Received for publication February 3, 2006.
Revised April 18, 2006.
Accepted for publication April 18, 2006.

NF-B-independent anti-inflammatory action of salicylate in human endothelial cells: induction of heme oxygenase-1 by the JNK/AP-1 pathway

Abstract

In contrast to aspirin, salicylate, its active metabolite, possesses profound anti-inflammatory properties without blocking cyclooxygenase. Inhibition of the transcription factor NF-B has been discussed to play a role in the anti-inflammatory profile of salicylate. However, in addition, NF-B-independent effects of salicylate have been assumed, but have as yet been poorly investigated. Therefore, aim of the present study was to investigate NF-B-independent anti-inflammatory mechanisms of salicylate in human umbilical vein endothelial cells (HUVEC) using IL-4 as NF-B-independent pro-inflammatory stimulus and P-selectin as inflammatory read-out parameter. Using quantitative real-time RT-PCR, we found that salicylate decreases IL-4-induced P-selectin expression. As judged by Western blot analysis, salicylate increased endothelial heme oxygenase-1 (HO-1) protein levels. Employing both the HO-1 inhibitor SnPP and HO-1 antisense oligonucleotides, we causally linked the induction of HO-1 to the decrease of P-selectin. Moreover, we were interested in the signaling mechanisms leading to the upregulation of HO-1 by salicylate. JNK was found to be activated by salicylate and we could causally link this activation to the induction of HO-1 by using the JNK inhibitor SP600125. By applying AP-1 decoys, it was shown that the transcription factor AP-1 is crucially involved in the upregulation of HO-1 downstream of JNK. In summary, our study introduces HO-1 as novel NF-B-independent anti-inflammatory target of salicylate in human endothelial cells. Moreover, we elucidated the JNK/AP-1 pathway as crucial for the induction of HO-1 by salicylate.

Key words: P-selectin, endothelium, heme oxygenase, inflammation, interleukin-4, salicylate

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