Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 134, Issue 5, Pages 1055-1065Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0704334
Keywords
P2Y receptor; CaMK; IKK; NF-kappa B; PKC; ERK; p38 MAPK; macrophages
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1 Although accumulating studies have identified I kappaB kinase (IKK) to be essential for controlling NF-kappaB activity in response to several cytokines, the upstream kinases that control IKK activity are still not completely known. We have previously reported that G protein-coupled P2Y(6) receptor activation by UTP potentiates lipopolysaccharide (LPS)-induced I kappaB phosphorylation and degradation, and NF-kappaB activation in J774 macrophages. In this study, we investigated the upstream kinases for IKK activation by UTP and LPS. 2 In murine J774 macrophages, LPS-induced NF-KB activation was inhibited by the presence of PDTC, D609, Ro 31-8220, PD 098059 and SB 203580. 3 Accompanying NF-kappaB activation, LPS induced I kappaB degradation and IKK activation were reduced by PDTC, D609, Ro 31-8220 and PD 098059, but not by SB 203580. 4 Although UTP itself slightly induced IKK activation, this response was synergistic with LPS. BAPTA/AM and KN-93 (a calcium/calmodulin-dependent protein kinase (CaMK) inhibitor) attenuated UTP- but not LPS-stimulated IKK activity. Synergistic IKK activation between LPS and thapsigargin was further demonstrated in peritoneal macrophages. 5 LPS and UTP co-stimulation additively increased p65 NF-kappaB phosphorylation. In vitro kinase assays revealed that LPS and UTP induced extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase activation were respectively inhibited by PD098059 and SB 203580. 6 Taken together, we demonstration that Gq protein-coupled P2Y(6) receptor activation can potentiate LPS-stimulated IKK activity. While PKC and ERK participate in IKK activation by LPS and UTP, the phosphatidylinositide-phospholipase C-dependent activation of CaMK plays a major role in UTP potentiation of the LPS response.
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