The pyrimidinergic P2Y6 receptor mediates a novel release of proinflammatory cytokines and chemokines in monocytic cells stimulated with UDP

The human P2Y(6) receptor (hP2Y(6)) is a member of the G protein-coupled pyrimidinergic P2 receptor family that responds specifically to the extracellular nucleotide uridine diphosphate (UDP). Recently, the hP2Y(6) receptor has been reported to mediate monocyte IL-8 production in response to UDP or lipopolysaccharide (LPS), but the role of hP2Y6 in regulating other pro-inflammatory cytokines or mediators is largely unknown. We demonstrate here that UDP specifically induces soluble TNF-alpha and IL-8 production in a promonocytic U937 cell line stably transfected with hP2Y(6). However, we did not detect IL-1 alpha, IL-1 beta, IL-6, IL-10, IL-18, and PGE(2), in the conditioned media from the same cell line. These results distinguish UDP/P2Y(6) signaling from LPS signaling. Interestingly, UDP induces the production of IL-8, but not TNF-alpha, in human astrocytoma 1321N1 cell lines stably transfected with hP2Y(6). Therefore, the immune effect of UDP/P2Y(6) signaling on the production of proinflammatory cytokines is selective and dependent on cell types. We further identify that UDP can also induce the production of proinflammatory chemokines MCP-1 and IP-10 in hP2Y(6) transfected promonocytic U937 cell lines, but not astrocytoma 1321N1 cell lines stably transfected with hP2Y(6). From the Taqman analysis, UDP stimulation significantly upregulates the mRNA levels of IL-8, 1P-10, and IL-1 beta, but not TNF-alpha. Taken together, these new findings expand the pro-inflammatory biology of UDP mediated by the P2Y(6) receptor. (c) 2005 Elsevier Inc. All rights reserved.