PG receptor and COX gene expression patterns and LPS induced PG production have been investigated in human macrophages and osteoclasts as cell models to study rheumatoid arthritis. The results suggest that PG receptors DP<sub>2</sub>, EP<sub>1</sub> and EP<sub>3</sub> may not be directly involved in macrophage-mediated inflammatory responses and osteoclast-mediated bone erosion due to the absence of receptor expression. Because of the undetectable levels of natural ligand, IP receptor effects are dependent on the availability of PGI<sub>2</sub> secreted from other types of cells in the close vicinity. Meanwhile, DP<sub>1</sub>, EP<sub>2</sub>, EP<sub>4</sub>, FP and TP receptors, and their natural agonists, may play important and diverse roles in these cells. TXA<sub>2</sub> is the most abundant prostanoid found in these cells with or without LPS stimulation. The TP receptor pathway in inflammation and bone resorption may have been previously overlooked. AGN-211377 was discovered with a unique pharmacological profile, which provided antagonism at specific proinflammatory PG receptor subtypes with the rank order of TP > DP<sub>1</sub> ≥FP >EP<sub>1</sub> > DP<sub>2</sub> and no apparent antagonism on EP<sub>2</sub>, EP<sub>3</sub>, and IP receptors. AGN-211377 significantly and dose-dependently suppresses LPS- or TNFα-induced release of 12 proinflammatory cytokines/ chemokines in macrophages, and osteolysis activity in osteoclasts. Collectively, these results suggest the existence of prostanoid receptors DP<sub>1</sub> FP, and TP in human macrophages and osteoclasts, which are likely to play a proinflammatory role. AGN-211377 is at least as effective as diclofenac (a NSAID) and rofecoxib (a COX1B) in suppression of proinflammatory cytokine/chemokine production in macrophages, and in suppression of osteoclast function. Moreover, AGN-211377 may represent a safer replacement for COX1Bs. The therapeutic advantages of AGN-211377 can be extended beyond RA treatment.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:522231 |
| Date | January 2010 |
| Creators | Wang, J. Weizhen |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128327 |
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