| First Author | Cook AD | Year | 2018 |
| Journal | JCI Insight | Volume | 3 |
| Issue | 6 | PubMed ID | 29563337 |
| Mgi Jnum | J:287206 | Mgi Id | MGI:6407708 |
| Doi | 10.1172/jci.insight.99249 | Citation | Cook AD, et al. (2018) TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight 3(6) |
| abstractText | TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF-->JMJD3 demethylase-->interferon regulatory factor 4 (IRF4)-->CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF-driven inflammatory pain and for initiation of GM-CSF-driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF-->CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated. |
