Background/Purpose: IL-22, a Th17 cytokine plays a key role in the formation of “pannus” in autoimmune arthritis such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), by inducing proliferation of synovial fibroblasts (FLS) ^{1, 2}. Among diverse functions of PI3K/Akt/mTOR signaling cascade, cell proliferation is an important one and is emerging as a potential therapeutic target for various malignant diseases. Here we are reporting that IL-22 induced FLS proliferation is PI3K/Akt/mTOR dependent.

Methods: FLS were derived from synovial tissues of PsA (n=5) and RA (n=5) patients. MTT assay in presence or absence of dual kinase (PI3K/mTOR) inhibitor, NVP-BEZ235 (BEZ) and mTOR inhibitor, Rapamycin were performed to determine the role of PI3K/Akt/mTOR in IL-22 induced FLS proliferation. Further we substantiate our findings by determining the expression of Akt/mTOR in presence or absence of IL-22, BEZ and Rapamycin with western blotting.

Results: IL-22 significantly increased proliferation of FLS (OD: 1.70 ± 0.09 vs. 0.86±0.04, p<0.0001, ANOVA) (Figure 1) derived from patients of autoimmune arthritis. Both Rapamycin and BEZ significantly inhibited IL-22 induced FLS proliferation. BEZ showed more inhibitory effect than rapamycin. In western blot, we observed that IL-22 significantly induced phosphorylation of Akt and mTOR in FLS (Figure 2). IL-22 induced phosphorylation of Akt and mTOR in FLS was significantly reduced by BEZ and Rapamycin respectively. This indicates that IL-22 induces FLS proliferation through the PI3K/Akt/mTOR pathway.

Conclusion: This is the first study showing the regulatory role of PI3K/Akt/mTOR signaling cascade in the IL-22 mediated FLS proliferation in autoimmune arthritis and thus provides a new insight in the signaling cascade of IL-22 in autoimmune arthritis.