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]

Petričević, Branka (2010) 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]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

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.

Abstract in Croatian

Protrahirana ili ponovljena stimulacija Toll-like receptora 4 izaziva hiporeaktivitet monocita odnosno makrofaga koji tako promijenjenog fenotipa posreduju u razvoju imunosupresije u sepsi te kod malignih bolesti. Nalazimo ih u perifernoj krvi pacijenata sa sepsom te kao dio infiltrata tumorske strome, gdje njihova prisutnost označava lošiju prognozu bolesti. Dvije signalne molekule, IRAK-M (interleukin-1 receptor-associated kinase-M) i Bcl-3 (B-cell leukaemia-3), negativni regulatori signalnog puta Toll-like receptora 4, povezuju se s indukcijom hiporeaktiviteta u monocita/makrofaga. Ovo istraživanje je pokazalo da dodavanje agonista Toll-like receptora 7/8, spoja CL097, u kulturu hiporeaktivnih monocita koči ekspresiju oba negativna regulatora, unatoč protrahiranoj stimulaciji Toll-like receptora 4 lipopolisaharidom ili hijaluronskom kiselinom. Smanjena ekspresija IRAK-M i Bcl-3 u navedenim uvjetima kulture makrofaga bila je popraćena povećanom proizvodnjom citokina TNF-α, IL-10 i IL-12. Proširujući istraživanje na ex vivo stimulaciju periferne krvi pacijenata sa sepsom i malignim diseminiranim tumorima, pokazalo se da TLR7/8 agonist zadržava učinak reaktivacije oslabljene sinteze TNF-α. Zaključno, navedeni rezultati mogli bi doprinjeti razumijevanju patogeneze imunosupresije u sepsi te kod diseminiranih malignih tumora.

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