Quinacrine but not chloroquine inhibits PMA induced upregulation of matrix metalloproteinases in leukocytes: quinacrine acts at the transcriptional level through a PLA2-independent mechanism.
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.


CONCLUSIONS
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.
Stuhlmeier
Karl M
KM
Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria. karlms@excite.com
Pollaschek
Christine
C
D016824:Antigens, Human Platelet / Q000235:genetics / Q000378:metabolism*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation
D016824:Antigens, Human Platelet; D018501:Antirheumatic Agents; D010703:Phorbol Esters; D012333:RNA, Messenger; C083451:human platelet antigen 1b; C119222:phorbol-12-myristate; D002738:Chloroquine; D020782:Matrix Metalloproteinases; D011796:Quinacrine