Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals.
Macrophage activation by bacterial lipopolysaccharide (LPS) promotes the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and of secondary mediators, such as leukotrienes and prostaglandins (PGs). Mice lacking the gene encoding the serine/threonine protein kinase Tpl2/Cot produce low levels of TNF-alpha in response to LPS because of an ERK-dependent post-transcriptional defect, and they are resistant to LPS/D-galactosamine-induced endotoxin shock. In this study we demonstrate that prostaglandin E2 and its regulatory enzyme, COX-2, are also targets of Tpl2-transduced LPS signals in bone marrow-derived mouse macrophages. Thus, LPS-stimulated Tpl2(-/-) macrophages express low levels of COX-2 and PGE2, compared with wild-type Tpl2(+/+) cells. The ability of Tpl2 to regulate COX-2 expression depends on ERK signals that activate p90Rsk and Msk1, which in turn phosphorylate CREB, a key regulator of COX-2 transcription. These data identify physiological targets of Tpl2 signaling downstream of ERK and further implicate Tpl2 in the pathophysiology of inflammation.
Eliopoulos
Aristides G
AG
Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA. ptsichlis@lifespan.org
Dumitru
Calin D
CD
Wang
Chun-Chi
CC
Cho
Jeonghee
J
Tsichlis
Philip N
PN
D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010544:Peroxidases / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010940:Plant Proteins; D011518:Proto-Oncogene Proteins; D010544:Peroxidases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D038362:Glycogen Synthase Kinase 3; C083365:Msk-1 protein, Medicago sativa; D015232:Dinoprostone