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Discordant effects of Janus kinases inhibition ex-vivo on inflammatory responses in colonic compared to ileal mucosa.
Kaboub, Kawsar; Abu-Taha, Hanan; Arrouasse, Jessica; Shaham-Barda, Efrat; Wasserberg, Nir; Hayman-Manzur, Lucille; Friedenberg, Adi; Levy-Barda, Adva; Goren, Idan; Levi, Zohar; Banai-Eran, Hagar; Avni-Biron, Irit; Ollech, Jacob E; Sharar-Fischler, Tali; Yanai, Henit; Cohen-Kedar, Sarit; Dotan, Iris; Rabinowitz, Keren M.
Afiliação
  • Kaboub K; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Abu-Taha H; The Felsenstein Medical Research Center, Rabin Medical Center and Tel-Aviv University, Petah-Tikva, Israel.
  • Arrouasse J; Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel.
  • Shaham-Barda E; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Wasserberg N; The Felsenstein Medical Research Center, Rabin Medical Center and Tel-Aviv University, Petah-Tikva, Israel.
  • Hayman-Manzur L; Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel.
  • Friedenberg A; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Levy-Barda A; The Felsenstein Medical Research Center, Rabin Medical Center and Tel-Aviv University, Petah-Tikva, Israel.
  • Goren I; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Levi Z; The Felsenstein Medical Research Center, Rabin Medical Center and Tel-Aviv University, Petah-Tikva, Israel.
  • Banai-Eran H; Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel.
  • Avni-Biron I; Department of Surgery, Beilinson Campus, Rabin Medical Center, Petah-Tikva, Israel.
  • Ollech JE; Department of Pathology, Beilinson Campus, Rabin Medical Center, Petah-Tikva, Israel.
  • Sharar-Fischler T; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Yanai H; Biobank, Rabin Medical Center, Petah-Tikva, Israel.
  • Cohen-Kedar S; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
  • Dotan I; Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel.
  • Rabinowitz KM; Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.
J Crohns Colitis ; 2024 Jul 29.
Article em En | MEDLINE | ID: mdl-39073573
ABSTRACT
BACKGROUND &

AIMS:

Janus kinase (JAK) inhibitors are used for treating inflammatory bowel diseases (IBD). We aimed to identify molecular effects of JAK inhibition in human intestinal mucosa, considering IBD location and phenotype.

METHODS:

Colonic and ileal explants from patients with ulcerative colitis (UC), Crohn's disease (CD), and non-IBD controls (NC) were assessed for phosphorylated signal transducers and activators of transcription (p-STAT) levels and Inflammatory genes expression panel in response to ex-vivo JAK inhibitor (tofacitinib). Cytokine production by lamina propria lymphocytes in response to tofacitinib was assessed. Human intestinal organoids were used to investigate JAK inhibitors' effects on iNOS expression.

RESULTS:

Explants were collected from 68 patients (UC=20; CD=20; NC=28). p-STAT1\3\5 inhibition rates varied, being higher in colonic compared to ileal explants. p-STAT1\3 inhibition rates negatively correlated with CRP levels. While significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in 5 genes, including NOS2. JAK inhibition significantly decreased Th1\Th2\Th17-related cytokine production from lamina propria lymphocytes. Various JAK inhibitors reduced IFN-γ-induced increase in iNOS expression in organoids.

CONCLUSIONS:

Site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noticed, whereby the colon was more robustly affected than the ileum. Ex-vivo response to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression. Ex-vivo mucosal platforms may be a valuable resource for studying personalized drug effects in patients with IBD.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: J Crohns Colitis Assunto da revista: GASTROENTEROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Israel

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: J Crohns Colitis Assunto da revista: GASTROENTEROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Israel