TNF and rheumatoid arthritis: Meanwhile, TNF-α stimulation upregulated HMGB1 expression and shifted the localization of HMGB1 from the nucleus to the cytoplasm, which further confirmed the key role of HMGB1 in the pathogenesis of RA and suggested the presence of a pro-inflammatory circuit between HMGB1 and TNF-α (Taniguchi et al. 2003).