Gadolinium Chloride Inhibits the Production of Liver Interleukin-27 and Mitigates Liver Injury in the CLP Mouse Model

Abstract

Background. Liver macrophages play an important regulatory role in the inflammatory response of liver injury after severe infection. Interleukin- (IL-) 27 is an inflammatory cytokine that plays an important role in diseases caused by bacterial infection. However, the relationship between IL-27 and liver macrophages in liver injury after severe infection is not yet clear. Methods. A cecal ligation puncture (CLP) model was established in wild-type (WT) and IL-27 receptor- (WSX-1-) deficient (IL-27r-/-) mice, and recombinant IL-27 and gadolinium chloride (GdCl3) were injected into WT mice in the designated groups. The serum and liver IL-27, IL-6, tumor necrosis factor alpha (TNF-α), and IL-1β expression levels were evaluated by ELISA, quantitative PCR, or Western blotting; serum ALT and AST were detected by detection kits; and the severity of liver damage was evaluated by hematoxylin and eosin staining and the TUNEL assay of the liver tissue from the different groups. Liver macrophage polarization was evaluated by immunofluorescence. In addition, the polarization of peritoneal macrophage was evaluated by flow cytometry. Results. The serum and liver IL-27 expression levels were elevated in WT mice after CLP-induced severe infection, which were consistent with the changes in HE scores in the liver tissue. The levels of serum ALT, AST, liver IL-6, TNF-α, and IL-1β mRNA and liver pathological injury scores were further increased when pretreated with recombinant IL-27 in WT mice, but these levels were decreased in IL-27r−/− mice after CLP-induced severe infection compared to WT mice. In WT mice pretreated with GdCl3, liver pathological scores, serum ALT and AST, TUNEL-positive cell proportion from liver tissues, liver IL-27 expression, and the liver macrophages M1 polarization proportion decreased after CLP; however, the serum IL-27, IL-6, TNF-α, and IL-1β levels and the pathological lung and kidney scores were not significantly changed. When supplemented with exogenous IL-27, the liver pathological scores, serum ALT, AST, TUNEL-positive cell proportion of liver tissues, liver IL-27 expression, and the liver macrophage M1 polarization proportion increased. The in vitro, IL-27 expression increased in peritoneal macrophages when stimulated with LPS. Recombinant IL-27 together with LPS promoted the elevations in IL-6, TNF-α, and IL-1β levels in supernatant and the M1 polarization of peritoneal macrophages. Conclusion. IL-27 is an important cytokine in the inflammatory response to liver injury after severe infection. The reduction of liver injury by gadolinium chloride in severe infection mice models may relate to the inhibition of liver IL-27 production. These changes may be mainly related to the decrease of liver macrophages M1 polarization. IL-27 may have a positive feedback on these macrophages.

L-AP Alleviates Liver Injury in Septic Mice by Inhibiting Macrophage Activation via Suppressing NF-κB and NLRP3 Inflammasome/Caspase-1 Signal Pathways

“…During sepsis, bone marrow-derived monocytes are recruited locally into liver tissues, where they mature into macrophages and boost the remission as well as regression of liver inflammatory damage. , However, activated macrophages can generate inflammatory cytokines and exacerbate liver injury, making the inhibition of macrophage infiltration in septic livers a potential strategy for attenuating inflammatory injury. , Using F4/80 as a specific marker for macrophages, the area positive for F4/80 was rarely seen in sham-WT mice treated without and with L-AP alone (120 and 600 mg/kg) and sham-NLRP3 –/– mice. Compared with sham-WT mice, 24 h CLP challenge alone led to a 5.08-fold increase in the area positive to F4/80 in WT mouse liver tissues, while 600 mg/kg L-AP treatment and NLRP3 deficiency significantly reduced this area, with 57.9 and 66.4% less, respectively, than CLP-treated WT mice (Figure A,C).…”

Rare Earths—The Answer to Everything

“…Fosrenol has lanthanum carbonate as the active ingredient and is used to lower phosphate levels in end-stage renal disease patients being treated by dialysis [155]. A possible role of GdCl 3 in mitigating toxicant-induced liver damage has been indicated [155], and recent studies indicate continuing interest in this area (e.g., [158,159]), but the treatment is a long way from medical use at present. Recently, the modification of luminescent lanthanoid complexes in order for them to be used in biomedical applications has been reviewed [160].…”