Ja. Sommer et al., Purinergic receptor modulation of LPS-stimulated signaling events and nitric oxide release in RAW 264.7 macrophages, J ENDOTOX R, 5(1-2), 1999, pp. 70-74
Purinergic receptors of the P2 class are cell surface receptors which are s
ensitive to extracellular adenine nucleotides, such as ATP and ADP. This cl
ass of receptors is divided into the P2Y family of G protein-coupled recept
ors and the P2X family of ligand-gated ion channels. The P2X receptors, sev
en of which have been cloned, are thought to possess two transmembrane doma
ins and function as multimeric complexes. Numerous studies have suggested a
role for P2 receptors in activation of macrophages by Cram-negative bacter
ial endotoxin (lipopolysaccharide; LPS). LPS is thought to exert its toxic
effects, in large part, by inducing macrophages to release inflammatory med
iators such as tumor necrosis factor alpha (TNF alpha), interleukin-l (IL-1
) and nitric oxide (NO). Although multiple signal transduction pathways are
activated by LPS in macrophages, the proximal mechanisms by which LPS exer
ts these effects remain unclear. The current study examines the role of the
P2X(7)/P2Z purinergic receptor in LPS signaling events and in nitric oxide
(NO) production. The results indicate that the P2X, receptor is required f
or maximal LPS activation of the mitogen-activated protein (MAP) kinases ex
t-acellular signal-regulated kinase (ERK)I and ERK2, for activation of nucl
ear factor (NF)-kappa B,as well as for upregulation of the inducible form o
f nitric oxide synthase (iNOS). These results are fortified by our recent o
bservation that the C-terminus of the P2X(7) receptor is homologous to cons
erved LPS binding domains of proteins critical to host responses to Gram-ne
gative bacterial infection, such as LPS-binding protein (LBP) and bacterici
dal permeability-increasing protein (BPI). Taken together, these observatio
ns suggest that the P2X(7) receptor plays a fundamental role in LPS signal
transduction and activation of macrophages, and thus may represent a therap
eutic target for Gram-negative bacterial septicemia.