Article ID: b20-00270
Matrix metalloproteinases (MMPs) are required for collagen degradation which play a key pathological role in arthritis progression. Herein, the effect of sinomenine (SN) on Interleukin 1 beta (IL-1β)-induced MMPs production and its underlying mechanism were explored in SW1353 cells. The MTT assay showed that 200 and 400 µM SN significantly inhibited SW1353 cell proliferation, thus the lower dose of SN (25-100 µM) were used in the subsequent experiments. Notably, the increased mRNA and protein levels of suppressor of cytokine signaling (SOCS) 3 were dose-dependently induced by SN. SN significantly suppressed mRNA and protein levels of MMPs in IL-1β-induced SW1353 cells. Through western blot analysis, SN showed inhibitory effect on IL-1β-induced TAK1 and p65 phosphorylation. Moreover, SN blocked the interaction of TRAF6 and TAK1 resulting in inactivation of IL-1β pathway. Mechanistically, the inhibitory effect of SN on MMPs levels alongside TRAF6 and TAK1 interactions was abrogated by silencing SOCS3. Moreover, SN didn’t inhibit TAK1 kinase activity. In TAK1 silencing cells, the levels of MMPs and p65 phosphorylation of SN-treatedcells were lower than DMSO-treated cells, indicating that blocking interaction was not a unique way for SN to inhibit MMPs levels. Finally, SN significantly inhibited IL-6-induced JAK2 and STAT3 phosphorylation in SW1353 cells. The levels of JAK2 phosphorylation and MMPs didn’t show a significant difference between IL-6+SOCS3-siRNA+SN group and IL-6+SOCS3-siRNA+DMSO group. These findings demonstrated that SOCS3 expression was increased by SN blocked IL-1β-induced interaction between TRAF6 and TAK1 as well as IL-6 pathway activation, thereby culminating in the inhibition of MMPs levels.
