlo Bo, Via S. Chiara 27, 61029 Urbino, Italy.}, author = {Palomba, L. and Persichini, T. and Mazzone, V. and Colasanti, M. and Cantoni, O.}, citeulike-article-id = {271751}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M312768200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15148326}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15148326}, day = {16}, doi = {10.1074/jbc.M312768200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {enos, fattyacids, nfkb, no}, month = {July}, number = {29}, pages = {29895--29901}, posted-at = {2005-08-02 15:19:52}, priority = {2}, title = {Inhibition of nitric-oxide synthase-I (NOS-I)-dependent nitric oxide production by lipopolysaccharide plus interferon-gamma is mediated by arachidonic acid. Effects on NFkappaB activation and late inducible NOS expression.}, url = {http://dx.doi.org/10.1074/jbc.M312768200}, volume = {279}, year = {2004} }

TY - JOUR ID - citeulike:271751 L3 - citeulike-article-id:271751 N2 - Previous results have indicated that lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) inhibits nitric-oxide synthase (NOS)-I activity in glial cells. We report here that arachidonic acid (AA) plays a pivotal role in this response, which was consistently reproduced in different glial cell lines and in primary rat astrocytes. This notion was established using pharmacological inhibitors of phospholipase A2 (PLA2), cytosolic PLA2 (cPLA2) antisense oligonucleotides, and AA add-back experiments. This approach not only allowed the demonstration that AA promotes inhibition of NOS-I activity but also produced novel experimental evidence that LPS/IFNgamma itself is a potential stimulus for NOS-I. Indeed, LPS/IFNgamma fails to generate nitric oxide (NO) via NOS-I activation simply because it activates the AA-dependent signal that impedes NOS-I activity. Otherwise, LPS/IFNgamma promotes NO formation, sensitive to exogenous AA, in cells in which cPLA2 is pharmacologically inhibited or genetically depleted. Because NO suppresses the NFkappaB-dependent NOS-II expression, inactivation of NOS-I by the LPS/IFNgamma-induced AA pathway provides optimal conditions for NFkappaB activation and subsequent NOS-II expression. Inhibition of cPLA2 activity, while reducing the availability of AA, consistently inhibited NFkappaB activation and NOS-II mRNA induction and delayed NO formation. These responses were promptly reestablished by addition of exogenous AA. Finally, we have demonstrated that the LPS/IFNgamma-dependent tyrosine phosphorylation of NOS-I and inhibition of its activity are mediated by endogenous AA. IS - 29 JF - J Biol Chem SN - 0021-9258 AD - Istituto di Farmacologia e Farmacognosia, Università di Urbino Carlo Bo, Via S. Chiara 27, 61029 Urbino, Italy. EP - 29901 TI - Inhibition of nitric-oxide synthase-I (NOS-I)-dependent nitric oxide production by lipopolysaccharide plus interferon-gamma is mediated by arachidonic acid. Effects on NFkappaB activation and late inducible NOS expression. VL - 279 SP - 29895 KW - enos KW - fattyacids KW - nfkb KW - no AU - Palomba, L AU - Persichini, T AU - Mazzone, V AU - Colasanti, M AU - Cantoni, O PY - 2004/07/16/ UR - http://dx.doi.org/10.1074/jbc.M312768200 ER -