Tumor Necrosis Factor-α (TNF-α)-Induced and Interleukin-1β (IL-1β)-Induced Shedding of TNF Receptors from Gingival Fibroblasts

Abstract

Tumor necrosis factor-α (TNF-α) exerts its functions by binding two different receptors (TNFR55 and TNFR75). Both TNFR55 and TNFR75 exist in cell-associated and soluble forms. Soluble TNF receptors(sTNFR), sTNFR55 and sTNFR75, are proteolytically shed upon inflammatory stimuli and then modulate various TNF-α bioactivities. As human gingival fibroblasts (HGF) can be potential targets for TNF-α in inflamed gingiva, we hypothesized that HGF partially modulate the cellular responses to TNF-α by regulating their own TNFR. In this study, the kinetics of expression of cell-associated and soluble forms of both receptors from cultured HGF in response to proinflammatory cytokines TNF-α and interleukin-1β (IL-1β) were investigated in vitro. Both TNF-α and IL-1β upregulated the gene expression of TNFR75 and did not affect that of TNFR55. TNF-α and IL-1β decreased binding of [¹²⁵I]TNF-α to HGF. Moreover, TNF-α and IL-1β upregulated the release of sTNFR75 from HGF but not that of sTNFR55. These results suggest that HGF under inflammatory conditions may contribute to the inactivation of circulating TNF-α through the preferential induction and shedding of TNFR75.