| First Author | Joetham A | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 21 | Pages | 17100-8 |
| PubMed ID | 22461627 | Mgi Jnum | J:185623 |
| Mgi Id | MGI:5429491 | Doi | 10.1074/jbc.M111.316943 |
| Citation | Joetham A, et al. (2012) Loss of T regulatory cell suppression following signaling through glucocorticoid-induced tumor necrosis receptor (GITR) is dependent on c-Jun N-terminal kinase activation. J Biol Chem 287(21):17100-8 |
| abstractText | Naturally occurring Foxp3(+)CD4(+)CD25(+) T regulatory cell (nTreg)-mediated suppression of lung allergic responses is abrogated following ligation of glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein. In vitro stimulation of nTregs with GITR ligand increased phosphorylation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinase (ERK) or p38 MAPK. SP600125, a known JNK inhibitor, prevented GITR-mediated phosphorylation of JNK. Activation of JNK was associated with increases in the upstream mitogen-activated protein kinase kinase 7 (MKK7) and the downstream transcription factor NF-kappabeta. Phosphorylated c-Jun (p-c-Jun), indicative of the activation of JNK, was detected in the immunoprecipitates of nTregs from wild-type but not JNK- or GITR-deficient mice. Treatment with an inhibitor of JNK phosphorylation resulted in complete reversal of all GITR-induced changes in nTreg phenotype and function, with full restoration of suppression of in vivo lung allergic responses and in vitro proliferation of activated CD4(+)CD25(-) T cells. Thus, regulation of JNK phosphorylation plays a central role in T regulatory cell function with therapeutic implications for the treatment of asthma and autoimmune diseases. |
