Increased mesangial cell hyaluronan expression in lupus nephritis is mediated by anti-DNA antibody-induced IL-1beta

The mechanism by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remains to be fully elucidated. Hyaluronan (HA) is an important extracellular matrix constituent that accumulates during tissue injury, and participates in lymphocyte recruitment to sites of inflammation. The role of HA in the pathogenesis of LN has not been defined. We investigated the expression of HA in renal biopsies and circulating HA levels in patients with diffuse proliferative LN, and the effect of human anti-DNA antibodies on HA synthesis in cultured human mesangial cells (HMC). HA expression was increased in the mesangium, and in the periglomerular and tubular distribution in LN kidney biopsies. LN patients showed increased levels of circulating HA, especially during active disease, which correlated with anti-DNA antibody titers (r=0.35, P=0.0234). Anti-DNA antibodies isolated during active LN but not remission increased de novo synthesis of (3)H-labeled HA, which was accompanied by induction of HA synthase (HAS) II transcription, and enhanced IL-1beta, IL-6, and tumor necrosis factor-alpha secretion in HMC (P<0.001 for all). Only anti-DNA antibody induction of IL-1beta enhanced HA synthesis, which was abrogated by inhibitors of de novo mRNA or protein synthesis. Our findings demonstrate that HA expression is significantly increased within the mesangium in diffuse proliferative LN mediated through anti-DNA antibody-induced IL-1beta. Given that HA plays a pivotal role during inflammatory responses, influences cellular behavior and assists in the recruitment of lymphocytes to sites of injury, it is likely that HA contributes to the pathogenesis of LN.