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-inflamma...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2016-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2016/1079851 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832566550081568768 |
|---|---|
| author | Jennie M. Gane Robert A. Stockley Elizabeth Sapey |
| author_facet | Jennie M. Gane Robert A. Stockley Elizabeth Sapey |
| author_sort | Jennie M. Gane |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-82b926b6073b437f9ea52f582eff9067 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-82b926b6073b437f9ea52f582eff90672025-02-03T01:03:51ZengWileyJournal of Immunology Research2314-88612314-71562016-01-01201610.1155/2016/10798511079851TNF-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 VivoJennie M. Gane0Robert A. Stockley1Elizabeth Sapey2Department of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UKLung Investigation Unit, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UKDepartment of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UKSelective 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.http://dx.doi.org/10.1155/2016/1079851 |
| spellingShingle | Jennie M. Gane Robert A. Stockley Elizabeth Sapey 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 Journal of Immunology Research |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://dx.doi.org/10.1155/2016/1079851 |
| work_keys_str_mv | AT jenniemgane tnfaautocrinefeedbackloopsinhumanmonocytestheproandantiinflammatoryrolesofthetnfareceptorssupporttheconceptofselectivetnfr1blockadeinvivo AT robertastockley tnfaautocrinefeedbackloopsinhumanmonocytestheproandantiinflammatoryrolesofthetnfareceptorssupporttheconceptofselectivetnfr1blockadeinvivo AT elizabethsapey tnfaautocrinefeedbackloopsinhumanmonocytestheproandantiinflammatoryrolesofthetnfareceptorssupporttheconceptofselectivetnfr1blockadeinvivo |