Abstract: Quinacrine But Not Chloroquine Inhibits PMA Induced Upregulation of Matrix Metalloproteinases in Leukocytes: Quinacrine Acts at the Transcriptional Level Through a PLA2-Independent Mechanism

Quinacrine But Not Chloroquine Inhibits PMA Induced Upregulation of Matrix Metalloproteinases in Leukocytes: Quinacrine Acts at the Transcriptional Level Through a PLA₂-Independent Mechanism

KARL M. STUHLMEIER and CHRISTINE POLLASCHEK

ABSTRACT.

Objective. Macrophages play an important role in rheumatoid arthritis (RA). RA is a disease characterized by the successive accumulation of leukocytes resulting in subsequent destruction of affected joints. Activation of matrix metalloproteinases (MMP) is essential for many physiological as well as many pathological events owing to the essential role of MMP in cell migration. We analyzed the effectiveness of quinacrine as an inhibitor of MMP activation in leukocytes and investigated the mode of action.

Methods. Leukocytes were isolated and treated with quinacrine with or without phorbol myristic acetate (PMA). ELISA and RT-PCR were used to monitor production of MMP-1, MMP-2, MMP-3, and MMP-8 at the mRNA and protein level.

Results. Quinacrine suppressed PMA induced MMP-1 release in mononuclear cells (MNC) in a dose- and time-dependent manner. RT-PCR showed that quinacrine downregulated induced as well as noninduced steady-state mRNA levels of MMP-1, MMP-2, and MMP-8, but had no effect on MMP-3. The observed inhibition was not due to effects of quinacrine on phospholipase A₂ (PLA₂) activity. Adding exogenous arachidonic acid to reconstitute the blocked PLA₂ signaling pathways did not result in restoration of PMA induced mRNA transcription.

Conclusion. Inhibition of MMP by quinacrine might, in part, account for its reported immunosuppressive action. Synthesizing more potent derivatives of quinacrine may be a means of suppressing undesired MMP activation. (J Rheumatol 2006;33:472-80)

Key Indexing Terms:

QUINACRINE
MATRIX METALLOPROTEINASES
INFLAMMATION

From the Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria.

Supported in part by grants from the City of Vienna, the "Medizinisch Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien," the Austrian Ministry of Social Security and Generations, and the Austrian Ministry of Education, Science and Culture.

Address reprint requests to Dr. K.M. Stuhlmeier, Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria. E-mail: karlms@excite.com

Accepted for publication October 14, 2005.