Interleukin-6-Production Is Responsible for Induction of Hepatic Synthesis of Several Chemokines as Acute-Phase Mediators in Two Animal Models: Possible Significance for Interpretation of Laboratory Changes in Severely Ill Patients

SIMPLE SUMMARY: The release of acute-phase proteins and cytokine storms are considered critical parameters for the progression of COVID-19 disease. The increase in the serum levels of cytokines such as IL6 and IL8 observed in patients primarily infected with the SARS-CoV-2 virus has been used to determine the severity of clinical conditions resulting from infection and for prognostic purposes. Animal models have been used to understand the mechanisms of the changes in homeostasis observed under pathological conditions. In the present study, we therefore report the changes in serum levels and hepatic gene expression of cytokines and chemokines in two different animal models of acute-phase responses. The acute-phase response is a transient emergency response aimed at preserving life and bringing about the changes necessary to reduce and repair tissue damage after the removal of damaging noxious agents. Our data suggest that the liver may be responsible for the increase in the serum levels of cytokines and chemokines as part of the body’s defense response to tissue damage. It is therefore doubtful that inhibiting this response at any stage after infection could improve the prognosis of patients. These results may help to interpret the laboratory changes observed in critically ill patients, as may be the case following SARS-CoV-2 infection. ABSTRACT: A mild to moderate increase in acute-phase proteins (APPs) and a decrease in serum albumin levels are detected in hospitalized COVID-19 patients. A similar trend is also observed for acute-phase cytokines (APC), mainly IL6, besides chemokines (e.g., CXCL8 and CCL2). However, the source of the chemokines in these patients at different stages of disease remains to be elucidated. We investigated hepatic gene expression of CXC- and CC-chemokines in a model of a localized extrahepatic aseptic abscess and in a model of septicemia produced by the intramuscular injection of turpentine oil (TO) into each hindlimb or lipopolysaccharide (LPS) intraperitoneally (i.p.) in rats and mice (wild-type (WT) and IL6-KO). Together with a striking increase in the serum IL6 level, strong serum CXCL2 and CXCL8 concentrations were detected. Correspondingly, rapid (2 h) upregulation of CXCL1, CXCL2, CXCL5, and CXCL8 was observed in rat liver after intramuscular TO injection. The induction of the gene expression of CXCL1 and CXCL8 was the fastest and strongest. The hepatic CXC-chemokines behaved like positive APPs that depend on IL6 production by activated macrophages recruited to extrahepatic damaged tissue. Chemokine upregulation was greatly reduced in IL6-KO mice. However, IL6 was dispensable in the LPS–APR model, as massive induction of hepatic chemokines studied was measured in IL6-KO mice.