Catestatin Regulates Epithelial Cell Dynamics to Improve Intestinal Inflammation.

Nour Eissa,Hayam Hussein,Sandra Bonin,Jean-Eric Ghia,Charles Bernstein,Ruth Mesgna,Geoffrey Hendy,Marie-Hélène Metz-Boutigue

doi:10.3390/vaccines6040067

Abstract

Ulcerative colitis (UC) is characterized by aberrant regulation of tight junctions (TJ), signal transducer and activator of transcription 3 (STAT3), and interleukin (IL)-8/18, which lead to intestinal barrier defects. Catestatin (CST), an enterochromaffin-derived peptide, regulates immune communication and STAT-3 in the inflamed intestine. Here, we investigated the effects of CST during the development of inflammation using human biopsies from patients with active UC, human colonic epithelial cells (Caco2), and an experimental model of UC (dextran sulfate sodium [DSS]-colitis). In UC patients, the protein and mRNA level of CST was significantly decreased. Colonic expression of CST showed a strong positive linear relationship with TJ proteins and STAT3, and a strong negative correlation with IL-8 and IL-18. Intra-rectal administration of CST reduced the severity of experimental colitis, IL-18 colonic levels, maintained TJ proteins and enhanced the phosphorylation of STAT3. CST administration increased proliferation, viability, migration, TJ proteins, and p-STAT3 levels, and reduced IL-8 & IL-18 in LPS- & DSS-induced Caco2 cell epithelial injury, and the presence of STAT-3 inhibitor abolished the beneficial effect of CST. In inflammatory conditions, we conclude that CST could regulate intestinal mucosal dynamic via a potential STAT3-dependent pathway that needs to be further defined. Targeting CST in intestinal epithelial cells (IECs) should be a promising therapeutic approach such as when intestinal epithelial cell homeostasis is compromised in UC patients.

Highlights

The intestinal epithelium incorporates a wide range of dynamic biological processes, including intestinal barrier function, which plays a crucial role in the intestinal homeostasis and Vaccines 2018, 6, 67; doi:10.3390/vaccines6040067 www.mdpi.com/journal/vaccinesVaccines 2018, 6, 67 inflammatory response [1]
We investigated the association between protein level of CST peptide and mRNA levels of human pathophysiological markers implicated in active ulcerative colitis (UC)
The protein level of CST was strongly positively correlated with mRNA levels of tight junctions (TJ) proteins, CLDN1, OCLN, and Zona occludens1 (ZO1), and signal transducer and activator of transcription 3 (STAT3) (Figure 1B)

Summary

Introduction

The intestinal epithelium incorporates a wide range of dynamic biological processes, including intestinal barrier function, which plays a crucial role in the intestinal homeostasis and Vaccines 2018, 6, 67; doi:10.3390/vaccines6040067 www.mdpi.com/journal/vaccines. Vaccines 2018, 6, 67 inflammatory response [1]. Cell-to-cell junctions, tight junctions (TJ), are essential proteins involved in regulating the epithelial barrier function. Dysregulation of the epithelial barrier integrity is a consequence of an aberrant and continuing inflammatory response due to the release of pro-inflammatory cytokines challenging mucosal homeostasis [3]. The loss of TJ proteins aggravates the intestinal inflammation by increasing the influx of luminal antigens in the lamina propria, which amplifies the inflammatory cascades and mediators within the intestinal mucosa [5,6]

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Discussion

Conclusion