Elsevier

Pancreatology

Volume 16, Issue 4, July–August 2016, Pages 477-488
Pancreatology

Review article
NF-κB in acute pancreatitis: Mechanisms and therapeutic potential

https://doi.org/10.1016/j.pan.2016.05.001Get rights and content

Abstract

The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies.

Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.

Introduction

Acute pancreatitis (AP) is an acute inflammation of pancreas that begins with intrapancreatic/acinar activation of trypsinogen to trypsin and culminates in a spectrum of varying degrees of severity including multiple organ failure and death. The incidence of AP is increasing globally and mortality rate could reach as high as 43% among patients with multiple organ failure along with infected pancreatic necrosis [1]. Unfortunately, despite several years of experimental and clinical research the precise pathophysiology of AP, particularly in the clinical context, still remains unclear. This has possibly precluded development of definitive treatment modalities for this potentially life-threatening illness. Irrespective of the etiology, AP mounts an early systemic inflammatory response syndrome (SIRS), the magnitude of which determines the minimal to life-threatening early multiorgan organ dysfunction (MODS) and mortality. Later in the clinical course (second week onwards), development of infected necrosis in a subgroup of patients mounts a second wave of SIRS and MODS (sepsis-related) that is responsible for the second wave of (late) mortality [2].

Experimental and clinical studies over the past decade has reported the profiles of intrapancreatic and circulating cytokines, chemokines, adhesion molecules, and transcription factors, including nuclear factor kappa B (NF-κB) [3], [4]. NF-κB is increasingly gaining importance over the past several years in human inflammation, immune regulation and cancer biology [5]. Studies from last two decades have incriminated NF-κB activation as an early and central event in the progression of inflammation in AP. In clinical practise, researchers have already started evaluating NF-κB as a therapeutic target in the context of cancer and other inflammatory diseases, which could also have profound implication in AP.

The objective of this manuscript is to review the recent literature on the role of NF-κB in the progression of AP and its potential as a therapeutic target in this illness.

Section snippets

Search methods and results

We searched pubmed/medline databases for relevant literature using Boolean logic with the search words acute pancreatitis, NF-κB and nuclear factor kappa B. We did not set any filter during the search so that all studies including experimental, mechanistic, preclinical, and clinical gets included, thus allowing us to achieve the maximum possible volume of relevant data. Three of the authors (AJ, RJ, and RR) evaluated the retrieved abstracts with relevance to the objectives of the review. Full

Overview of NF-κB biology

Often referred to as a ‘double edged sword’, NF-κB is a ubiquitous, pleiotropic, latent cytoplasmic transcription factor. It was discovered by Sen and Baltimore in 1986 as a factor in the nucleus of B cells that binds to enhancer of the kappa light chain of the immunoglobulin molecule [6]. Since then, a substantial volume of data on the biology of NF-κB has appeared in the literature. NF-κB is primarily constituted by a family of five Rel-domain containing proteins namely p65 (RelA), RelB,

Initial mechanisms of intra acinar NF-κB activation after onset of AP

The speculation that NF-κB activation is a key inflammatory event in AP arose from observations by Altavilla et al. in a constitutive model with specific pancreatic NF-κB p50 precursor protein deletion that resulted in a reduced severity of the disease [19]. Although the precise mechanisms responsible for intraacinar NF-κB activation have not been completely elucidated, pathologic calcium signalling, activation of protein kinase C isoforms, and generation of reactive oxygen species have been

NF-κB mediated cytokine release in acute pancreatitis

NF-κB activation during AP is capable of producing numerous types of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6 and IL-18, various chemokines such as IL-8, macrophage inflammatory protein (MIP)-1, and monocyte chemoattractant protein (MCP)-1, platelet activating factor and adhesion molecules [47], [48], [49]. Several experimental animal models of AP have clearly demonstrated that the acinar cells produce cytokines via activation of NF-κB. Rodent models fed

Activation of NF-κB by released cytokines and other mediators

As discussed earlier, cytokines produced by acinar cells have an emerging role in driving the pancreatic inflammation to systemic inflammation, which possibly activate NF-κB primarily through proinflammatory mediators, specifically TNF-α and IL-1β, which are released from the acinar cells. These signalling cytokines further activates cells with inflammatory property such as lymphocytes, neutrophils, macrophages, and acinar cells.

Therapeutic implications

Despite extensive experimental and clinical research, there still does not exist scientifically proven (based on high quality randomized controlled studies) definitive curative therapy for AP. Several preclinical/experimental studies using a wide array of naturally occurring and synthetic compounds have been conducted so far; and the results demonstrated beneficial effects on murine AP. Several ameliorative mechanisms have also been elucidated in these studies in vivo, in vitro, and in cell

Role of NF-κB inhibition: rationale and implications

Even though several agents have been used for amelioration of AP in an experimental (Table 1) or clinical setting (Table 2), majority of them are unlikely to act via direct NF-κB inhibition. Most of the experimental studies were not specifically targeted against NF-κB and treatment was initiated before induction of injury. Therefore it is not clear whether the beneficial effect followed NF-κB inhibition or it occurred as a part of general reduction in inflammation. However, it would be prudent

Disclosures

  • 1.

    None of the authors have any conflict of interest to disclose.

  • 2.

    This manuscript has been supported by Wellcome DBT Fellowship no. IA/I/11/2500257

Author contributions

  • Aparna: Literature search, data compilation and manuscript drafting.

  • Ramaiah Jangala and B Ratnakar Reddy: Literature search and manuscript drafting.

  • Sasikala Mitnala and D. Nageshwar Reddy: Manuscript review and critical inputs.

  • Rupjyoti Talukdar: Concept, design, critical analysis, revising and finalizing the manuscript.

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