| First Author | Fielding CA | Year | 2008 |
| Journal | J Immunol | Volume | 181 |
| Issue | 3 | Pages | 2189-95 |
| PubMed ID | 18641358 | Mgi Jnum | J:139226 |
| Mgi Id | MGI:3807588 | Doi | 10.4049/jimmunol.181.3.2189 |
| Citation | Fielding CA, et al. (2008) IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol 181(3):2189-95 |
| abstractText | The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp130(Y757F/Y757F) mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130(Y757F/Y757F) mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STAT1/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130(Y757F/Y757F) mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130(Y757F/Y757F) mice failed to rescue the altered responses observed in gp130(Y757F/Y757F) mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response. |
