INTRACELLULAR PATHWAYS INVOLVED IN TUMOR-NECROSIS-FACTOR-ALPHA RELEASE BY HUMAN MONOCYTES ON STIMULATION WITH LIPOPOLYSACCHARIDE OR STAPHYLOCOCCAL PEPTIDOGLYCAN ARE PARTLY SIMILAR

This study compared the effects of intracellular pathway inhibitors on tumor necrosis factor-alpha (TNF-alpha) release from human monocytes, Cells were stimulated with peptidoglycan (PG) from Staphylococcus epi dermidis or with Escherichia coli lipopolysaccharide (LPS), both in th e presence of 10% human serum. Of 10 substances tested, only the prote in tyrosine kinase inhibitor tyrphostin AG 126 discriminated significa ntly between PG and LPS: TNF-alpha release induced by PG, but not by L PS, was dose-dependently suppressed. The results obtained with other m odulatory substances, including different protein kinase and G protein inhibitors, suggest that calmodulin-dependent protein kinase, protein tyrosine kinase, and a cholera-toxin-sensitive G protein are involved in both PG- and LPS-induced TNF-alpha release. Further, drugs such as pentoxifylline, chloroquine, and the antioxidant apocynin similarly i nhibited TNF-alpha release by PG- as well as LPS-stimulated cells.