• How Does Cigarette Smoking Lead to Chronic Pancreatitis?

How Does Cigarette Smoking Lead to Chronic Pancreatitis?

Aryl hydrocarbons in cigarette smoke activate an immune response that promotes pancreatic fibrosis and contributes to pancreatitis, researchers report in the December issue of Gastroenterology.

The authors show that constituents of tobacco smoke activate signaling via the aryl hydrocarbon receptor (AHR) to induce T-cell production of interleukin 22 (IL22), activating pancreatic stellate cells and inducing deposition of collagen, which promotes progression of chronic pancreatitis progression.

Cigarette smoke promotes pancreatic fibrosis and deposition of ECM proteins during development of CP. Cigarette smoke contains AHR ligands such as dioxin and benzo(a)pyrene. During acinar cell damage, CD4+ T cells are recruited to sites of injury, and the AHR ligands in the pancreas of smokers interact with receptors to up-regulate production of IL22 by CD4+ T cells. IL22 is secreted and interacts with IL22RA1 on pancreatic stellate cells. The activation of IL22RA1 phosphorylates STAT3, resulting in its nuclear translocation and up-regulation of ECM proteins such as collagen 1A1 and fibronectin 1. The increased deposition of ECM proteins progressively replaces pancreatic parenchyma during development of fibrosis.

Cigarette smoke promotes pancreatic fibrosis and deposition of ECM proteins during development of CP. Cigarette smoke contains AHR ligands such as dioxin and benzo(a)pyrene. During acinar cell damage, CD4+ T cells are recruited to sites of injury, and the AHR ligands in the pancreas of smokers interact with receptors to up-regulate production of IL22 by CD4+ T cells. IL22 is secreted and interacts with IL22RA1 on pancreatic stellate cells. The activation of IL22RA1 phosphorylates STAT3, resulting in its nuclear translocation and up-regulation of ECM proteins such as collagen 1A1 and fibronectin 1. The increased deposition of ECM proteins progressively replaces pancreatic parenchyma during development of fibrosis.

Chronic pancreatitis (CP) is characterized by progressive fibrosis of the pancreas, often diagnosed late in its course. CP has high levels of morbidity and treatment is mainly supportive in nature. Risk factors include certain medications, chronic renal disease, autoimmune disease, alcohol consumption, and tobacco use, but it is not clear how these risk factors contribute to CP development. CP increases risk for pancreatic cancer, which is also associated with tobacco use.

Although there has been much research on the role of nicotine in development of CP, cigarette smoke also contains agonists of the AHR, such as dioxin and benzo(a)pyrene.

Jing Xue et al therefore assessed the effects of AHR ligands found in cigarette smoke (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] and benzo(a)yrene) on immune cell activation in mice with caerulein-induced CP and analyzed human cells and serum for evidence of this pathway.

Xue et al found that 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 the 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 beta.

Xue et al found that serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.

The authors explain that once ligands bind the AHR, the complex forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT) and translocates to the nucleus. There, it activates genes such as cytochrome P450 family 1 subfamily A member 1 (CYP1A1) and also the AHR repressor (AHRR). TCDD and cigarette smoke exposure each induced expression of AHRR in pancreata of mice.

Limitations of the study include the use of a relatively short duration animal model of CP. The authors explain that rodents metabolize TCDD much faster (half life of 12–31 days) than humans (TCDD half-life of approximately 5.8–14.1 years). It is not possible to provide years of chronic exposure to rodents, so the doses used in this study, over relatively short time period, are the best way to study mechanisms of AhR activation during cigarette smoking.

Although previous studies focused on the effects of nicotine and nicotine derivatives, this study identifies other component of cigarette smoke that contribute to CP and identified AhR signaling via IL22 as a potential marker of CP. Agents that block IL22 might be developed to prevent or reduce pancreatitis in smokers.

In an editorial that accompanies the article, Sushil Kumar and Surinder K. Batra write that during CP progression, cigarette smoke simultaneously activates nicotinic acetylcholine receptor and IL22RA1 on pancreatic stellate cells, so it will be interesting to investigate the interactions between these receptors and synthesis of the ECM proteins. They say that additional studies are needed to identify the subset of CD4+ T cells (T-helper 17, T-helper 22, and γδT-cells) that mediate the response of IL22 and contribute to CP pathogenesis.

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