title: The phosphatidylinositol 3-kinase/protein kinase B signaling pathway is activated by lipoteichoic acid and plays a role in Kupffer cell production of interleukin-6 (IL-6) and IL-10.
abstract: Sepsis caused by gram-positive bacteria lacking lipopolysaccharide (LPS) has become a major and increasing cause of mortality in intensive-care units. We have recently demonstrated that the gram-positive-specific bacterial cell wall component lipoteichoic acid (LTA) stimulates the release of the proinflammatory cytokines in Kupffer cells in culture. In the present study, we have started to assess the signal transduction events by which LTA induces the production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 in rat Kupffer cells. LTA was found to trigger phosphorylation of mitogen-activated protein kinases (MAPK) (p38 MAPK and ERK 1/2) and protein kinase B (PKB). Compared to LPS, LTA was more potent in inducing PKB phosphorylation after 40 min, although we found that the cytokine responses were similar. For both bacterial molecules, blocking phosphatidylinositol 3-kinase (PI3-K; Ly294002) or Janus kinase 2 (JAK-2; AG490) particularly affected the induction of IL-6 and IL-10 release, whereas TNF-alpha levels were strongly reduced by inhibition of Src family tyrosine kinases (PP2). All three cytokines were reduced by inhibition of p38 MAPK (SB202190) or the broad-range tyrosine kinase inhibitor genistein, whereas IL-6 release was particularly blocked by inhibition of ERK 1/2 (PD98059). Divergences in the regulatory pathways controlling TNF-alpha, IL-10, and IL-6 production in Kupffer cells following LPS or LTA stimulation may create a basis for understanding how the balance between pro- and anti-inflammatory cytokines is regulated in the liver following infections by gram-positive or gram-negative bacteria.
authors.affiliation: Institute for Surgical Research, Rikshospitalet University Hospital, N-0027 Oslo, Norway. m.k.dahle@basalmed.uio.no
authors.forename: Maria K
authors.initials: MK
authors.lastname: Dahle
authors.forename: Gunhild
authors.initials: G
authors.lastname: Øverland
authors.forename: Anders E
authors.initials: AE
authors.lastname: Myhre
authors.forename: Jon Fredrik
authors.initials: JF
authors.lastname: Stuestøl
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Claus Danckert
authors.initials: CD
authors.lastname: Krohn
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Mathiesen
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Wang
authors.forename: Ansgar O
authors.initials: AO
authors.lastname: Aasen
mesh_terms: D000818:Animals; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D053613:Janus Kinase 1; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013682:Teichoic Acids / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016753:Interleukin-10; D015850:Interleukin-6; D053613:Janus Kinase 1; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src); D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; C507906:Jak1 protein, rat