Tags

Type your tag names separated by a space and hit enter

Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis.
Gastroenterology. 2016 12; 151(6):1206-1217.G

Abstract

BACKGROUND & AIMS

Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.

METHODS

We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.

RESULTS

Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.

CONCLUSIONS

AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

Authors+Show Affiliations

State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California. Electronic address: jingxue@sjtu.edu.cn.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Cedars-Sinai Medical Center and Department of Veterans Affairs, Los Angeles, California.Cedars-Sinai Medical Center and Department of Veterans Affairs, Los Angeles, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California. Electronic address: aidah@stanford.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27769811

Citation

Xue, Jing, et al. "Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis." Gastroenterology, vol. 151, no. 6, 2016, pp. 1206-1217.
Xue J, Zhao Q, Sharma V, et al. Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology. 2016;151(6):1206-1217.
Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., & Habtezion, A. (2016). Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology, 151(6), 1206-1217. https://doi.org/10.1053/j.gastro.2016.09.064
Xue J, et al. Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology. 2016;151(6):1206-1217. PubMed PMID: 27769811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. AU - Xue,Jing, AU - Zhao,Qinglan, AU - Sharma,Vishal, AU - Nguyen,Linh P, AU - Lee,Yvonne N, AU - Pham,Kim L, AU - Edderkaoui,Mouad, AU - Pandol,Stephen J, AU - Park,Walter, AU - Habtezion,Aida, Y1 - 2016/10/18/ PY - 2016/01/26/received PY - 2016/08/18/revised PY - 2016/09/02/accepted PY - 2016/11/5/pubmed PY - 2017/6/7/medline PY - 2016/11/5/entrez KW - BaP KW - CP KW - Immune Regulation KW - PSC KW - TCDD SP - 1206 EP - 1217 JF - Gastroenterology JO - Gastroenterology VL - 151 IS - 6 N2 - BACKGROUND & AIMS: Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP. METHODS: We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses. RESULTS: Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers. CONCLUSIONS: AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/27769811/Aryl_Hydrocarbon_Receptor_Ligands_in_Cigarette_Smoke_Induce_Production_of_Interleukin_22_to_Promote_Pancreatic_Fibrosis_in_Models_of_Chronic_Pancreatitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(16)35234-9 DB - PRIME DP - Unbound Medicine ER -