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-␣), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 in rat Kupffer cells. LTA was found to trigger phosphorylation of mitogenactivated 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-␣ 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-␣, 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.

Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells following hypoxia

“…In contrast, the production of MCP-1 was found to be independent of p38. Other studies (12) suggest that ERK1/2 is more critical in regulating Kupffer cell IL-6 production compared with p38. The difference between these studies is likely a result of different animal models and different stimuli used but may also reflect the differential regulatory pathways of Kupffer cells following various types of injury.…”

Myricetin blocks lipoteichoic acid-induced COX-2 expression in human gingival fibroblasts

“…The D-alanine content is directly related to the inflammatory potential of LTA. Numerous recent articles have reported that LTA stimulates immune cells to synthesize TNF-α [51], IL-6 [52], IL-8 [53] and nitric oxide [50]. LTA associates with type 2 TLRs and activates kinases such as mitogen-activated protein kinase [54,55] and AKT [52].…”

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

“…These data, coupled with reports that double-knockout Hck 2/2 Fgr 2/2 cells also express higher levels of Fyn, Lyn, and Yes than wild-type cells (27), suggest that functional redundancy might have operated in these early experiments. Furthermore, our group and others have shown that the SFKselective inhibitors PP1 and PP2 inhibit LPS-induced cytokine production (21,26,(28)(29)(30). Thus, an increasing body of apparently contradictory data on the role of SFKs in LPS signaling has now accumulated and deserves to be addressed.…”