TNF receptor type 2 transmits caspase-dependent apoptotic signals in fibroblast-like synoviocytes derived from rheumatoid arthritis.

Signals from tumor necrosis factor α (TNFα) are transduced through two types of receptors, tumor necrosis factor receptor type1 (TNFR1) and type2 (TNFR2), which commonly transduce activation signals for NF-κB, affecting cellular survival, growth, and inflammation. TNFR1 is ubiquitously expressed and mediates caspase-dependent apoptotic signals, whereas TNFR2 is selectively expressed on hematopoietic cells without transducing death signals. We detected TNFR2 transcription in fibroblast-like synoviocytes derived from rheumatoid arthritis (RA-FLS) at various levels, but usually much lower than those of TNFR1. To investigate the function of TNFR2 on RA-FLS in TNFα signaling, we established a stable transfectant overexpressing TNFR2 using the human RA-FLS cell line MH7A and stimulated it with 50 ng/ml TNFα, a concentration that usually induces apoptosis in parent MH7A cells. Since TNFR2 is known to transduce anti-apoptotic signals via NF-κB activation, we expected to observe a reduction in apoptotic cells. Contrary to our expectations, the ratio of apoptotic cells in TNFR2 transfectants was higher than that of mock stable transfectants used as a control. This enhanced sensitivity to apoptosis was not inhibited by the addition of either antiTNFR2 monoclonal antibody (mAb) 80M2, which blocks ligand passing, or antagonistic anti- TNFR1 Ab, indicating that apoptosis was independent of TNFR1 signals. Furthermore, in the presence of antagonistic anti-TNFR1 Ab, the addition of agonistic anti-TNFR2 Ab induced apoptosis with a rapid decrease in TNF receptor-associated factor 2 (TRAF2) and cleavage of caspase-8 and -3. The observed apoptosis was sensitive to an inhibitor of pan-caspase, but not of receptor-interacting protein (RIP) 1. These data clearly indicate the presence of a caspasedependent, apoptotic signaling pathway downstream of TNFR2.doi:10.11482/KMJ-E41(2)29 (Accepted on October 6, 2015)

Hirano H, et al