Role of endoplasmic reticulum stress in omega-3 polyunsaturated fatty acids supplementation for attenuating inflammatory response in experimental rat models of colitis

Abstract

Objective To investigate the effects and mechanisms of omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation on colonic macroscopic and histological score, inflammatory response, and endoplasmic reticulum stress (ERS) response in experimental rat models of colitis. Methods Experimental rat models of colitis were induced by trinitro-benzene-sulfonic acid (TNBS). Totally 100 male SD rats were randomly divided into 5 groups according to the random data tables: sham operation group (Sham group), inflammatory bowel disease group (IBD group), ω-3 PUFA supplementation group (IBD+ ω-3 group), 5-aminosalicylic acid group (IBD+ 5-ASA group), and ERS activation 2-deoxy-D-glucose group (IBD+ ω-3+ 2-DG group). Colonic macroscopic and histological scores were evaluated on days 1, 3, 7 and 14 after modeling. The serum levels of tumor necrosis factor-α(TNF-α), interleukin (IL)-1, and IL-6 were measured using enzyme-linked immunosorbent assay, whereas ERS cytokines including glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1(IRE-1), and C/EBP homologous protein (CHOP) were tested by Western blot. Results Compared with the Sham group, colonic macroscopic and histological score, the serum levels of inflammation relatived factors (TNF-α, IL-1, IL-6) and ERS relatived factors (GRP78、IRE-1, CHOP) were significantly increased on the rest of the four groups (all P<0.001). Compared with the IBD group, ω-3 PUFA supplementation reduced colonic macroscopic [7 d: 3.55±0.29 vs. 4.37±0.39, P=0.03, 14 d: 2.46±0.17 vs. 3.86±0.21, P=0.04] and histological score [7 d: (2.56±0.27) scores vs. (3.45±0.40) scores, P=0.02, 14 d: (2.23±0.20) scores vs. (3.06±0.26) scores, P=0.04]. Meanwhile, ω-3 PUFA supplementation suppressed the expressions of inflammation [TNF-α: (43.71±11.39)pg/ml vs. (84.97±13.81)pg/ml, P=0.02, IL-1: (38.51±10.60)pg/ml vs. (73.04±12.48)pg/ml, P=0.01, IL-6: (28.91±7.27)pg/ml vs. (53.45±9.40)pg/ml, P=0.02] and ERS relatived factors (GRP78: 2.41±0.29 vs. 1.47±0.21, P=0.01, IRE-1: 2.83±0.31 vs. 1.23±0.20, P<0.001, CHOP: 1.89±0.17 vs. 1.32±0.11, P=0.04). However, the salutary effects of ω-3 PUFA would been reversed by ERS activation 2-deoxy-D-glucose [TNF-α: (72.67±10.37)pg/ml vs. (43.71±11.39)pg/ml, P=0.02, IL-1: (57.66±13.88)pg/ml vs. (38.51±10.60)pg/ml, P=0.02, IL-6: (46.10±9.67)pg/ml vs. (28.91±7.27)pg/ml, P=0.01, GRP78: 1.47±0.21 vs. 1.82±0.24, P=0.03, IRE-1: 1.23±0.20 vs. 2.21±0.23, P=0.02, CHOP: 1.32±0.11 vs. 1.61±0.16, P=0.04]. Conclusion The salutary effects of ω-3 PUFA supplementation on the colitis induced by TNBS appear to be mediated by inhibited inflammatory responses, which may suppress the activation of ERS response. Key words: Inflammatory bowel disease; Fatty acids, unsaturated; Inflammatory; Endoplasmic reticulum stress