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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Nuclear Factor-B-Independent Anti-Inflammatory Action of Salicylate in Human Endothelial Cells: Induction of Heme Oxygenase-1 by the c-Jun N-Terminal Kinase/Activator Protein-1 Pathway

Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany (R.F., S.B.B., S.Z., A.M.V.); and Institute of Pharmaceutical Biology, Saarland University, Saarbrücken, Germany (A.K.K.)

In contrast to aspirin, salicylate, its active metabolite, possesses profound anti-inflammatory properties without blocking cyclooxygenase. Inhibition of the transcription factor nuclear factor-B (NF-B) has been discussed to play a role in the anti-inflammatory profile of salicylate. However, NF-B-independent effects of salicylate have been assumed but have up to now been poorly investigated. Therefore, the aim of the present study was to investigate NF-B-independent anti-inflammatory mechanisms of salicylate in human umbilical vein endothelial cells using interleukin-4 (IL-4) as NF-B-independent proinflammatory stimulus and P-selectin as inflammatory read-out parameter. Using quantitative real-time reverse transcription-polymerase chain reaction, 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. Using both the HO-1 inhibitor tin(II) protoporphyrin IX 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 up-regulation of HO-1 by salicylate. c-Jun NH₂-terminal kinase (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 1,9-pyrazoloanthrone. By applying activator protein-1 (AP-1) decoys, it was shown that the transcription factor AP-1 is crucially involved in the up-regulation 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.

Address correspondence to: Dr. Robert Fürst, Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany. E-mail: robert.fuerst{at}cup.uni-muenchen.de

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