RESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Interleucina-17 , Queratinócitos , Receptores de Interleucina-17 , Ribonucleases , Transdução de Sinais , Fator de Transcrição 4 , Animais , Fator de Transcrição 4/metabolismo , Fator de Transcrição 4/genética , Humanos , Interleucina-17/metabolismo , Interleucina-17/genética , Camundongos , Queratinócitos/metabolismo , Ribonucleases/metabolismo , Ribonucleases/genética , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Inflamação/metabolismo , Inflamação/genética , Modelos Animais de Doenças , Epiderme/metabolismo , Dermatite/metabolismo , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Retroalimentação Fisiológica , Regulação da Expressão GênicaRESUMO
Psoriasis is a chronic inflammatory skin disease with profound effects on patients' health-related quality of life (HRQoL). Twenty-nine patients with plaque psoriasis and a history of streptococcal-associated psoriasis exacerbations were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and followed for 24 months. Patients were evaluated with the Psoriasis Disability Index, Psoriasis Life Stress Inventory and Psoriasis Area and Severity Index. HRQoL and psoriasis-related stress improved significantly in the tonsillectomy group compared with the control group (p = 0.037 and p = 0.002, respectively), with a mean 50% improvement in HRQoL and a mean 59% improvement in psoriasis-induced stress. Clinical improvement correlated significantly with improved HRQoL (r = 0.297, p = 0.008) and psoriasis-related stress (r = 0.310, p = 0.005). Of the tonsillectomized patients, 87% concluded that the procedure was worthwhile. Tonsillectomy may improve quality of life for selected patients with plaque psoriasis.
Assuntos
Medidas de Resultados Relatados pelo Paciente , Psoríase/cirurgia , Tonsilectomia , Adulto , Efeitos Psicossociais da Doença , Avaliação da Deficiência , Feminino , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/psicologia , Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Tonsilectomia/efeitos adversos , Resultado do TratamentoRESUMO
Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.
