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

Figure 7

TNF-α effects on monocytes via TNR1 and TNFR2. The figure shows two adjacent monocytes. (1) LPS induces both pro- and anti-inflammatory cytokine gene/protein expression. (2) TNF-α, induced by LPS stimulation, is expressed at the monocyte surface as mTNF-α and cleaved to sTNF-α by the enzyme TACE. (3) sTNF-α signals in an autocrine/paracrine fashion via TNFR1 to augment the expression of CXCL8, IL1-β, IL-6, and IL-10 mRNA and (4) mTNF-α via TNFR2 to further augment IL-10 mRNA expression. (5) Autocrine/paracrine binding of membrane TNF-α to TNFR2 also upregulates the expression of TNFR1 at the cell surface. (6) TNFR2 binds sTNF-α. Selective TNFR1 blockade will switch off TNF-α driven proinflammatory cytokine production whilst leaving TNFR2 free to upregulate the immunoregulatory cytokine, IL-10, and possibly clear a proportion of sTNF-α from the pericellular environment.