RESUMO
BACKGROUND: High SOCS3 expression in intestinal epithelial cells (IECs) of patients with ulcerative colitis (UC) in remission reflects the shorter time to relapse. We investigated whether high SOCS3 increased risk for relapse through violating STAT3-dependent protective effects of interleukin (IL)-22 during UC remission. METHODS: Expression of IL-22 and c-Myc in UC remission mucosa was analyzed by immunohistochemistry. Effects of IL-22 on migration and proliferation of IEC cell lines with enforced SOCS3 expression were assessed with wounding assay and CCK-8 assay, respectively. Influence of STAT3 interference and SOCS3 overexpression on IL-22-regulated expression of antimicrobial peptide and proliferation-related molecules, including DMBT1, c-Myc, Survivin, Bcl-2, and Bcl-xL, were performed with quantitative real-time polymerase chain reaction or Western blot. RESULTS: Patients with UC in remission showed significantly more IL-22-positive immune cells, but no difference of epithelial c-Myc levels, in mucosa compared with healthy controls. Overexpression of SOCS3 nearly abolished IL-22-induced activation of STAT3. By inhibiting STAT3 signaling, SOCS3 influenced IL-22-induced expression of DMBT1, c-Myc, Survivin, and Bcl-2 as well as proliferation and migration processes in cultured IEC cell line. CONCLUSIONS: SOCS3 overexpression impairs IL-22-mediated epithelial homeostasis and mucosal wound healing, which could be the mechanism for high SOCS3 IEC expression contributed early relapse of mucosal inflammation. Prevention of SOCS3 expression or enhancement of IL-22/STAT3 signaling in IEC seems to be rational therapeutic strategies for UC remission maintenance.
Assuntos
Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/genética , Mucosa Intestinal/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Western Blotting , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colite Ulcerativa/genética , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Interleucina 22RESUMO
AIMS: To investigate the antitumor effects of probiotics Clostridium butyricum and Bacillus subtilis on colorectal cancer (CRC) progression. MATERIALS & METHODS: The effects of C. butyricum and B. subtilis on CRC cells were studied. Male C57BL/6 mice with 1,2-dimethylhydrazine dihydrochloride (DMH)-induced CRC were intervened by these two probiotics and the antitumor effects were examined by comparing the tumor incidence and detecting the inflammatory and immune-related markers. RESULTS & CONCLUSIONS: C. butyricum and B. subtilis inhibited the proliferation of CRC cells, caused cell cycle arrest and promoted apoptosis. In vivo, these two probiotics inhibited the development of DMH-induced CRC. The molecular mechanism involved reduced inflammation and improved immune homeostasis. This work establishes a basis for the protective role of probiotics B. subtilis and C. butyricum in intestinal tumorigenesis.