Cyclopentenone prostaglandins inhibit cytokine-induced nf-kappab activation and chemokine production by human mesangial cells.

In the kidney an uncontrolled inflammatory response to an acute insult may lead to chronic inflammation, permanent tissue damage, and progressive renal insufficiency. Resolution of acute inflammation likely is dependent on endogenous regulatory mechanisms activated in parallel with mediators of renal inflammation. These mechanisms are postulated to attenuate the renal expression of proinflammatory cytokines, including the chemokines responsible for recruiting leukocytes to the kidney, thus facilitating the transition from inflammation to healing. To understand the regulation of the inflammatory response within the kidney, the effects of anti-inflammatory J series cyclopentenone prostaglandins on chemokine production by human mesangial cells were examined. Treatment of mesangial cells with prostaglandin J(2) and 15-deoxy-Delta(12,14)-prostaglandin J(2) blocked interleukin-1beta-induced monocyte chemoattractant protein-1 mRNA expression and protein production. This correlated with failure of the transcription factor nuclear factor-kappaB (NF-kappaB) to translocate to the nucleus and bind to its recognition motif, a step required for cytokine-induced monocyte chemoattractant protein-1 gene activation. NF-kappaB failed to translocate because the cyclopentenone prostaglandins attenuated degradation of the NF-kappaB inhibitor IkappaB-alpha. These data suggest that certain prostaglandins can limit the extent of renal chemokine expression and thus may have an important role in resolving renal inflammation.