title: CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression.
abstract: 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.
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Branka
authors.initials: B
authors.lastname: Petricevic
authors.forename: Barbara
authors.initials: B
authors.lastname: Wessner
authors.forename: Monika
authors.initials: M
authors.lastname: Sachet
authors.forename: Damir
authors.initials: D
authors.lastname: Vrbanec
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann