3,3'-diindolylmethane, from cruciferous vegetables, ameliorates cigarette smoke-induced inflammatory amplification in CIA model mice by targeting the AhR/NF-κB crosstalk.

Environmental factors are important inducement triggering Rheumatoid Arthritis (RA). Smoke exposure would worse RA by aggravating RA inflammation and bone damage. Previous studies have demonstrated that a plant-based diet can improve RA patients' clinical symptoms. 3,3'-Diindolylmethane (DIM), a phytochemical from cruciferous vegetables, has been proven to have anti-inflammatory effect. Here, we investigated the effects and potential mechanism of DIM on RA inflammation amplification induced by smoking. Our experiment in vivo confirmed the favorable effects of DIM in CIA mice with smoke exposure, including an improved inflammatory swelling and reduced synovial hyperplasia, in addition to a decrease in serum inflammatory cytokines. Additionally, various experiments demonstrated that DIM effectively inhibited RA fibroblast-like synoviocytes (RA-FLSs) abnormal proliferation, migration and invasion induced by Cigarette Smoke Extract, while reducing the expression of the pro-inflammatory cytokines, growth factors and MMPs in vitro. AhR is an important target for RA with smoking and smoke exposure. Immunohistochemistry verified that DIM may ameliorate inflammation amplification in mice with CIA by inhibiting AhR expression in synovium. Moreover, our findings indicated DIM and AhR have strong binding affinity and interference AhR expression with siRNA had similar effects to DIM in RA-FLSs. In summary, DIM can ameliorate RA inflammation amplification, which is through disrupting the AhR/NF-κB P65 interaction and inhibiting MAPK pathway activation. Our results provided novel insight into the molecular mechanism of DIM underlying the anti-inflammation effect by targeting the AhR/NF-κB crosstalk. Furthermore, DIM probably as a dietary supplement may improve life quality specially for RA with smoking and smoke exposure.