| First Author | Lee H | Year | 2016 |
| Journal | Am J Physiol Renal Physiol | Volume | 311 |
| Issue | 3 | Pages | F505-19 |
| PubMed ID | 27306982 | Mgi Jnum | J:280771 |
| Mgi Id | MGI:6369584 | Doi | 10.1152/ajprenal.00533.2015 |
| Citation | Lee H, et al. (2016) Cln 3-requiring 9 is a negative regulator of Th17 pathway-driven inflammation in anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol 311(3):F505-19 |
| abstractText | T helper 17 (Th17) lymphocytes promote renal inflammation in anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), and signal transducer and activator of transcription 3 (STAT3) mediates activation of Th17 lymphocytes by IL-6 and transforming growth factor-beta (TGF-beta). Cln 3-requiring 9 (Ctr9), a subunit of RNA polymerase-associated factor complex (PAFc), regulates the transcription of IL-6/STAT3-dependent genes. Here, we investigated the role of Ctr9 in regulating Th17-driven inflammation in anti-GBM GN. In mice, STAT3beta or IL-17 knockout ameliorated anti-GBM autoantibody-induced renal injury. This phenomenon was associated with decreases in retinoic acid receptor-related orphan receptor gammat (RORgammat), IL-17, phosphorylated STAT3, and proinflammatory cytokines. Compared with wild-type mice, Ctr9 increased in both STAT3beta(-/-) and IL-17(-/-) mice injected with anti-GBM IgG, showing a negative correlation with Th17-related transcripts. Small interfering RNA (siRNA)-mediated knockdown of Ctr9 in intrarenal lymphocytes further upregulated Th17-related transcripts, consistent with repression of Th17 differentiation by Ctr9. Interestingly, Ctr9 was also expressed in human and mouse mesangial cells and downregulated in response to anti-GBM IgG or to TGF-beta plus IL-17. Ctr9 in mesangial cells was even more repressed in the presence of both anti-GBM IgG and Th17-activating cytokines. Consistent with these findings, renal biopsies obtained from patients with anti-GBM GN showed consistent downregulation of Ctr9 and upregulation of phosphorylated STAT3 and IL-17 in the glomerulus. We conclude that Ctr9 is a negative regulator of Th17 differentiation in anti-GBM GN and repressed by anti-GBM IgG and IL-17 in mesangial cells. |
