Utjecaj agonista Toll-like receptora 7/8 (CL097) na ekspresiju signalnih molekula IRAK-M i Bcl-3, važnih za imunosupresiju induciranu protrahiranom sepsom i malignim tumorom The influence of Toll-like receptor 7/8 (CL097) agonist on the expression of signalling molecules IRAK-M and Bcl-3, hallmarks of immunosuppression in prolonged sepsis and cancer

摘要

Prolonged or repeated stimulation of Toll-like receptor (TLR)-4 leads to hypo-responsiveness of monocyte derived macrophages which appears to be a hallmark of immunosuppression related to sepsis and cancer. Such hyporesponsive monocytes/macrophages are found in peripheral blood of septic patients and in tumor stroma, where their presence correlates with worse disease outcome. Two negative regulators of TLR-4 signalling are connected with the induction of hyporesponsive state of monocytes/macrophages, interleukin-1 receptor-associated kinase (IRAK)-M and B-cell leukemia (Bcl)-3. Here we demonstrate that the expression of both proteins is inhibited when the TLR-7/8 agonist CL097 is added to monocyte cultures, despite co-stimulation with the TLR-4 agonist lipopolysaccharide (LPS) or hyaluronic acid. Reduction of IRAK-M and Bcl-3 was paralleled by a significant increased cytokine induction of TNF-α, IL-10 and IL-12 observed after intra- and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients suffering from prolonged sepsis or metastatic cancer, TLR-7/8 agonists retained their ability of increased stimulation of TNF-α. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.