TNF-αAutocrine Feedback Loops in Human Monocytes: The Pro- and Anti-Inflammatory Roles of the TNF-αReceptors Support the Concept of Selective TNFR1 BlockadeIn Vivo

Abstract

Selective TNFR1 blockade in inflammatory diseases is emerging as a clinical strategy. We studied the roles of the two TNF-αreceptors, TNFR1 and TNFR2, in human monocytes, the principal producer of TNF-αand central to many TNF-αdriven diseases. We hypothesised that TNF-αhas 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-αor 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-αled to sustained upregulation of proinflammatory cytokines via TNFR1. In contrast, autocrine binding via TNFR2 upregulated theanti-inflammatory cytokine, IL-10, without proinflammatory effect. TNFR2 was responsible for binding soluble TNF-αsecreted 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 blockadein vivoin order that positive anti-inflammatory effects of TNF-αcan be retained via TNFR2 ligation.