THE NEUROPEPTIDE SUBSTANCE-P ACTIVATES TRANSCRIPTION FACTOR NF-KAPPA-B AND KAPPA-B-DEPENDENT GENE-EXPRESSION IN HUMAN ASTROCYTOMA-CELLS

The neuropeptide substance P is a major mediator of neurogenic inflamm ation and immunomodulatory activities within the central and periphera l nervous system, In several cell types, substance P induces the expre ssion of proinflammatory cytokines that have been implicated in the pa thogenesis of different neuropathologies. Substance P preferentially b inds to NK-1, a receptor of the neurokinin family, but how the recepto r-elicited signal is translated into inflammatory gene expression is n ot yet understood. In this work, we describe that in U373 MG astrocyto ma cells, nanomolar concentrations of substance P potently triggered a ctivation of NF-kappa B, a transcription factor involved in the contro l of cytokine expression and apoptosis. Substance P-induced NF-kappa B activation was associated with the increased mRNA expression and secr etion of IL-8, an NF-kappa B-controlled target gene. The stimulatory e ffect of substance P was specific, since an NK-1-selective receptor an tagonist completely prevented NF-kappa B activation in response to sub stance P, but not IL-1 beta. In addition, we show that the activity of substance P required mobilization of intracellular calcium and format ion of reactive oxygen intermediates as second messengers. Our results suggest that NF-kappa B may be an important component controlling neu rogenic inflammation within the peripheral and central nervous system.