Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide.
Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
Martin
Michael
M
Department of Microbiology, University of Alabama, Birmingham, AL 35294, USA.
Schifferle
Robert E
RE
Cuesta
Natalia
N
Vogel
Stefanie N
SN
Katz
Jannet
J
Michalek
Suzanne M
SM
D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D016966:Porphyromonas gingivalis / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000502:physiology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D016753:Interleukin-10; D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C495342:TLR2 protein, human; C494918:AKT1 protein, human