Abstract
We previously demonstrated that, in the MC615 cartilage cell line, the p38/NF-kB pathway is activated both during differentiation and in response to an inflammatory stimulus. In both cases, the p38/NF-kB pathway activation leads to the expression of the lipocalin SIP24 and of COX-2. Given the fact that, in the same cells, the COX-2 expression is sustained during the inflammation resolution, at the same time that the SIP24 expression is suppressed, in the present study we tested the hypothesis that COX-2 products play a role in SIP24 repression. Taken together, our results suggest that, during the resolution of inflammation, COX-2 represses the acute phase protein SIP24 and restores physiological conditions, possibly through a pathway involving PPARgamma. Experimental evidences being the following: (1) 15-deoxy-delta 12,14-prostaglandin J(2), but not PGE(2): (i) inhibits the expression of SIP24 in the inflammatory phase and induces COX-2 synthesis; (ii) represses NF-kB activation induced by LPS; (iii) represses the synthesis of microsomal PGE Synthase-1 induced by LPS. (2) PPARgamma and PPARalpha are present in MC615 cells in both proliferating and hyperconfluent cultures. (3) PPARgamma ligand GW7845, but not PPARalpha ligand GW7647: (i) represses the expression of SIP24 induced by LPS; (ii) induces COX-2 expression. (4) p38 is involved in the PPARgamma mediated induction of COX-2. In fact 15-deoxy-delta 12,14-prostaglandin J(2) activates p38 and the cell pretreatment with the p38 specific inhibitor SB203580 represses the expression of COX-2 induced by both the 15-deoxy-delta12,14-prostaglandin J(2) and the PPARgamma ligand GW7845.
(c) 2008 Wiley-Liss, Inc
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / metabolism*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Butyrates / pharmacology
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Cartilage / drug effects
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Cartilage / enzymology*
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Cells, Cultured
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Chondrocytes / drug effects
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Chondrocytes / enzymology*
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Cyclooxygenase 2 / biosynthesis*
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Diclofenac / pharmacology
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Dinoprostone / metabolism
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Down-Regulation
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Enzyme Induction
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Enzyme Repression
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Imidazoles / pharmacology
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Inflammation / enzymology
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Inflammation / metabolism*
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Inflammation / prevention & control
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Intramolecular Oxidoreductases / biosynthesis
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Lipocalin-2
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Lipocalins / metabolism*
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Lipopolysaccharides / pharmacology
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Mice
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NF-kappa B / metabolism
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Oncogene Proteins / metabolism*
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Oxazoles / pharmacology
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PPAR alpha / agonists
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PPAR alpha / metabolism
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PPAR gamma / agonists
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PPAR gamma / metabolism
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Phenylurea Compounds / pharmacology
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / metabolism
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Prostaglandin-E Synthases
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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Signal Transduction
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Time Factors
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Tyrosine / analogs & derivatives
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Tyrosine / pharmacology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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15-deoxy-delta(12,14)-prostaglandin J2
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Acute-Phase Proteins
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Anti-Inflammatory Agents, Non-Steroidal
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Butyrates
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GW 7647
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Imidazoles
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Lipocalin-2
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Lipocalins
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Lipopolysaccharides
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NF-kappa B
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Oncogene Proteins
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Oxazoles
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PPAR alpha
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PPAR gamma
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyridines
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Lcn2 protein, mouse
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Diclofenac
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GW 7845
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Tyrosine
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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p38 Mitogen-Activated Protein Kinases
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Intramolecular Oxidoreductases
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Prostaglandin-E Synthases
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Ptges protein, mouse
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Dinoprostone
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SB 203580
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Prostaglandin D2