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Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
Background: Liver cirrhosis is associated with profound immunodysfunction, i.e. a parallel presence of chronic systemic inflammation and immunosuppression, which can result in acute-on-chronic liver failure (ACLF). Omega-3 fatty acids are precursors of pro-resolving mediators and support the resolution of inflammation.
Objective: The aim of this study was to determine plasma levels of omega-3 fatty acids in patients with liver cirrhosis and ACLF.
Methods: Patients with liver cirrhosis with and without ACLF were enrolled in a prospective cohort study and analyzed post-hoc for the present sub-study. Clinical data and biomaterials were collected at baseline and at day 7, 28 and after 3 months of follow-up. Plasma concentrations of arachidonic acid (ARA) and docosahexaenoic acid (DHA), which represent key omega-6 and -3 fatty acids, respectively, were quantified and associated with markers of systemic inflammation and severity of liver cirrhosis.
Results: A total of 117 patients were included in the present analyses. Of those, 26 (22.2%), 51 (43.6%) and 40 (34.2%) patients had compensated or decompensated liver cirrhosis, and ACLF. Plasma levels of ARA and DHA were similar in patients with compensated cirrhosis, decompensated cirrhosis, and ACLF. Furthermore, no significant association between plasma ARA or DHA and C-reactive protein or peripheral blood leukocytes were observed (P>0.05).
Conclusion: In our study plasma levels of key omega-3 and omega-6 fatty acid are neither associated with the severity of liver cirrhosis nor with liver-cirrhosis-associated systemic inflammation.