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Activation of the NADPHox complex is poorly understood in AMs, although in neutrophils it is known to be mediated by kinases including PI3K\/Akt, protein kinase C (PKC) \u03b4, p21-activated protein kinase (PAK), casein kinase 2 (CK2), and MAPKs. The p40phox cytosolic subunit of NADPHox has been recently recognized to function as a carrier protein for other subunits and a positive regulator of oxidase activation, a role previously considered unique to another subunit, p47phox. The regulation of p40phox remains poorly understood, and the effect of PGE2 on its activation is completely undefined. We addressed these issues in rat AMs activated with IgG-opsonized K. pneumoniae. The kinetics of kinase activation and the consequences of kinase inhibition and silencing revealed a critical role for a PKC\u03b4-PAK-class I PI3K\/Akt1 cascade in the regulation of p40phox activation upon bacterial challenge in AMs; PKC\u03b1, ERK, and CK2 were not involved. PGE2 inhibited the activation of p40phox, and its effects were mediated by protein kinase A type II, were independent of interactions with anchoring proteins, and were directed at the distal class I PI3K\/Akt1 activation step. Defining the kinases that control AM p40phox activation and that are the targets for inhibition by PGE2 provides new insights into immunoregulation in the infected lung.<\/jats:p>","DOI":"10.1189\/jlb.1211590","type":"journal-article","created":{"date-parts":[[2012,4,29]],"date-time":"2012-04-29T00:29:43Z","timestamp":1335659383000},"page":"219-231","source":"Crossref","is-referenced-by-count":26,"title":["Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2"],"prefix":"10.1093","volume":"92","author":[{"given":"Emilie","family":"Bourdonnay","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine , Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos H","family":"Serezani","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine , Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M","family":"Aronoff","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Health Systems , Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Peters-Golden","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine , Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,7,1]]},"reference":[{"key":"2023012312542897700_B1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/S0140-6736(96)07493-4","article-title":"Mortality by cause for eight regions of the world: Global Burden of Disease Study","volume":"349","author":"Murray","year":"1997","journal-title":"Lancet"},{"key":"2023012312542897700_B2","doi-asserted-by":"crossref","first-page":"e76","DOI":"10.1371\/journal.pmed.0030076","article-title":"Lung infection\u2014a public health priority","volume":"3","author":"Mizgerd","year":"2006","journal-title":"PLoS Med."},{"key":"2023012312542897700_B3","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/SMJ.0b013e3181fd7d5a","article-title":"Emergence of Klebsiella pneumoniae carbapenemaseproducing bacteria","volume":"104","author":"Arnold","year":"2011","journal-title":"South. 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