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 inflammation and immunomodulatory activities within the central and peripheral nervous system. In several cell types, substance P induces the expression of proinflammatory cytokines that have been implicated in the pathogenesis of different neuropathologies. Substance P preferentially binds to NK-1, a receptor of the neurokinin family, but how the receptor-elicited signal is translated into inflammatory gene expression is not yet understood. In this work, we describe that in U373 MG astrocytoma cells, nanomolar concentrations of substance P potently triggered activation of NF-kappa B, a transcription factor involved in the control of cytokine expression and apoptosis. Substance P-induced NF-kappa B activation was associated with the increased mRNA expression and secretion of IL-8, an NF-kappa B-controlled target gene. The stimulatory effect of substance P was specific, since an NK-1-selective receptor antagonist completely prevented NF-kappa B activation in response to substance P, but not IL-1 beta. In addition, we show that the activity of substance P required mobilization of intracellular calcium and formation of reactive oxygen intermediates as second messengers. Our results suggest that NF-kappa B may be an important component controlling neurogenic inflammation within the peripheral and central nervous system.
Lieb
K
K
Department of Psychiatry, Albert-Ludwigs-University, Freiburg, Germany.
Fiebich
B L
BL
Berger
M
M
Bauer
J
J
Schulze-Osthoff
K
K
D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016209:Interleukin-8; D016328:NF-kappa B; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D012333:RNA, Messenger; C068032:GR 73632; D013373:Substance P; D002118:Calcium