Intracellular Pathways Involved in Tumor Necrosis Factor-α Release by Human Monocytes on Stimulation with Lipopolysaccharide or Staphylococcal Peptidoglycan Are Partly Similar

Eva Mattsson, H. Van Dijk, K. Van Kessel, J. Verhoef, A. Fleer, J. Rollof
1996 Journal of Infectious Diseases  
This study compared the effects of intracellular pathway inhibitors on tumor necrosis factor-a (TNF-a) release from human monocytes. Cells were stimulated with peptidoglycan (PG) from Staphylococcus epidermidis or with Escherichia colilipopolysaccharide (LPS), both in the presence of 10%human serum. Of 10 substancestested, only the protein tyrosine kinase inhibitor tyrphostin AG 126 discriminated significantly between PG and LPS: TNF-a release induced by PG, but not by LPS, was dose-dependently
more » ... suppressed. The results obtained with other modulatory substances, including different protein kinase and G protein inhibitors, suggest that calmodulin-dependent protein kinase, protein tyrosinekinase, and a cholera-toxin-sensitiveG protein are involvedin both PG-and LPS-induced TNF-a release. Further, drugs such as pentoxifylline, chloroquine, and the antioxidant apocynin similarly inhibited TNF-a release by PG-as well as LPS-stimulated cells. Tumor necrosis factor-a (TNF-a) is regarded as a major mediator of both gram-negative and gram-positive bacterial septic shock [I, 2]. In animal models for septic shock, Staphylococcus aureus and Staphylococcus epidermidis induce cardiovascular abnormalities and cytokine levels similar to those induced by Escherichia coli [2, 3] . Lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria induces monocytes and macrophages to release TNF-a in vivo as well as in vitro [1, 4] . In gram-positive bacteria, the cell wall component( s) responsible for TNF-a induction has not been identified. However, we recently showed that staphylococcal peptidoglycan (PG), the main cell wall product, in the presence of human serum is almost as potent as LPS in inducing TNF-a release by human monocytes [5] . PG also induces interleukin-I,B and interleukin-6 release [6] . The intracellular signal transduction pathways leading to TNF-a gene activation and TNF-a production in LPS-stimulated monocytes or macrophages have been the subject of several studies but are largely unknown [7] [8] [9] [10] [11]. In this study, we investigated the intracellular pathways leading to TNF-a secretion by monocytes stimulated by PG in the presence of serum. For this purpose, chloroquine, pentoxifylline, apocynin, inhibitors ofGTP-binding (G) proteins (cholera and pertussis toxin), and different protein kinase inhibitors were used. To study the protein tyrosine kinase (PTK) pathways,
doi:10.1093/infdis/173.1.212 pmid:8537661 fatcat:326y5k27qvactilcdcjq7xc7m4