Amplification of the response to Toll‐like receptor ligands by prolonged exposure to interleukin‐6 in mice: Implication for the pathogenesis of macrophage activation syndrome

Abstract

Objective. To investigate whether prolonged exposure to interleukin-6 (IL-6) affects the inflammatory response induced by Toll-like receptor (TLR) ligands.Methods. IL-6-transgenic mice and wild-type mice were stimulated with different TLR ligands; survival rates, blood cell counts, and biochemical parameters were analyzed. Murine splenic mononuclear cells and peritoneal macrophages were stimulated with lipopolysaccharide (LPS), lipoteichoic acid, poly(I-C), or CpG. Human macrophages were cultured for 4 days in the presence of IL-6 and then stimulated with LPS. Inflammatory cytokine expression was measured by enzyme-linked immunosorbent assay or reverse transcription-polymerase chain reaction. Activation of STAT-3, ERK-1/2 (MAPK), and p65 NF-B was evaluated by Western blotting or confocal analysis.Results. Treatment of IL-6-transgenic mice with TLR ligands led to an increased fatality rate and elevated levels of IL-1␤, tumor necrosis factor ␣ (TNF␣), IL-6, and IL-18. Macrophages from IL-6-transgenic mice produced increased levels of inflammatory cytokines, which were associated with increased phosphorylation of STAT-3 and ERK-1/2 and with increased NF-B nuclear translocation. Human macrophages treated with IL-6 and then stimulated with LPS showed elevated levels of cytokines and similarly elevated signaling pathway activation. After LPS administration, IL-6-transgenic mice showed an increase in ferritin and soluble CD25 levels, as well as a decrease in platelet and neutrophil counts and in hemoglobin levels compared to wild-type mice.Conclusion. Our findings indicate that prolonged exposure to IL-6 in vivo and in vitro leads to an exaggerated inflammatory response to TLR ligands. Hematologic and biochemical abnormalities in IL-6-transgenic mice treated with LPS show striking similarities to macrophage activation syndrome.

Inflammatory Cytokine TSLP Stimulates Platelet Secretion and Potentiates Platelet Aggregation via a TSLPR-Dependent PI3K/Akt Signaling Pathway

“…Raffaele Strippoli et al reported that IL-6-transgenic mice treated with lipopolysaccharide showed a quantitative difference in platelets compared with wild-type mice. [40] Regarding whether the absence of TSLPR affected the platelet quantity, our data demonstrated that there was no obvious difference in the platelet count in the TSLPR KO mice (Fig. 5B).…”

Mouse Cytomegalovirus Infection in BALB/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis

“…As to secondary HLH, despite the availability of various animal models, reflecting virus-associated (16), bacterial-associated (12), and autoinflammation-associated forms of the disease (13,14), the underlying mechanisms remain poorly understood. In particular, the role of herpesvirus infection in HLH development requires further examination, because such infection is recognized as the dominant triggering event of primary and secondary HLH episodes (21,23,58).…”

“…In the current study, we demonstrated that experimental infection of WT C57BL/6 mice with MCMV provoked a controlled and limited inflammatory response, whereas the susceptible BALB/c mouse strain developed an acute hyperinflammatory syndrome whose clinicopathological features closely resembled the life-threatening syndrome observed in HLH patients. Fever, lymphopenia, thrombocytopenia, anemia, hemophagocytosis, hyperferritinemia, elevated plasma levels of sCD25, liver dysfunction, lymphadenopathy, decreased NK cell numbers, hyperactivation of CD8 + and CD11b (14) and in IL-6-transgenic mice treated with TLR4-triggering LPS (13), two models of autoinflammation-associated secondary HLH, four of eight and three of eight of the diagnostic criteria are fulfilled, respectively. Nevertheless, they provide valuable insights into the immunological mechanisms underlying the hyperinflammatory syndrome of HLH.…”

“…In these patients, the syndrome must have developed in an IFN-g-independent way, arguing against the existence of a general pathogenic pathway that would cause both primary and secondary HLH (19,64). Alternative pathways, also IFN-g-independent ones (13,18,65), are capable of inducing a similar syndrome. Therefore, caution should be exercised when extrapolating treatment options from primary to secondary HLH (19).…”

“…Although some animal models have been proposed for secondary HLH (12)(13)(14)(15)(16)(17), few specifically addressed the possible pathogenic role of IFN-g or CD8 + T cells (14,18). Those that did revealed an ambiguous role for IFN-g in disease development (14,18), whereas CD8 + T cells were dispensable for disease pathogenesis (14).…”