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Infection and Immunity, October 2004, p. 5704-5711, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5704-5711.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Maria K. Dahle,1* Gunhild Øverland,1 Anders E. Myhre,1 Jon Fredrik Stuestøl,1 Thomas Hartung,2 Claus Danckert Krohn,1 Øystein Mathiesen,3 Jacob E. Wang,1 and Ansgar O. Aasen1

Institute for Surgical Research,1 Department of Surgery, Rikshospitalet University Hospital, Oslo, Norway,3 Biochemical Pharmacology, University of Konstanz, Konstanz, Germany2

Received 1 March 2004/ Returned for modification 23 April 2004/ Accepted 14 July 2004

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.

* Corresponding author. Mailing address: Institute for Surgical Research, Rikshospitalet University Hospital, N-0027 Oslo, Norway. Phone: 47 23071404. Fax: 47 23073530. E-mail: m.k.dahle{at}basalmed.uio.no.

Editor: S. H. E. Kaufmann

Infection and Immunity, October 2004, p. 5704-5711, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5704-5711.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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