TNF- α Autocrine Feedback Loops in Human Monocytes: the Pro- and Anti-Inflammatory Roles of the TNF- α Receptors Support the Concept of Selective TNFR1 Blockade in Vivo

Selective tnfr1 blockade in inflammatory diseases is emerging as a clinical strategy. we studied the roles of the two tnf-α receptors,tnfr1 and tnfr2,in human monocytes,the principal producer of tnf-α and central to many tnf-α driven diseases. we hypothesised that tnf-α has pro- and anti-inflammatory effects on monocytes,occurring differentially via tnfr1 and tnfr2. monocytes were isolated from healthy human subjects and exposed to lps,plus/minus the addition of blocking antibodies to tnf-α or its receptors. pro- and anti-inflammatory cytokine production was quantified using real-time pcr and elisas. cell surface expression of tnfr1/2 was measured by flow cytometry. we demonstrated that monocytes vary in the expression patterns of tnfr1 and tnfr2. autocrine binding of tnf-α led to sustained upregulation of proinflammatory cytokines via tnfr1. in contrast,autocrine binding via tnfr2 upregulated the anti-inflammatory cytokine,il-10,without proinflammatory effect. tnfr2 was responsible for binding soluble tnf-α secreted by monocytes,clearing the cytokine from the pericellular environment. tnfr1 blockade did not change the cell surface expression of tnfr2,leaving this receptor free to upregulate il-10. these novel results support the concept of selective tnfr1 blockade in vivo in order that positive anti-inflammatory effects of tnf-α can be retained via tnfr2 ligation. � 2016 jennie m. gane et al.