(10Z)-Debromohymenialdisine from Marine Sponge Stylissa sp. Regulates Intestinal Inflammatory Responses in Co-Culture Model of Epithelial Caco-2 Cells and THP-1 Macrophage Cells.

Seon Min Lee,Na-Hyun Kim,Sangbum Lee,Jeong-Doo Heo,Yun Na Kim,Jung-Rae Rho,Eun Ju Jeong

doi:10.3390/molecules24183394

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are autoimmune diseases characterized by chronic inflammation within the gastrointestinal tract. Debromohymenialdisine is an active pyrrole alkaloid that is well known to serve as a stable and effective inhibitor of Chk2. In the present study, we attempted to investigate the anti-inflammatory properties of (10Z)-debromohymenialdisine (1) isolated from marine sponge Stylissa species using an intestinal in vitro model with a transwell co-culture system. The treatment with 1 attenuated the production and gene expression of lipopolysaccharide (LPS)-induced Interleukin (IL)-6, IL-1β, prostaglandin E2 (PGE2), and tumor necrosis factor-α in co-cultured THP-1 macrophages at a concentration range of 1–5 μM. The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were down-regulated in response to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation into the nucleus in cells. In addition, we observed that 1 markedly promoted the nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) and subsequent increase of heme oxygenase-1 (HO-1) expression. These findings suggest the potential use of 1 as a pharmaceutical lead in the treatment of inflammation-related diseases including IBD.

Highlights

The prevalence of inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) has been increasing worldwide [1]
[28,29], which are produced by alkaloids including hymenialdisine and debromohymenialdisine [28,29], which are produced by marine sponge and the genus
Our results demonstrated that 1 disrupts the interactions of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 with a specific set of genes to mediate an inflammatory response in macrophages

Summary

Introduction

The prevalence of inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) has been increasing worldwide [1]. CD is characterized by abdominal pain, diarrhea, narrowing of the gut lumen, and pathological features include transmural. Whereas the clinical features of UC include predominantly left-sided lower abdominal pain, diarrhea, rectal bleeding, and frequent and bloody stool [3]. Numerous studies with clinical patients and the credited animal models have revealed that the disturbance of intestinal homeostasis in IBD results from an inappropriate and continuing mucosal inflammatory response to commensal microflora [3]. During the initiation and progression of IBD, an abnormal intestinal immune response with subsequent inflammation are driven by intestinal flora leading to the disruption of the mucosal epithelial barrier [4]. The disturbance of epithelial integrity is known to trigger IBD development via dysfunctions in signal transduction between the immune system and adjacent microflora [5]

Results

Discussion

Conclusion