Autor: |
Jiang Y; Department of Dermatology, Ann Arbor, Michigan, USA.; Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China., Gruszka D; Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, Ohio, USA., Zeng C; Department of Dermatology, Ann Arbor, Michigan, USA., Swindell WR; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Gaskill C; Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Sorensen C; Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Brown W; Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Gangwar RS; Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, Ohio, USA., Tsoi LC; Department of Dermatology, Ann Arbor, Michigan, USA., Webster J; Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, Ohio, USA., Sigurðardóttir SL; Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, Ohio, USA., Sarkar MK; Department of Dermatology, Ann Arbor, Michigan, USA., Uppala R; Department of Dermatology, Ann Arbor, Michigan, USA., Kidder A; Department of Dermatology, Ann Arbor, Michigan, USA., Xing X; Department of Dermatology, Ann Arbor, Michigan, USA., Plazyo O; Department of Dermatology, Ann Arbor, Michigan, USA., Xing E; Department of Dermatology, Ann Arbor, Michigan, USA., Billi AC; Department of Dermatology, Ann Arbor, Michigan, USA., Maverakis E; Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA., Kahlenberg JM; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Gudjonsson JE; Department of Dermatology, Ann Arbor, Michigan, USA., Ward NL; Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.; Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) and Vanderbilt Center for Immunobiology (VCI), Vanderbilt University Medical Center, Nashville, Tennessee, USA. |
Abstrakt: |
IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator, also increased following TCF4 siRNA knockdown, and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together, these findings identify a role for TCF4 in the negative regulation of IL-17C, which, alone and with TNF-α and IL-17A, feed back to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation. |