IL-8 Is an Important Contributor to Both the Progression of Systematic Inflammation and Increasing Severity of Non-Alcoholic Fatty Liver Disease (NAFLD)

Introduction: Previous studies have shown that inflammatory cytokines are involved in the development and progression of non-alcoholic fatty liver disease (NAFLD). Aim: To further understand the involvement of inflammatory cytokines in NAFLD we assessed the correlation of the levels of these cytokines to the various stages of liver disease as detected by histopathology. Methods: To assess the serum levels of cytokines, the Bio-PlexPro™ Human Cytokine 17-Plex and Bio-PlexProTM TGF-β assays (BioRad Laboratories, Hercules, CA) were performed on samples of morbidly obese patients with the NAFLD spectrum of disease. Data were analyzed using non-parametric Spearman’s rank sum correlation. Results: In a cohort of 241 morbidly obese patients (39.1% NASH, 33.9% NAFLD (non-NASH), 3.32% cirrhosis, 28.6% with type II diabetes, age 43.61±11.41 years, BMI 46.39±10.91 kg/m2, AST 29.18±41.01 U/L, ALT 34.67±29.05 U/L). IL-8 correlated with numerous cytokines, including positive correlations between IL-10 (r=0.41; p<3.93e-11), IL-12 (r=0.38; p<1.36e-09), IL-13 (r=0.44; p<3.28e-12), IL-17 (r=0.46; p<8.04e-14), G-CSF (r=0.41; p<1.14e-10), IFN-g (r=0.33; p<3.60e-07), MCP-1 (r=0.16; p<0.02), MIP-1B (r=0.39; p<8.59e-10), and TNF-α (r=0.50; p<3.14e-16). The serum levels of IL-8 were inversely correlated with that of TGF-b1 (r=-2.4; p<1.54e-4) and with BMI (r=-0.15; p<0.02). The indicators of liver damage, i.e. ballooning (r=0.28; p<1.76e-05) and bridging (r=0.26; p<8.32e-05) were positively correlated with serum levels of IL-8, as well as with the presence of infiltrating Kupffer cells (r=0.23; p<0.001), PMN (polymorphonuclear neutrophils) (r=0.23; p<0.001), and Mallory-Denk bodies (r=0.29; p<8.71e-06). Pericellular fibrosis (r=0.32; p<1.22e-06), portal fibrosis (r=0.21; p<0.002), and portal inflammation (r=0.20; p<0.002) were also positively correlated with serum levels of IL-8. Notably, there was a correlation of diabetes comorbidity with the levels of IL-8 in serum (r=0.14; p<0.03). Conclusion: These studies indicate that IL-8 plays a critical role in the progression of systematic inflammation, but more importantly plays a pivotal role in the development of increasing severity of liver disease in NAFLD.