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

Abstract EN

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.