Received for publication November 8, 2005.
Revised February 7, 2006.
Accepted for publication February 7, 2006.

Celecoxib Inhibits Interleukin-12 and ₂ Folding and Secretion by a novel COX2- independent Mechanism Involving Chaperones of the Endoplasmic Reticulum

Abstract

Celecoxib (CE) is a non-steroidal anti-inflammatory drug (NSAID) that is a specific inhibitor of cyclooxygenase 2 (COX-2). It is indicated for a variety of chronic inflammatory conditions including rheumatoid arthritis. Over the last few years, adverse cardiovascular effects and increased risk for heart attacks have been associated with this drug. Also, evidence is emerging for COX2-independent molecular targets. CE has been shown to induce apoptosis in various cancer cells lines through a COX2-independent mechanism that seems to involve inactivation of protein kinase Akt and inhibition of endoplasmic reticulum (ER) Ca²⁺ATPase. In this study we show that both CE, and an analogue devoid of COX2 inhibitory activity (CEA) inhibit the secretion of the dimeric interleukin-12 (IL-12) and ₂ forms with identical IC₅₀ values of 20 and 30 µM, respectively, while no such effect was seen with rofecoxib. RT-PCR analysis showed that this inhibition was not due to blockage of transcription of the and -chain expression cassettes. Secretion of the monomer form was less strongly inhibited suggestive for a mechanism primarily targeting dimer assembly in the ER. Analysis of intracellular fractions revealed that both CE and CEA increased the association of IL-12 with calreticulin, an endoplasmic reticulum- resident chaperone involved in retention of misfolded cargo proteins, while blocking interaction with ERp44. Our findings reveal a previously undescribed effect of celecoxib on oligomer protein folding and assembly in the endoplasmic reticulum and ensuing secretion, and suggest that celecoxib-driven alteration of the secretome may be involved in some of its clinical side effects.

Key words: Tachykinin, Interferons, Interleukins, Pharmacogenomic analyses, Cyclooxygenases

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