The role of cytokines in acute gastroenteritis

Introduction

Acute gastroenteritis defines, according to the World Health Organization (WHO), the passage of three or more stools of soft or liquid consistency in a 24-hour period, being a pathology frequently encountered in the clinical practice of pediatricians^(1,2).

The increased frequency and presence of this pathology in all age groups are the factors probably responsible for the unwritten classification of gastroenteritis in a category of common pathologies that we often have the impression that we can manage without repercussions⁽³⁾.

The lack of a diagnostic protocol, fast, cheap and effective, helping us to identify the etiology of gastroenteritis, makes the therapeutic management not always the most appropriate, and in these conditions we begin to talk about gastroenteritis beyond a relatively simple pathology⁽⁴⁾.

Errors in diagnostic management along with the patient’s own risk factors and environmental factors make gastroenteritis responsible for short- and long-term complications^(5,6).

Malnutrition caused by repeated episodes of gastroenteritis along with resistance to antibiotic therapy due to often unjustified administration, as a consequence of the lack of a rapid etiological diagnosis protocol, are among the most feared complications of gastroenteritis in the long term^(2,7).

Cytokines are a family of small proteins, with similar structures, represented by interleukins, chemokines, interferons, along with other mediators, which together with their receptors are validated in many pathologies – not only in the gastrointestinal sphere – as diagnostic markers, but also as important treatment methods⁽⁸⁾. Cytokines are vital components of the immune system, being produced largely by helper T cells and macrophages, and for this reason, the imbalance in their production is at the root of multiple pathologies.

Interleukins, part of the cytokine family, with pro- and anti-inflammatory properties, based on the main function of modulating differentiation and activation during the inflammatory and immune response, are produced by multiple cells: T lymphocytes, macrophages, mast cells, epithelial cells, stromal cells and neutrophils⁽³⁾.

Anti-inflammatory cytokines play a vital role in controlling the response of pro-inflammatory cytokines, so thanks to recent research, we are beginning to understand the variant of simultaneous release of cytokines, both pro- and anti-inflammatory, necessary for any immune response^(8,9).

Interleukin-6

IL-6, originally discovered as a B cell differentiator, is a multifunctional cytokine, structurally having four cytokine bundles. It is a glycosylated protein, being a main inducer of C-reactive protein. The receptor complex consists of the transmembrane glycoprotein type I that binds IL-6/IL-6R and the transmembrane signal transducer protein type GP130^(10-13).

Representing a common receptor component of the IL-6 cytokine family, Gp130 is found in the liver, lungs, spleen and heart, and is also involved in maintaining the integrity of tissues and organs, including the integrity of the intestinal epithelial barrier⁽¹⁴⁾. IL-6 has three signaling pathways: trans-presentation, the most recent form identified, trans-signaling, with pro-inflammatory action of IL-6, and classic IL-6 receptor signaling, anti-inflammatory^(14-19).

IL-6 is composed of ten ligands and nine receptors, being made up of 184 amino acids, having a common basic structure with a common signal transducer in their receptor complex, with multiple roles in the body, starting with autoimmune diseases and ending with metabolic side effects, not to be ignored the role of biomarker in sepsis or after major trauma^(9,14).

Currently, the fact that IL-6 contributes to the activation of innate and adaptive immune responses, being responsible for the immune response of B and T cells, along with numerous anti-inflammatory and regenerative functions, is generally accepted^(20-24).

Studies targeting acute infection show IL-6’s ability to defend anti-microbially and limit excessive tissue damage^(8,15,25,26).

It is currently used to establish inflammation in patients with autoimmune diseases, cancer or infections, and because of the central role it plays in activating and maintaining the inflammatory response, it justifies its title as biomarker^(3,27,28).

Interleukin-8

IL-8 was originally described as a low molecular weight protein and observed for its chemoattractant property for granulocytes, CXCL-8 expression is identified in epithelial cells, fibroblasts, macrophages, monocytes, neutrophils and endothelial cells^(29-31).

IL-8 is a 99-amino acid long precursor peptide, and the two N-terminal cysteine remnants are separated by a single amino acid^(29,32,33). IL-8 binds with a high affinity to CXCR1 and CXCR2 receptors, the former responding to high concentrations of IL-8 at the site of infection, and the latter initiates the migration of neutrophils away from the site of inflammation^(34,35).

Due to the fact that the secretion of IL-8 leads to the activation of neutrophils, which will migrate to the site of infection, IL-8 is considered a central mediator in acute neutrophil-mediated inflammation^(34,36). The late response of neutrophils makes IL-8 also play a role in chronic inflammation^(37-39).

Thus, IL-8 values are proposed as a diagnostic and/or prognostic marker in several pathologies, from acute gastroenteritis to sepsis⁽²⁹⁾.

Discussion

The IL-6 analysis of both stool and blood samples identifies significantly higher values of IL-6 in the group of those who were diagnosed with diarrhea of bacterial origin, compared to the group of diarrhea of nonbacterial origin (p<0.05), given that the ratio of the groups was approximately equal⁽⁴⁰⁾.

During an epidemic caused by Shigella dysenteriae 1, the concentration of IL-6 was significantly higher in children who developed complications following infection with Shigella dysenteriae 1, compared to the group of infected children, but without complications in the first and second weeks after infection⁽⁴¹⁾.

Another study that enrolled children with ages between 4 months and 14 years old, diagnosed with acute gastroenteritis, determined the IL-6 and IL-8 values in the first three days after admission. IL-6 correlated with the severity of the disease, while IL-8 correlated with the duration of fever⁽⁴²⁾.

Serum IL-6 levels were determined in the main age group vulnerable to the development of complicated forms of acute gastroenteritis, namely the 1-5-year-old age group, and the results showed significantly higher increases of IL-6 levels in children with bacterial pathogens⁽⁴⁰⁾. 

Schreiber et al. shed light on the possibility of a new and beneficial therapy for patients with inflamma­tory bowel disease, by blocking IL-6 trans-signaling. In Crohn’s disease, the level of IL-6 was associated with severity, and IL-8 was associated with inflammation in the colon⁽³⁾.

Many studies associate an IL-6 predictive value for mortality from sepsis or post-major trauma. However, the IL-6 so far does not enjoy the notoriety it deserves, given the multiple advantages it has⁽⁹⁾.

It seems that IL-6 does not only show increased values in pathological states, but also in the case of physical exertion. Thus, in a study carried out on athletes who participated in the Brussels Marathon, there was demon­strated an increase in IL-6 up to 45 times immediately after the marathon, values that were maintained in the first hour as well⁽⁴³⁾. These serum increases in IL-6 values make it questionable as a biomarker for the identification of overtraining syndrome in athletes⁽⁴⁴⁾.

A study that analyzed the systemic values of IL-8 in children with burns, for 60 days, demonstrated that the IL-8 values correlated with the percentage of body surface area that suffered from burns, so the IL-8 level can be used as a predictive value for mortality⁽⁹⁾.

Conclusions

The gastrointestinal tract is constantly subjected to stimuli capable of producing inflammation, so the use of IL-6 and IL-8 as biomarkers in diagnosing the etiology and correlation with the severity of acute diarrheal disease in children can reduce the prevalence of morbidity and mortality caused by this pathology.

Thus, we hope for future, larger studies on groups of pediatric patients with IL-6 and IL-8 in relation to acute gastroenteritis that would justify their role in the etiological and prognostic diagnosis.

Autori pentru corespondenţă: Heidrun Adu­mi­­trăchioaiei E-mail: ad.heidi91@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.