Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

Abstract

Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.

Platelet-derived Growth Factor Primes Cancer-associated Fibroblasts for Apoptosis

“…A murine model of CCA, driven by sleeping beauty transposase-mediated biliary introduction of constitutively active AKT (myr-AKT) and Yes-associated protein (YAPS127A) (34) followed by interleukin-33 (IL-33) administration, was used (35). Each animal was given intraperitoneal injections of 1 g of IL-33 (R&D Systems) starting on post-operative day 1 for 3 days.…”

“…We now sought to determine whether ABT-199, a newer BH3 mimetic with an improved safety profile, had a similar therapeutic effect in a more robust model of CCA. We recently generated a murine model of CCA combining ectopic oncogene expression with constitutively active AKT and YAP (Yes-associated protein) in the biliary tree combined with systemic IL-33 administration (35). In this model ␣-SMA-expressing myofibroblasts first appear ϳ6 weeks after biliary oncogene transduction (data not shown).…”

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

“…Among these genes, we focused on IL-33, which exhibited the 13th highest magnitude of up-regulation. IL-33 is a member of the IL-1 family originally described as an inducer of type 2 innate immunity (20), and it was recently reported to promote BEC proliferation particularly in the EHBD (21). Real-time PCR revealed an ∼75-fold increase in IL-33 mRNA levels in Cre + KTC organoids compared with Cre − KTC organoids.…”

“…A previous study reported that IL-33-induced proliferation of BECs was mediated by type 2 innate lymphoid cells (ILC2s) (21). Thus, the number of hepatic ILC2s in KTC-K19 CreERT mice was determined by flow cytometry.…”

“…S6 K and L). ILC2s have been reported to produce the effector cytokines IL-4, IL-5, IL-9, IL-13, and amphiregulin (AREG) in response to IL-33 (20), among which IL-13 was reported to contribute to proliferation of BECs (21). Although IL-4 and IL-9 mRNAs were not detected by real-time PCR, the expression levels of IL-5, IL-13, and AREG mRNA were significantly increased in the ECC tissues of KTC-K19 CreERT mice compared with control EHBD tissues of KTC mice (Fig.…”