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

Author:

Gane Jennie M.1ORCID,Stockley Robert A.2,Sapey Elizabeth1ORCID

Affiliation:

1. Department of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK

2. Lung Investigation Unit, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK

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.

Funder

West Midlands Chest Fund

Publisher

Hindawi Limited

Subject

Immunology,General Medicine,Immunology and Allergy

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