Cross-talk between innate cytokines and the pancreatic polypeptide family in acute pancreatitis
Introduction
Acute pancreatitis (AP) is a classic inflammatory disorder associated with strong up-regulation of innate pro-inflammatory cytokines, in particular interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumour-necrosis factor (TNF) α [1], [2]. While it is conventionally believed that AP self-resolves during the hospital admission, recent evidence shows that low-grade inflammation continues to persist after hospital discharge, and is linked to insulin resistance, diabetes mellitus (DM), and obesity [3]. Activation of the immune system is one of the most important pathogenetic factors that govern the aforementioned metabolic derangements; in particular DM, with which AP shares a bi-directional relationship [4], [5]. While it has long been known that diabetes is an independent risk factor for development of AP [6], [7], recent meta-analyses show that nearly 40% of patients develop new-onset pre-diabetes or diabetes after an attack of AP [8], [9]. Although a similar bi-directional relationship between obesity and AP has not been established, a recent population-based study shows that obesity is a risk factor for developing AP with similar underlying inflammatory state and patients with high body mass index (BMI) are at a two times greater risk of developing AP. Evidence also shows that circulating pro-inflammatory cytokines levels are increased in individuals with metabolic disorders such as DM and obesity, long after their hospitalization due to AP [10], [11].
The gut-brain axis has recently emerged as an important contributor to persistent low-grade inflammation in gastrointestinal (GI) diseases, DM, and obesity [12], [13], [14]. According to its most conventional definition, the gut-brain axis comprises the GI tract, the nervous system, and the immune system. The interaction between these three constituents is mediated by a wide array of regulatory molecules, including gut peptides and neuropeptides [15], [16]. In particular, neuropeptide Y (NPY), belonging to the pancreatic polypeptide (PP) family – one of the most phylogenetically conserved family of regulatory peptides, has been implicated in GI inflammation and in the pathogenesis of associated disorders, including but not limited to ulcerative colitis, Crohn’s disease, and pancreatitis [17], [18]. Neuropeptide Y is the most abundant peptide in the brain, which is expressed at all levels of the gut-brain axis and acts on the Y receptors, primarily Y1, Y2, Y4, and Y5 [17]. Neuropeptide Y activates and negatively regulates antigen-presenting cell function and T-cell function, respectively, and its involvement in GI inflammation is multifaceted [17]. Pancreatic polypeptide and peptide YY (PYY), the other two members of the PP family, share a remarkable structural similarity with NPY – all consisting of 36 amino acids and the same hairpin-shaped PP-fold tertiary structural motif [17], [19]. Peptide YY is secreted by the L cells in the gut and preferentially binds to the Y2 receptor. Pancreatic polypeptide is secreted by the γ cells in the pancreas and preferentially binds to the Y4 receptor. [17]. Given the similar evolutionary origin and relative structural homogeneity of the three members of the PP family, we hypothesized that PYY and PP are functionally involved in GI inflammation, along with NPY.
Therefore, the aim of this study was to investigate the association between PYY, PP, and NPY and circulating levels of the innate pro-inflammatory cytokines (IL-6, MCP-1, and TNFα) in patients after AP.
Section snippets
Study design
The study was a follow-up study of AP patients who had been admitted to Auckland City Hospital (Auckland, New Zealand). The study protocol was approved by the Auckland District Health Board (ADHB) Institution (A+6139) and the Health and Disability Ethics Committee (13/STH/182) and all patients gave informed consent.
Individuals were recruited into the study if they had a primary diagnosis of AP based on the international guidelines [20]; were at least 18 years of age; and resided in Auckland at
Study population
Ninety-three individuals were recruited into the study. Of these 57 (61.3%) were men. Forty-seven (50.5%) patients were overweight, while 23 (24.7%) were obese. Thirty (32.3%) patients had pre-diabetes while 11 (11.8%) had DM (Table 1). Table 1 shows the baseline characteristics of the study participants.
Association between the pancreatic polypeptide family and interleukin-6
Of the three peptides, PYY and PP were significantly associated with IL-6 in the unadjusted and five adjusted models (Table 2). Compared with the lowest quartile of PYY, PR [95% CI] of 1.58
Discussion
This is the first clinical study to provide insights into the cross-talk between innate cytokines, namely, IL-6, MCP-1, and TNFα, and the PP family. The study had a homogeneous population of patients after AP – an exemplar of acute inflammatory disease with high frequency of chronic metabolic derangements. Acute pancreatitis was diagnosed prospectively and in line with the most recent international guidelines. Multi-level statistical modeling was used, and several patient-, pancreatitis-, and
Competing interests
The authors have no conflict of interest to declare.
Submission
The authors declare that this work has not been submitted elsewhere for publication.
Acknowledgements
This study was part of the Clinical and epidemiOlogical inveStigations in Metabolism, nutritiOn, and pancreatic diseaseS (COSMOS) programme. COSMOS is supported in part by the Health Research Council of New Zealand (grant 15/035 to M.S.P.).
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