Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

Abstract

Background/Aims: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. Methods: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AP. Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NF-κB signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines’ transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. Results: The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-κB pathway is required for the activation of Hh signaling, as blockade of the NF-κB pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NF-κB pathway correspondingly, as well as the cell apoptosis in cerulein-induced AP. Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (IL)-6, interferon-γ, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. Conclusions: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage.

Mesenchymal stem cells regulate M1 polarization of peritoneal macrophages through the CARD9‐NF‐κB signaling pathway in severe acute pancreatitis

“…Proinflammatory mediators produced and secreted by M1 macrophages, such as TNF‐α and IL‐6, play an important role in the pathology of SAP 26 . Conversely, IL‐10 and Arg1 are anti‐inflammatory cytokines produced and secreted by M2 macrophages that can attenuate SAP 27,28 . In vivo, we investigated the possible mechanism underlying the ability of MSCs to alleviate SAP by intravenous administration of MSCs in a rat model of SAP.…”

MicroRNA expression profile of Chicken cecal in different stages during Histomonas meleagridis infection

“…Activating the Hedgehog signal pathway inhibits the development of colitis by up-regulating the expression of anti-in ammatory cytokine IL-10[68] while inhibiting the Hedgehog signal pathway lead to in ammatory bowel disease [69]. In DEMs involved in the Hedgehog signaling pathway, down-regulated gga-miR-6606-5p and gga-miR-7460-3p may activate the Hedgehog signal pathway to inhibit cecal in ammation and balance in ammatory cytokines by targeting Gli1 and Gli2, respectively [70] [71]. The Phagosome (Additional le 6, 8) at 15 DPI has been shown to play an important role in the removal of pathogenic microorganisms [72] [73].…”

MicroRNA expression profile of chicken cecum in different stages during Histomonas meleagridis infection

“…Activating the Hedgehog signal pathway inhibits the development of colitis by up-regulating the expression of anti-inflammatory cytokine IL-10 [ 83 ] while inhibiting the Hedgehog signal pathway lead to inflammatory bowel disease [ 84 ]. Gli1 and Gli2 has been shown to involved in activate the Hedgehog signal pathway to inhibit intestinal inflammation and balance inflammatory cytokines [ 85 , 86 ]. In DEMs involved in the Hedgehog signaling pathway, gga-miR-6606-5p/Gli1 and gga-miR-7460-3p/Gli2 may have an important role in activating Hedgehog signaling pathway.…”