Premium
Mechanical stretch induces MCP‐1 production via aTNF‐alpha/cPLA2‐dependent pathway in human proximal tubular (HK‐2) cells
Author(s) -
Alexander Larry D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1234.11
Subject(s) - arachidonic acid , epoxygenase , epoxyeicosatrienoic acid , cyclooxygenase , chemistry , phospholipase a2 , eicosanoid , tumor necrosis factor alpha , prostaglandin e , proinflammatory cytokine , lipoxygenase , prostaglandin , endocrinology , inflammation , medicine , monocyte , biochemistry , biology , enzyme
Increased tumor necrosis factor (TNF)‐alpha and monocyte chemoattractant protein‐1 (MCP‐1) production in obstructive nephropathy are considered major events leading to persistent inflammation in the kidney, but the molecular mechanisms involved in this process are poorly understood. This study was designed to investigate the effect of mechanical stretch on the production of cytokines in kidney epithelial cells. The levels of TNF‐alpha and MCP‐1 were significantly increased by cyclic stretch and the exogenous application of arachidonic acid. Prostaglandin (PG) E 2 production and cytosolic phospholipase A 2 (cPLA 2 ) activity was also increased by cyclic stretch. Stretch‐ induced TNF‐alpha and MCP‐1 production was blocked by inhibition of cPLA 2 , cytochrome p450 epoxygenase, and cyclooxygenase, but not lipoxygenase, suggesting that stretch‐ induced TNF‐alpha and MCP‐1 production is dependent on synthesis of arachidonic acid and its subsequent metabolism to epoxyeicosatrienoic acids and/ or prostaglandins. Furthermore, TNF‐alpha blockade resulted in significant inhibition of both, stretch‐ and arachidonic acid‐ induced MCP‐1 and PGE 2 production. Overall, these findings suggest that TNF‐alpha mediates stretch‐ induced proximal tubular MCP‐1 production through cPLA 2 /arachidonic acid activation and that stretch induced pro‐inflammatory effects could be regulated, in part, by inhibition of prostaglandins and/ or epoxyeicosatrienoic acids production and function.