Abstract | OBJECTIVE: METHODS: RESULTS: Physiologically relevant concentrations (10(-10) to 10(-9) mol/l) of LTB4 were produced in the presence of LIT. Bay-x-1005 abrogated LTB4 release, while NS-398 was without effect. LTB4 stimulated IL-1beta and TNF-alpha synthesis with an EC50 of 190 +/- 35 and 45 +/- 9 nmol/l, respectively. Significant concentrations of IL-1beta and TNF-alpha were released (100-200 and 500-600 pg/ml, respectively). Basal and LIT induced IL-1beta and TNF-alpha production were inhibited by Bay-x-1005 in a dose dependent manner, while the addition of NS-398 caused a potent stimulatory effect. The preferential COX-2 inhibitor also induced MMP-1 synthesis in a manner essentially identical to the proinflammatory cytokines. The antiinflammatory cytokine IL-4 blocked LTB4 dependent stimulation of IL-1beta and TNF-alpha synthesis. In contrast, IL-10 markedly stimulated both cytokines when incubated alone or in the presence of LTB4 where the effect was additive. CONCLUSION: Endogenous and locally produced eicosanoids regulate proinflammatory cytokine and MMP-1 synthesis under basal and stimulated conditions in vitro, with leukotrienes and prostaglandins having opposite effects in general. The clinical use of antiinflammatory drugs that inhibit eicosanoid synthesis requires an appreciation of their relative capacity to inhibit LO/COX in order to predict their effect on the synthesis of proinflammatory cytokines and matrix metalloproteases. IL-10 stimulated proinflammatory cytokine synthesis in our ex vivo culture system.
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Authors | Wendy He, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Stefan Laufer, John A Di Battista |
Journal | The Journal of rheumatology
(J Rheumatol)
Vol. 29
Issue 3
Pg. 546-53
(Mar 2002)
ISSN: 0315-162X [Print] Canada |
PMID | 11908571
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Eicosanoids
- Interleukin-1
- Lipoxygenase Inhibitors
- Quinolines
- Tumor Necrosis Factor-alpha
- 2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid
- Leukotriene B4
- Matrix Metalloproteinase 1
- Dinoprostone
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Topics |
- Aged
- Cells, Cultured
- Dinoprostone
(pharmacology)
- Eicosanoids
(metabolism, pharmacology)
- Fibroblasts
(cytology, drug effects, metabolism)
- Humans
- Interleukin-1
(biosynthesis)
- Leukotriene B4
(metabolism, pharmacology)
- Lipoxygenase Inhibitors
(pharmacology)
- Matrix Metalloproteinase 1
(biosynthesis)
- Middle Aged
- Osteoarthritis
(immunology, metabolism)
- Quinolines
(pharmacology)
- Synovial Membrane
(cytology, immunology, metabolism)
- Tumor Necrosis Factor-alpha
(biosynthesis)
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