SIGNALING PATHWAY TRIGGERED BY A SHORT IMMUNOMODULATING PEPTIDE ON HUMAN MONOCYTES

A short synthetic peptide (Pa) containing a structural motif (''2-6-11 .'' motif) present in a number of human extracellular matrix proteins was found to stimulate the production of cytokines IL-1 alpha, IL-1 be ta, IL-6, and TNF alpha by human peripheral blood mononuclear cells. W e have now investigated the signal transduction pathway involved in th e elicitation of these immuno-modulating properties on isolated human monocytes. Our results show that active peptide Pa provoked phosphoino sitide hydrolysis, intracellular calcium elevation, and cAMP accumulat ion. Herbimycin A, an inhibitor of protein tyrosine kinases (PTK), mar kedly reduced these effects of peptide Pa. We have also found that thi s peptide stimulated CREB, NF-kappa B, and AP-1 DNA-binding activity. With the help of inhibitors of PTK (herbimycin A), phospholipase C (ne omycin sulfate), protein kinase C (bis-indolyl maleimide), protein kin ase A (H89), and the calmodulin antagonist W-7, as well as cholera tox in, an agent that increases intracellular cAMP, we showed that cytokin e (LL-1 alpha, IL-1-beta, IL-6, and TNP alpha) production could be mod ified by the signal transduction pathway triggered by peptide Pa on mo nocytes. (C) 1997 Academic Press.