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The antagonistic actions of endogenous interleukin-1? and 15-deoxy-?12,14-prostaglandin J2 regulate the temporal synthesis of matrix metalloproteinase-9 in sheared chondrocytes.

ABSTRACT: Mechanical overloading of articular cartilage producing hydrostatic stress, tensile strain, and fluid flow results in irreversible cartilage erosion and osteoarthritis (OA). Application of high fluid shear to chondrocytes recapitulates the earmarks of OA as evidenced by the induction of proinflammatory cytokines and prostaglandins, which are capable of inducing the expression of matrix-degrading enzymes. Matrix metalloproteinase-9 (MMP-9) synthesis is detected at early but not late stages of OA. However, the underlying mechanism(s) of the MMP-9 temporal regulation remains unknown. Using the T/C-28a2 chondrocyte cell line as a model system, we demonstrated that high fluid shear induces a marked increase in MMP-9 expression at short shear exposure times (3-6 h), which falls below basal levels after prolonged shear exposure (12-48 h). High fluid shear stress induced the rapid and sustained synthesis of IL-1?, activating PI3K, ERK1/2, and JNK, which are in turn responsible for MMP-9 expression. Prolonged shear exposure (>12 h) induced 15-deoxy-?(12,14)-prostaglandin J(2) (15d-PGJ(2)) synthesis, which exerted an antagonistic effect on IL-1?-mediated PI3K-, ERK1/2-, and JNK-dependent NF-?B activation, thereby suppressing MMP-9 expression in human chondrocytes. Reconstructing the signaling network that regulates shear-mediated MMP-9 expression in human chondrocytes may provide insights for developing strategies to treat arthritic disorders.

SUBMITTER: Wang P

PROVIDER: S-EPMC3442521 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The antagonistic actions of endogenous interleukin-1β and 15-deoxy-Δ12,14-prostaglandin J2 regulate the temporal synthesis of matrix metalloproteinase-9 in sheared chondrocytes.

Wang Pu P Zhu Fei F Konstantopoulos Konstantinos K

The Journal of biological chemistry 20120724 38

Mechanical overloading of articular cartilage producing hydrostatic stress, tensile strain, and fluid flow results in irreversible cartilage erosion and osteoarthritis (OA). Application of high fluid shear to chondrocytes recapitulates the earmarks of OA as evidenced by the induction of proinflammatory cytokines and prostaglandins, which are capable of inducing the expression of matrix-degrading enzymes. Matrix metalloproteinase-9 (MMP-9) synthesis is detected at early but not late stages of OA. ...[more]

PMID: 22829602

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Project description:15-deoxy-?(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-?. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.

Dataset Information

The antagonistic actions of endogenous interleukin-1? and 15-deoxy-?12,14-prostaglandin J2 regulate the temporal synthesis of matrix metalloproteinase-9 in sheared chondrocytes.

Publications

The antagonistic actions of endogenous interleukin-1β and 15-deoxy-Δ12,14-prostaglandin J2 regulate the temporal synthesis of matrix metalloproteinase-9 in sheared chondrocytes.

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