Investigation for the possibility of CaMKII activity modulation for the therapeutic optical in rheumatoid arthritis

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The remarkable proliferation as well as apoptosis resistance are crucial for rheumatoid arthritis (RA). Among them, we have focused on the importance of PI3K/Akt pathway, and in the current 2 years, we have tried to investigate the role of CaMKII pathway. FLS in culture expressed CaMKII γ and δ, especially δ isoform. The addition of CaMKII chemical inhibitor, KN93, significantly augmented apoptosis sensitivity of FLS in response to TRAIL and anti-Fas antibody. The additional experiment showed that CaMKII-induced phenomena of apoptosis sensitivity are mediated through Akt. CaMKII is an enzyme that is activated by Ca ion influx. Ca ion influx also activates PADI, which is an essential enzyme for post-transcriptional mechanism of peptide citrullination. Post-transcriptional mechanism of peptide citrullination is thought to be crucial for anti-CCP antibodies production in patients with RA, a RA-specific autoantibodies. However, we could not detect the citrullinated peptides in cultured FLS in response to Ca ion influx, pro-inflammatory cytoltines or pro-apoptotic stimuli. Thus, we conducted the experiment by the use of human cell line, HL-60. HL-60 expressed CaMKII γ isoform. A significant expression of PADI4, citrullinated peptides and Akt phosphorylation was found during the course of granulocyte-lineage differentiation of HL-60 by ATRA According to the results obtained in the current 2 years, an association between CaMKII and FLS apoptosis is demonstrated. Considering a possible cross-talk between CaMKII and Akt, another cross-talk among CaMKII, Akt and the peptide citrullination process appears to be present. These mechanisms are thought to be important research issue of RA that strengthens a role of CaMKII for a target molecule in RA.