Article

Apo J/clusterin expression and secretion: evidence for 15-deoxy-Δ(12,14)-PGJ(2)-dependent mechanism.

Nutrition and Metabolism Group, Centre for Public Health, Queen's University Belfast, Pathology Building, RVH, Grosvenor Road, BT12 6BJ, Belfast, Northern Ireland, UK.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 11/2011; 1821(2):335-42. DOI: 10.1016/j.bbalip.2011.11.004
Source: PubMed

ABSTRACT Cyclooxygenase-2 (Cox-2) and Apo J/clusterin are involved in inflammatory resolution and have each been reported to inhibit NF-κB signalling. Using a well-validated rat pheochromocytoma (PC12) cell culture model of Cox-2 over-expression the current study investigated inter-dependence between Cox-2 and clusterin with respect to induction of expression and impact on NF-κB signalling. Both gene expression and immunoblot analysis confirmed that intracellular and secreted levels of clusterin were elevated in Cox-2 over-expressing cells (PCXII). Clusterin expression was increased in control (PCMT) cells in a time- and dose-dependent manner by 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), but not PGE(2), and inhibited in PCXII cells by pharmacological Cox inhibition. In PCXII cells, inhibition of two transcription factors known to be activated by 15d-PGJ(2), heat shock factor 1 (HSF-1) and peroxisome proliferator activated receptor (PPAR)γ, by transcription factor oligonucleotide decoy and antagonist (GW9662) treatment, respectively, reduced clusterin expression. While PCXII cells exhibited reduced TNF-α-induced cell surface ICAM-1 expression, IkB phosphorylation and degradation were similar to control cells. With respect to the impact of Cox-2-dependent clusterin upregulation on NF-κB signalling, basal levels of IκB were similar in control and PCXII cells, and no evidence for a physical association between clusterin and phospho-IκB was obtained. Moreover, while PCXII cells exhibited reduced NF-κB transcriptional activity, this was not restored by clusterin knock-down. These results indicate that Cox-2 induces clusterin in a 15d-PGJ(2)-dependent manner, and via activation of HSF-1 and PPARγ. However, the results do not support a model whereby Cox-2/15d-PGJ(2)-dependent inhibition of NF-κB signalling involves clusterin.

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