| First Author | Nishihara M | Year | 2007 |
| Journal | Int Immunol | Volume | 19 |
| Issue | 6 | Pages | 695-702 |
| PubMed ID | 17493959 | Mgi Jnum | J:122296 |
| Mgi Id | MGI:3713968 | Doi | 10.1093/intimm/dxm045 |
| Citation | Nishihara M, et al. (2007) IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol 19(6):695-702 |
| abstractText | IL-17-producing T(h) (T(h)17) comprise a distinct lineage of pro-inflammatory T(h) that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4(+) T cells to generate T(h)17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4(+) T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into T(h)17, while CD4(+) T cells whose mutant gp130 transduces the STAT3 signal only generated T(h)17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of T(h)17. Moreover, we found that gp130-STAT3 pathway is essential for T(h)17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of T(h)17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4(+) T cells could be a good target for controlling unwanted T(h)17-mediated immune responses including autoimmune diseases. |
