Lippincott, Williams & Wilkins, Shock: Injury, Inflammation and Sepsis, 5(32), p. 484-490, 2009
DOI: 10.1097/shk.0b013e3181a5ac8a
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Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-[alpha], IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-[alpha]. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.