Importance of oestrogen, xenoestrogen and phytoestrogen metabolism in breast cancer risk.

TNF-stimulated gene 6 (TSG-6) is activated in a variety of cell types by the proinflammatory cytokines TNF-a and IL-1. The TSG-6 gene encodes a secreted 35 kDa glycoprotein abundant in synovial fluids of patients with various forms of arthritis and detectable in sera of patients with different inflammatory or autoimmune disorders. TSGB protein consists of two structural domains. The N-terminal domain, a link module, defines TSG-6 as a member of the hyaladherin family of proteins and provides TSG-6 with affinity for hyaluronan. The link module is followed by a C-terminal CUB domain, a module shared by a variety of structurally and functionally diverse proteins. TSG-6 forms a stable complex with components of the plasma protein inter-a-inhibitor (lal), a Kunitz-type serine protease inhibitor that is also a hyaluronan-binding protein. Recombinant human TSG-6 protein exerts a potent antiinflammatory effect in a murine model of acute inflammation. Site-directed mutagenesis was used to target amino acid residues potentially involved in the interaction with hyaluronan. TSG-6 mutants were examined for their interaction with hyaluronan, their antiinflammatory activity and their ability to form a stable complex with lal. Activation of the TSG-6 gene by proinflammatory cytokines, the presence of TSG-6 protein at sites of inflammation and its antiinflammatory effect suggest a role for TSG-6 as a negative feed-back regulator of the inflammatory response. . .